Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C[O:48]CC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:48])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3)ncc2c1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3)ncc2c1
Reaction time: 1 h
Yield: 68 %

Procedure:
1-(3-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (30 mg, 0.050 mmol) was dissolved in 4 mL of THF and 0.5 mL of water. Then dihydrogen tris(dimethylphosphinito)hydroplatinate (2.3 mg, 0.0052 mmol) was added and the mixture was stirred under fluxing. After 1 hr, TLC indicated complete consumption of the starting material. LC/MS indicated clean desired product formed. The mixture was evaporated and the residue was dissolved in dichloromethane and dried over sodium sulfate, filtered through micron filter and evaporated. The residue was purified through flash column chromatography using methanol in methylene chloride (0% to 5% methanol in 10 minutes, 12 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a white solid (21 mg, 68% yield). LC/MS clacd for C33H32FN7O4 (m/e) 609.25, obsd 608.0 (M−H, ES−); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.51 (br. s., 4H), 3.59 (br. s., 4H), 7.39 (d, J=8.3 Hz, 3H), 7.56 (d, J=7.8 Hz, 1H), 7.65-7.73 (m, 3H), 7.75-7.86 (m, 3H), 7.89 (s, 1H), 7.98 (br. s., 1H), 8.60 (d, J=2.0 Hz, 1H), 9.04 (s, 1H), 9.42 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1)([O-:3])=[O:2].I[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([O:10][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Temperature: 110 °C
Yield: 95 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-nitro-5-hydroxypyridine (2.00 g, 14.3 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (6.06 g, 21.5 mmol), sodium hydride (800 mg, 20.2 mmol) and DMF (30 mL). The reaction mixture was heated at 110° C. for 24 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 251a in 95% yield (4.00 g) as a yellow oil: 1H NMR (500 MHz, CDCl3) d 8.27 (d, 1H, J=9.0 Hz), 8.14 (d, 1H, J=3.0 Hz), 7.26 (dd, 1H, J=9.0, 3.0 Hz), 5.04 (m, 1H), 4.39 (m, 2H), 4.06 (m, 2H), 1.44 (s, 9H); MS (ESI+) m/z 196.1 (M-Boc+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([N:40]1[CH2:41][CH2:42][CH:37]([CH3:36])[CH2:38][CH2:39]1)=[O:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CCc1ccccc1Cl)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
A mixture of 1.7 g (5.4 mmol) of 2-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)butanoic acid, 2.1 g (11 mmol) of EDC, 1.5 g (11 mmol) HOBt, and 1.9 mL (11 mmol) of iPrNEt in 25 mL of CH2Cl2 is stirred for 10 min, and 0.77 mL (6.5 mmol) of 4-methylpiperidine is added. After stirring overnight, the mixture is washed twice with 10% citric acid, and once each with water, saturated NaHCO3, water, and brine. The extract is concentrated to provide 1.8 g (85%) of tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CCCCCCC>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: CCCCCCC
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g) and 2-chloroacrylonitrile (26.6 g) is stirred at about 80° C. for 24 hours. n-Heptane (125 ml) is allowed to run in, and unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as n-hepiarie are distilled off (distillate 50 ml) by raising the external temperature to about 130° C. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 1 hour. The product is isolated by filtration and washed with n-heptane (100 ml). The product is dried in vacuo at about 60° C. Yield: 31.55 g=71.6% (beige powder).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].I[CH2:14]I>[Cu].[Zn].C(OCC)C>[CH:1]1([C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[CH2:14][CH2:2]1
Reactant: C=Cc1ccc2ccccc2c1
Reactant: ICI
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Product: c1ccc2cc(C3CC3)ccc2c1

Procedure:
A mixture of 15.5 g. of 2-vinylnaphthalene, 23 g. of diiodomethane, 19.6 g. of zinc-copper couple (comprising 19.5 g. of zinc and 0.1 g. of copper) and 500 ml. of diethyl ether is refluxed for eight hours; the cooled mixture is then filtered, washed with dilute hydrochloric acid, washed with water to neutrality, dried and evaporated to yield 2-cyclopropylnaphthalene.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[N:10][N:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[CH3:25])=[C:15]([C:26](OCC)=[O:27])[CH:14]=[N:13][C:12]=23)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[N:10][N:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[CH3:25])=[C:15]([C:26]([N:42]4[CH2:43][CH2:44][CH:39]([C:36]5[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=5)[CH2:40][CH2:41]4)=[O:27])[CH:14]=[N:13][C:12]=23)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC3CC3)cnn2c1Nc1ccc(F)cc1C
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(S(=O)(=O)NC3CC3)cnn12
Yield: 14.9 %

Procedure:
Using ethyl 3-(N-cyclopropylsulfamoyl)-7-(4-fluoro-2-methylphenylamino)-pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.496 g, 1.145 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine hydrochloride (0.072 g, 0.335 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.0283 g, 3%) was obtained.
Reaction SMILES: [CH:1](=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH:1](=[N:8][C:9]1[N:10]=[CH:11][N:12]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(N=Cc2ccccc2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
12.8 g (60 mmol) of 4-benzylideneamino-5-imidazole carboxamide which is an intermediate material obtained in the Reference Example 1 was suspended in a mixed solvent of 240 ml dimethylformamide and 30 ml distilled water, and 16.6 g (120 mmol) of potassium carbonate was added to the suspension. 13.8 ml of benzyl chloride was added dropwise to the solution over 45 minutes at 80° C. After the addition, the mixture was stirred for one hour. The solvent was evaporated under vacuum, the residue was dissolved in chloroform, and the chloroform layer was washed with distilled water. Crude crystals obtained after evaporation of solvent was recrystallized from ethanol to obtain 14.4 g of 4-benzylideneamino-1-benzyl-5-imidazole carboxamide (yield 79%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12]O)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][Cl:19])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCCl
Reaction time: 4 h

Procedure:
To a stirred mixture of 10 parts of 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol and 75 parts of trichloromethane are added dropwise 11.2 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 4,5-dichloro-N-(3-chloropropyl)-2-nitrobenzenamine; mp. 78° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[N:16]=[C:15]([C:17](O)=O)[CH:14]=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[N:16]=[C:15]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1cccc(C(=O)O)n1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cccc(-c2nc3ccccc3[nH]2)n1

Procedure:
2.2 g. of o-phenylenediamine, 3 g. of 6-ethylpicolinic acid and 15 g. of polyphosphoric acid were heated at 160°-180° C. under a nitrogen gas current for 2 hours with stirring. The reaction mixture was diluted with 200 ml. of water and neutralized with sodium carbonate. The resulting precipitate was filtered off, dried, subjected to silica gel column chromatography(developed with 1:1 by volume mixture of benzene and ethyl acetate) and recrystallized from benzene. 3.3 g. of colorless needles of the product (74% of theory) was obtained. M.P. 161°-161.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[C:6]1\[C:7](=[O:15])[NH:8][C:9]2[C:14]\1=[CH:13][CH:12]=[CH:11][CH:10]=2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:35])=[C:24]([CH:26]=[N:27][C:28]([O:30][Si](C)(C)C)=[CH2:29])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:29][C:28](=[O:30])[NH:27][CH:26]([C:24]3[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[CH3:35])[C:6]32[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]3=[O:15])[CH:16]=[CH:17][CH:18]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: O=C1Nc2ccccc2/C1=C/c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1ccccc12
Yield: 15 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 169a was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 15%).
Reaction SMILES: [NH:1]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:14].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:1][C:2]1=[O:14]
Reactant: O=C1CCCCCc2ccccc2N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCCCC1Br

Procedure:
To a solution of 1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (4.7 g) in chloroform (75 ml), phosphorus pentachloride (5.9 g) is added in portions, while maintaining the temperature at 0°-5°. When addition is complete, iodine (60 mg) is added, followed by bromine (4.5 g), which is added dropwise over five minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue partitioned between ice/water (60 ml) and dichloromethane (100 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether/hexane mixtures. Concentration of the appropriate fractions yields 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22]N)[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:19]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[NH:22][C:11]=2[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1ccc(F)c(Br)c1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(F)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 1-(3-Bromo-4-fluoro-phenylsulfanyl)-propan-2-one and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:37]([O:39][C:40]([CH:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1)=[O:41])[CH3:38]>CN(C)C=O>[CH2:37]([O:39][C:40]([CH:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[N:47]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1)=[O:41])[CH3:38]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NCc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(Cc1ccccn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Reaction time: 16 h
Yield: 25.3 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.10 g, 0.30 mmol) and N,N′-dicyclohexylcarbodiimide (0.068 g, 0.33 mmol) in N,N-dimethylformamide (10 mL) was treated with 2-[(pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester and stirred for 16 h. The mixture was filtered, the filtrate was concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-10% methanol in dichloromethane) to afford the desired product, 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-pyridin-2-ylmethyl-amino}-cyclopentanecarboxylic acid ethyl ester (0.043 g, 0.076 mmol, 25.3%), as a pale white solid. LC-MS (ESI) calcd for C24H29N5O7S2 563.15, found 564.6 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:30][C:29]([Cl:32])=[CH:28]C=1)=O>CO.O>[Cl:32][C:29]1[CH:30]=[CH:3][C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:28]=1
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the sequence described in examples 1.5 and 1.6, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] to yield trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 340 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=O.[CH3:18][NH:19][NH2:20]>C(O)(=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:19]([CH3:18])[N:20]=1
Reactant: CNN
Reactant: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
34.5 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione was dissolved in 250 ml of acetic acid and 9.5 mL of methylhydrazine slowly added. The mixture was heated at 100° C. for 5 minutes then cooled and diluted with ether. The ether solution was washed with water and potassium carbonate solution, then dried with magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 9.5 g of 3-(2,5-difluorophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH2:3][CH2:2]1.CC(O)=O.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:27]([N:23]1[CH:22]=[C:21]2[C:25]([CH:26]=[C:18]([C:10]3[CH:9]=[C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:1]([CH:41]5[CH2:43][CH2:42]5)[CH2:2][CH2:3]4)[N:16]4[C:11]=3[C:12]([NH2:17])=[N:13][CH:14]=[N:15]4)[CH:19]=[CH:20]2)=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(C3CCCN(C4CC4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 49.2 %

Procedure:
To a solution of 7-azepan-4-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in MeOH (2 mL) containing 3 Å molecular sieves was added AcOH (112 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (236 μL, 1.18 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 15 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 47 mg (50%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1 H), 7.58 (s, 1 H), 7.48 (d, 1 H), 7.28 (s, 1 H), 6.97-7.07 (m, 5 H), 6.84 (dd, 1 H), 6.27 (s, 1 H), 5.34 (s, 2 H), 3.04-3.15 (m, 1 H), 2.56-2.64 (m, 1 H), 2.44-2.53 (m, 2 H), 1.27-1.77 (m, 6 H), 0.07-0.14 (m, 2 H), −0.03-0.05 (m, 2 H); ES-MS m/z 478.33 [M+H]+, HPLC RT (min) 2.10.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[NH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:39])[CH2:18][C@H:19]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][OH:15]>C(Cl)Cl>[CH2:32]([O:31][C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][C:17]([NH:16][C@H:13]([CH2:12][CH2:11][CH2:10][NH:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:14][OH:15])=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCN)OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCCNCCC[C@H](CO)NC(=O)C[C@@H](CCCCCCCCCCC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of freshly prepared triflate hereinabove (956 mg; 3.88 mmol.) in CH2Cl2 (10 ml) is added dropwise to a solution of (2R)-5-amino-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (Section 1.1.2.) (1.69 g; 3.88 mmol) in CH2Cl2 (10 ml) and the mixture is stirred for 4 hours at room temperature under argon flow. After dilution with CH2Cl2, the reaction medium is successively washed with an aqueous saturated solution of NaHCO3 and with H2O. The organic layer thus obtained is dried over MgSO4 and concentrated under vacuum. By running a flash chromatography purification on a silica gel (15/1 CH2Cl2/MeOH eluent), there is recovered the desired secondary amine (862 mg; 43%) Rf=0.3 (8/1 CH2Cl2/MeOH). ES/MS: m/z ratio 532.0 [M+H]+. 1H-NMR (CDCl3, 250 MHz), δ in ppm: 7.2-7.4; 7.1; 5.8; 5.0; 4.6; 3.95; 3.5; 2.9; 2.5; 2.1; 1.9-1.5; 1.5-1.2; 0.9. 13C-NMR (CDCl3, 62.89 MHz), δ in ppm: 172.17; 138.28; 138.21; 128.39; 127.96; 127.71; 114.82; 76.80; 71.40; 63.81; 50.87; 48.30; 47.75; 41.57; 34.10; 33.39; 31.89; 29.66; 29.62; 29.33; 28.19; 28.03; 25.21 26.11; 25.78; 22.82; 22.66; 14.10. 1H-NMR (CDCl3, 250 MHz), δ in ppm: 7.2-7.4; 6.75; 5.8; 5.0; 4.5; 3.9; 3.5; 2.5; 2.0; 2.1; 1.7-1.2; 0.9. 13C-NMR (CDCl3, 62.89 MHz), δ in ppm: 172.77; 138.68; 138.14; 128.23; 127.72; 127.56; 114.22; 76.64; 71.37; 64.58; 51.45; 49.79; 49.37; 41.53; 33.90; 33.53; 31.77; 29.65; 29.20; 28.64; 28.57; 25.00; 26.68; 25.93; 22.53; 13.98 (ammonium salt and free base spectra, respectively).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8]1.[NH3:24]>CO>[CH2:16]([O:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:24])=[O:2])[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N
Reactant: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Solvent: CO
Product: NC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
Compound 3a (1.30 g, 4.0 mmol) was dissolved in 7 N NH3 in methanol (25 mL) in a sealed tube. The resulting solution was stirred at 50° C. for 3 days. After that the solvent was removed under vacuum and the residue was purified by Flash™ chromatography (BIOTAGE, Inc) (9.5:0.45:0.05 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 4a (0.93 g, 78%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.27 (m, 5H), 1.65 (m, 4H), 2.11 (m, 4H), 2.65 (m, 2H), 2.96 (d, 2H), 3.62 (m, 2H), 4.51 (s, 2H), 7.37 (m, 5H). m/z (ESI): 305 [C18H28N2O2+H]+.