Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][N:3]=1.[N:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C:22](=O)[CH2:21][CH2:20]2.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[C:21]3[CH2:20][N:19]4[CH2:27][CH2:26][CH:23]([C:22]2=3)[CH2:24][CH2:25]4)=[CH:6][CH:7]=1
Reactant: O=C1CCN2CCC1CC2
Reactant: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)nc2)C2CCN(CC2)C1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a 50 mL round-bottom flask were combined 2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (0.272 g, 1.039 mmol; Example 117D), and 1-azabicyclo[3.2.2]nonan-4-one (0.188 g, 1.351 mmol; Example 2A) in dioxane (5 mL). After 10 minutes of warming to 50° C., the suspension cleared. Concentrated sulfuric acid (0.277 mL, 5.20 mmol) was added and the mixture was heated at 80° C. After 1.5 hours, the mixture was cooled and concentrated to about 3 mL. The residue was dissolved in water (75 mL), basified with concentrated sodium hydroxide (30 mmol), extracted with chloroform (4×25 mL), dried over magnesium sulfate, and concentrated. The residue was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes] to give the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.63 (dddd, J=14.3, 9.3, 5.2, 2.4 Hz, 2H), 1.95 (ddt, J=13.6, 9.2, 5.2 Hz, 2H), 2.39 (s, 3H), 2.95 (m, 1H), 3.00 (m, 2H), 3.06 (t, J=6.4 Hz, 2H), 3.19 (ddd, J=14.1, 9.0, 5.2 Hz, 2H), 4.22 (s, 2H), 4.38 (t, J=6.4 Hz, 2H), 6.92 (dd, J=8.5, 1.4 Hz, 1H), 7.11 (br s, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.36 (dd, J=8.3, 2.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][NH:10][C:9]3([Br:23])[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])=[N:2]1.[C:24]1([C:30](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:9]1([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]3[N:4]=[CH:5][N:1]([C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:2]=3)[CH:7]=2)[NH:11][NH:10]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3nc[nH]n3)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc21
Temperature: 80 °C

Procedure:
To a solution of 2-(5-(1H-1,2,4-triazol-3-yl)-3-bromo-1H-indazoyl)perhydro-2H-pyran in 60 mL in dimethyl formamide, was added triphenylmethyl chloride (3.48 g, 12.5 mmol), and triethyl amine (4.64 mL, 33.32 mmol). The reaction mixture was heated to 80° C. for 12 hours. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between water and ethyl acetate. The oil resulting from evaporation of the extracts was purified by column chromatography (SiO2, 25% ethyl acetate in hexanes (2.90 g, 61% over 4 steps): 1H NMR (CDCl3) δ 8.3 (s, 1H), 8.2 (d, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.4-8.1 (m, 15H), 5.68 (dd, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 2.5 (m, 1H), 2.1 (m, 2H), 1.7 (m, 3H); ES-MS (m/z) 592 [M+2]+.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[C:29](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]#[CH:29])[CH2:21][CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)[Si](OC1CCC(C=O)CC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A suspension of 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarbaldehyde (4.74 g), dimethyl (1-diazo-2-oxopropyl)phosphonate (2.98 g) and potassium carbonate (3.57 g) in methanol (40 mL) was stirred at room temperature for 2 hr. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (4.15 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:27])[CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[C:4]([F:27])[CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=443.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[C:37]1(S)[CH:42]=[CH:41]C=[CH:39][CH:38]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:1]1([S:2][C:5]2[N:6]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:8]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10][C:9]=3[N:25]=2)[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Nc2nc(Sc3ccccc3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 100 °C

Procedure:
To a microwave reaction vial were added [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (53 mg, 0.1 mmol), thiophenol (16 mg, 0.15 mmol), p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol), and DMF (0.4 mL). The vial was capped, and the mixture was heated via microwave irradiation at 100° C. for 10 min, filtered through a 0.45 μm filter, and the filtrate was purified by reversed phase HPLC (Phenomenex Gemini 30 mm×100 mm column, gradient of acetonitrile in 20 mM aqueous NH4OH). The title compound was obtained as a white solid (27 mg, 48%). MS (ESI): mass calcd. for C27H21F6N5S, 561.14; m/z found, 562 [M+H]+. 1H NMR (CDCl3): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.56-7.50 (m, 1H), 7.50-7.42 (m, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.96 (dd, J=7.4, 4.6 Hz, 1H), 6.58 (bs, 1H), 3.66-3.55 (m, 4H), 3.23-3.17 (m, 2H), 2.96-2.90 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[N:34]=[C:33]2[N:28]([C:29](SC)=[N:30][CH2:31][CH2:32]2)[N:27]=1>C(O)CCC>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH:13][C:29]1[N:28]2[N:27]=[C:26]([CH3:25])[N:34]=[C:33]2[CH2:32][CH2:31][N:30]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: CSC1=NCCc2nc(C)nn21
Solvent: CCCCO
Product: Cc1nc2n(n1)C(NNC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)=NCC2

Procedure:
A solution of 139 mg (0.4 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4) and 72.9 mg (0.4 mmol) of 2-methyl-5-(methylthio)-7,8-dihydro[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 30) in 5 mL of 1-butanol was stirred at reflux for 76 h. The cooled solution was concentrated, and the residue containing the title compound was used directly in the next step. LC-MS 482 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:2].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:16]=[O:18])=[C:8]([Cl:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-chloro-phenyl)-acetic acid ethyl ester was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 48 h to give the title compound as brown solid which was used in the next step without further purification. MS: m/e=257.0 [M+NH4+].
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCC2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:13]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc(C2CCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCC2)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 830 mg of 1-bromo-4-cyclobutyl-benzene (3.93 mmol), 2.7 ml of a 1.6 molar solution of n-BuLi in hexane (4.32 mmol) and 605 μl of DMF (7.86 mmol). The isolated residue was purified by flash column chromatography (5:95 EtOAc/cyclohexane) to give 422 mg of 4-cyclobutyl-benzaldehyde (67%) as a colourless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.89 (m, 1H), 1.97-2.26 (m, 3H), 2.40 (m, 2H), 3.63 (quint, J=8.5 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:24])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 38 %

Procedure:
With 600 mg of the compound obtained in Example 219 and 129 mg of piperidine as starting materials, 250 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:17]=3F)[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:8][CH2:7]1>C(O)C>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[C:17]=3[O:1][CH2:2][CH3:3])[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 52 h

Procedure:
To a solution of sodium ethoxide prepare from sodium (0.75 g) and absolute ethanol (30 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.8 g) and the mixture in sealed tube was stirred for 52 hours at 140° to 150° C. and then concentrated. Water (60 ml) was added to the residue, and the solution was adjusted pH 7 with acetic acid and and extracted with chloroform. The chloroform layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol (2:1)→chloroform-methanol-concentrated aqueous ammonia (20:6:1→10:10:1) and recrystallized from ethanol to give the title compound (75 mg) as light brown prisms, mp 119°-122° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:28]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([C:21]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:31][CH:32]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(=O)NCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
Add TFA (0.6 mL, 7.94 mmol) to a solution of 3′-[4-(Acetylamino-methyl)-phenyl]-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (650 mg, 1.58 mmol) in DCM (6.5 mL) and maintain stirring for 3 hr. Concentrate material to dryness. Redissolve in DCM (10 mL) and add TFA (1.2 mL). Heat reaction mixture at 40° C. for 3 hr. Purify the mixture by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH to give the title compound as a yellow oil (454 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ 8.14 (d, 1H), 8.08 (d, 1H), 7.90 (d, 2H), 7.36 (d, 2H), 5.81 (bs, 1H), 4.49 (d, 2H), 3.17 (m, 4H), 2.88 (m, 4H), 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:34]=[CH:33][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[C:35](OC(N1C(C)C2C(=NC=C(C(O)=O)C=2)[C@@H]1C(C)C)=O)(C)(C)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH:22]([CH3:35])[N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@@H:20]([CH:30]([CH3:31])[CH3:32])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:33][CH:34]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2C(C)N1C(=O)OC(C)(C)C
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)C(C)N(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using (7S)-6-(tert-butoxycarbonyl)-7-isopropyl-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid as a starting material. LC-MS tR=0.95 min in 1 min chromatography, MS (ESI) m/z 502.6 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of diastereomers): δ 8.93 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.24 (s, 1H), 5.06-4.88 (m, 2H), 4.82-4.70 (m, 2H), 3.06 (q, J=7.2 Hz, 2H), 2.48-2.26 (m, 1H), 1.59 (d, J=7.2 Hz, 0.9H), 1.56 (d, J=7.2 Hz, 2.1H), 1.53 (s, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 0.9H), 0.97 (broad s, 2.1H), 0.83 (broad s, 2.1H), 0.48 (d, J=7.2 Hz, 0.9H).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:20][C:19]([NH2:36])=[CH:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[CH:18]=[C:19]([NH2:36])[CH:20]=2)=[CH:31][CH:30]=1
Reactant: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
1-Chloroethyl chloroformate (864 mg, 6 mmol) was added dropwise to the solution of 2-benzyl-N5-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine (1.2 g, 3 mmol) and diisopropylethyl amine (774 mg, 6 mmol) in 1,2-dichloroethane (30 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature for 10 h. Solvent was removed in vacuo and solid residue was washed by diethyl ether. Product was obtained as a light brown solid (834 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([CH2:18]O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:22]>CC#N>[Cl:22][CH2:18][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Solvent: CC#N
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (28.5 g, 0.1 mol) was dissolved in 100 ml of CH3CN and the solution was heated to 70° C. (26 g, 0.22 mol) of SOCl2 (0.12 mol) was slowly added dropwise at this temperature. The mixture was after-stirred for 1 hour at 70° C. and concentrated by evaporation in vacuo. This gave 27.6 g (92%) of the product as viscous oil with a purity of 95%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH:31]C(=O)OC(C)(C)C)[CH3:30])=[CH:25][CH:24]=1)=[O:22])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:31][CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:4]2[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:22])=[CH:28][CH:27]=1)[CH3:30]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butyl [1-(4-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]carbamoyl}phenyl)ethyl]carbamate (1.7 g) was dissolved in methylene chloride (20 ml). To the solution, trifluoroacetic acid (1.5 g) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the residue was neutralized by adding water and potassium carbonate followed by extraction twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium bicarbonate aqueous solution and water in turns and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(1-aminoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benzamide as a crude product (1.8 g).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[Cl:27].Cl>C(Cl)(Cl)(Cl)Cl>[CH:4]1([CH2:7][CH2:8][CH2:9][C:10]([C:23]2[CH:24]=[C:19]([O:18][CH3:17])[C:20]([Cl:27])=[CH:21][C:22]=2[O:25][CH3:26])=[O:11])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: COc1ccc(OC)c(Cl)c1
Reactant: O=C(Cl)CCCC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)CCCC2CCCCC2)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
3.77 g of 4-cyclohexanebutyryl chloride dissolved in 10 ml of CCl4 are added to a suspension of 2.8 g of AlCl3 in 20 ml of CCl4 at +4° C. under nitrogen. 5.2 g of 2,5-dimethoxychlorobenzene in 10 ml of CCl4 are added dropwise and the mixture is then left stirring for 3 hours at RT. The reaction medium is hydrolysed with dilute HCl solution, the phases are then separated by settling and the organic phase is extracted with DCM. After drying over MgSO4, the solution is evaporated and the residue is then purified by chromatography on silica, eluting with a heptane/DCM mixture (60/40; v/v) and then with pure DCM. 3.37 g of the expected compound are obtained: m.p.=80-81° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[C:5](/[CH:8]=[N:9]/O)=[N:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]#[N:9])=[N:4][CH:3]=1
Reactant: Cn1c(Br)cnc1/C=N/O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1c(Br)cnc1C#N
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
(E)-5-Bromo-1-methyl-1H-imidazole-2-carbaldehyde oxime (Preparation 155, 38 mg, 0.186 mmol) and TEA (39 uL, 0.279 mmol) was stirred in THF (6 mL) and cooled at 0° C., TFAA (28 uL, 0.205 mmol) was added. Then the mixture was stirred at 60° C. under microwave irradiation for 3 hours. The reaction was purified directly by Biotage silica gel column chromatography eluting with 20% EtOAc in cyclohexanes to give the title compound as yellow solid (15 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.ClCCl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5 g (27.64 mmol) of 4-fluoro-2-(trifluoromethyl)aniline is dissolved in 25 ml of dry pyridine, and the solution is cooled to 0° C. While maintaining the temperature, a solution of 4.82 g (27.4 mmol) of chlorosulfonylacetic acid methyl ester in 20 ml of dichloromethane is added dropwise to the cooled solution during the course of about 10 minutes. Then the mixture is stirred for 6 hours at room temperature. The reaction solution is then diluted with 100 ml of dichloromethane, the pyridine is extracted by shaking with 2N hydrochloride acid, the organic phase is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is crystallized from diethyl ether/hexane 1:1, thus obtaining 7.35 g (23.32 mmol)=84.35% of theory of a crystallized product, mp 84°14 86° C.