Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH2:73]O)[CH2:67][CH2:66]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:73][CH2:72][CH2:71][N:68]5[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]5)[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CN1CCN(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
250 mg (0.55 mmol) of methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxlate are dissolved in 5 ml of THF. At room temperature, 216 mg (0.825 mmol) of triphenylphosphine, 142 μl (0.825 mmol) of DEAD and 120 mg (0.825 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-ol are added, and the solution is stirred at room temperature for 18 hours. The solvent is then removed, and the residue is chromatographed on silica gel, allowing the desired product to be isolated as a colorless solid. Yield 76%.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13].C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[CH3:9][N:10]([CH2:11][CH2:12][OH:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CNCCO
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CN(CCO)c1ccncc1
Yield: 18.6 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (4.50 g), 2-(methylamino)ethanol (2.25 g) and sodium bicarbonate (7.56 g) in isoamyl alcohol (50 ml) was heated under reflux for 70 hours and then evaporated. The residue was extracted several times with hot ethyl acetate and the combined extracts were filtered and evaporated until crystallisation commenced. The solution was allowed to cool and the solid was filtered off to give the title compound, (0.85 g), m.p. 90°-91°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(=O)NOC(C)(C)C)[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)ONC(=O)N1CCC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 1.0 g of N-(3-chlorophenyl)-2-(1-tert-butoxycarbamoylpiperidin-4-ylamino)nicotinamide obtained in Example 6, in 10 ml of ethanol was mixed with 5 ml of a conc. HCl aqueous solution and stirred for 8 hrs under reflux. The reaction solution was cooled to a room temperature, concentrated in a reduced pressure to remove the solvent, and adjusted to a pH of 9˜10 by dropwise adding saturated sodium hydrogen carbonate aqueous solution. After three rounds of extraction with 30 ml of ethylacetate per round, the extracts were dried over a desiccant to remove water, and concentrated in a reduced pressure and dried in vacuum to afford 0.69 g of the title compound (Yield: 89.9%). 1H NMR (CDCl3) δ 8.23 (d, 1H), 7.99 (d, 2H), 7.7 (d, 1H), 7.66 (s, 1H), 7.36 (d, 1H), 7.27 (t, 1H), 7.10 (d, 1H), 6.53-5.45 (m, 1H), 4.18-4.05 (m, 1H), 3.43 (t, 1H), 3.09 (d, 2H), 2.74 (t, 2H), 2.15-2.01 (m, 2H), 1.57-1.36 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:23][N:22]=[N:21][C:10]=2[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(C#Cc2ccncc2)cc1
Product: COc1ccc(-c2[nH]nnc2-c2ccncc2)cc1
Temperature: 150 °C
Yield: 53 %

Procedure:
4-(2-(4-methoxyphenyl)ethynyl)pyridine (1.48 g, 7.1 mmol) and trimethylsilylazide (2.5 g, 21.3 mmol) were combined in a sealed tube which was heated 48 h in a 150° C. oil bath. The mixture was chromatographed on silica using an ethyl acetate-hexanes gradient giving a yellow solid (950 mg, 53%). 1H NMR (CDCl3, 400 mHz) δ 8.50 (d, 2H, J=5.8 Hz), 7.60 (d, 2H, J=5.8 Hz), 7.36 (d, 2H, J=8.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 3.81 (s, 3H), 2.80 (br, 1H). MS (AP+) m/e 253 (MH+).
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CON(C)[C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(CC(=O)N(C)OC)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To a solution of sec-BuLi (1.3 M in THF, 22.6 mL, 29.5 mmole) in dry THF (50 mL) was added 4-bromobenzotrifluoride (3.3 g, 14.7 mmole) in dry THF (20 mL) dropwise at −78° C. After 20 min, N-methoxy-N-methyl-2(4-methoxyphenyl)acetamide (1.5 g, 7.4 mmole) in dry THF (20 mL) was added dropwise. After 1 hr the mixture was quenched with saturated NH4Cl (10 mL), warmed to RT, and extracted with Et2O (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (15% EtOAc/hexanes) to give the title compound (2.2 g, 100%) as a slightly-yellow solid: TLC (1.5% EtOAc/hexanes) Rf0.81; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.2 Hz, 2 H), 7.72 (d, J=8.2 Hz, 2 H), 7.18 (d, J=8.7 Hz, 2 H), 6.88 (d, J=8.7 Hz, 2 H), 4.25 (s, 2 H), 3.79 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:29])[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][C:31]1[N:35]=[C:34]([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[O:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([C:34]4[O:33][N:32]=[C:31]([CH3:30])[N:35]=4)=[CH:44][CH:43]=3)[CH2:11][CH:10]2[N:14]([CH3:29])[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]([F:27])([F:25])[F:26])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(-c4nc(C)no4)cc3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 633.1 [M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][CH2:17][C:18]([NH:20][CH2:21][C@H:22]([OH:37])[CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32](=[NH:35])[NH:33]O)=[CH:27][C:26]=1[Cl:36])=[O:19]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:33]=[C:32]([C:28]3[CH:29]=[C:30]([CH3:31])[C:25]([O:24][CH2:23][C@@H:22]([OH:37])[CH2:21][NH:20][C:18](=[O:19])[CH2:17][OH:16])=[C:26]([Cl:36])[CH:27]=3)[N:35]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H](O)CNC(=O)CO
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(Cl)c3)no2)cc1C
Yield: 50.7 %

Procedure:
The title compound (31 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (S)-2-hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2-chloro-6-methyl-phenoxy]-propyl)-acetamide (39 mg, 117 μmol) according to Method A; LC-MS: tR=0.53 min; [M+1]+=523.14; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 2.22 (s, 3H), 2.40 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 3.20-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.74 (s, 2H), 3.83 (d, J=5.8 Hz, 2H), 3.86-4.01 (m, 3H), 5.32 (d, J=5.3 Hz, 1H), 5.55 (t, J=6.0 Hz, 1H), 7.70 (t br, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.86-7.89 (m, 1H), 7.89-7.90 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:13].[BH4-].[Na+].CC(C)=O.[BH4-]>CCO>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[CH:3]1[OH:13]
Reactant: Cc1ccc(C)c2c1CC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(C)c2c1CC(C)C2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
8.95 g of 2,4,7-trimethylindanone (51.4 mmol) were dissolved in 70 ml of EtOH; the solution was cooled to 0° C. and 2.00 g of NaBH4 (51.8 mmol) were added to it in small aliquots. At the end of the addition, the reaction mixture was allowed to reach ambient temperature and then heated at 50° C. for 3 hours and 30 min. The reaction mixture was cooled to 0° C., and 50 ml of acetone were slowly (careful: exothermic reaction!) added to it to deactivate the residual borohydride. All volatiles were then removed in vacuo, the white solid obtained was treated with 50 ml of 1H2O and stirred for 30 min. The organic layer was extracted with Et2O (2×100 ml), washed with H2O, dried and essiccated in vacuo to leave 9.06 g of a white solid (100%).
Reaction SMILES: NC1C(NC2C=CC=C(O)C=2)=NC(NC2C=CC=C(O)C=2)=NC=1C(OCC)=O.[CH2:29]([O:31][C:32]([C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]3[O:47][CH2:48][CH2:49][O:50][C:43]=3[CH:42]=2)[N:37]=[C:36]([NH:51][C:52]2[CH:57]=[CH:56][C:55]3[O:58][CH2:59][CH2:60][O:61][C:54]=3[CH:53]=2)[C:35]=1[N+:62]([O-])=O)=[O:33])[CH3:30].[H][H]>[Pd]>[NH2:62][C:35]1[C:36]([NH:51][C:52]2[CH:57]=[CH:56][C:55]3[O:58][CH2:59][CH2:60][O:61][C:54]=3[CH:53]=2)=[N:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]3[O:47][CH2:48][CH2:49][O:50][C:43]=3[CH:42]=2)=[N:39][C:34]=1[C:32]([O:31][CH2:29][CH3:30])=[O:33]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(Nc2ccc3c(c2)OCCO3)nc(Nc2ccc3c(c2)OCCO3)c1[N+](=O)[O-]
Agent: [Pd]
Agent: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N
Product: CCOC(=O)c1nc(Nc2ccc3c(c2)OCCO3)nc(Nc2ccc3c(c2)OCCO3)c1N

Procedure:
In a manner similar to the preparation of 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine, hydrogen, and 10% Pd/C were reacted to yield 5-amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.16 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=2.4 Hz), 7.04 (dd, 1H, J=2.4 and 9.0 Hz), 6.84-6.79 (m, 2H), 6.70 (d, 1H, J=9.0), 4.43 (q, 2H, J=7.8 Hz), 4.25 (s, 4H), 4.21 (bs, 4H), 1.43 (t, 3H, J=7.8 Hz); LCMS: ret. time: 23.70 min.; purity: 100%; MS (m/e): 466 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:33]=[C:34]([S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[CH:35]=[CH:36][C:37]=1[CH2:38]Br>>[Br:31][C:32]1[CH:33]=[C:34]([S:40]([N:43]([CH3:44])[CH3:45])(=[O:41])=[O:42])[CH:35]=[CH:36][C:37]=1[CH2:38][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: BrCc1ccccc1Br
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c(Br)c1

Procedure:
Compound 146.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of with 2-bromobenzyl bromide, with 3-bromo-4-bromomethyl-N,N-dimethylbenzenesulfonamide (146.3, prepared by reacting 3-bromo-4,N,N-trimethylbenzenesulfonamide with N-bromosuccinimide and N,N′-azobis(2-methylpropionitrile) in tetrachloromethane). 3-Bromo-4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]-N,N-dimethylbenzenesulfonamide was obtained. (Molecular weight 572.03 (C22H20BrF3N4O4S); retention time Rt=2.38 min. [B]; MS (ESI): 573.25 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](N)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OC(C)(C)C)=O.[BrH:27]>[Cu]Br>[Br:27][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][C:10]=1[CH2:12][CH3:13]
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3-ethylbiphen-4-ylamine (14.3 g, 0.06 mol) is added to acetonitrile (143 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tert-butyl nitrite (90%, 9.8 ml, 0.074 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (4.87 g, 0.034 mol) in hydrobromic acid (4.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×500 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3-ethylbiphenyl (12 g).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.[Cl-].[NH4+]>O1CCOCC1.[Cu](I)I>[N:23]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Reactant: c1c[nH]cn1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(-n3ccnc3)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
10.4 mg (0.025 mmol) of the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step A, 0.48 mg (0.0025 mmol) of copper iodide (I), 2.0 mg (0.03 mmol) of imidazole, and 11.1 mg (0.0525 mmol) of potassium phosphate were suspended in 0.25 ml of 1,4-dioxane. Then, 2.6 μl of N,N′-dimethylethylenediamine was added to the suspension, and the obtained mixture was then stirred at 110° C. overnight. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=25:1 to 20:1), so as to obtain 8.3 mg (93%) of 7-imidazol-1-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless viscous oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:22](=[O:29])[NH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](OC(OCC)OCC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[N:21]=[CH:30][N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:22]3=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CCOC(OCC)OCC
Product: COC(=O)Cn1cnc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Reaction time: 18 h

Procedure:
4-[4-Amino-3-(methoxycarbonylmethyl-carbamoyl)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (30.6 g) was treated with 375 mL of triethylorthoformate at 125° C. with stirring for 18 hours. At this time, reaction mixture was concentrated in vacuo and the resulting residue was taken up in ethyl acetate and water. The organic phase was washed thrice with 10% KHSO4 aqueous solution, once with water, once with brine. The organic layer was then dried over magnesium sulfate and was filtered. The filtrate was concentrated in vacuo. The product was purified by flash column chromatography (500 g of silica) eluting with 60% to 70% ethyl acetate in hexane. Appropriate fractions were collected and evaporated to dryness. The resulting residue was dissolved in diethyl ether and re-evaporated; this dissolution and re-evaporated was repeated using pentane. All solids obtained as foams were pooled, resulting in a total yield of 15.56 g of 4-(3-methoxycarbonylmethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([OH:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][O:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: COc1cccc(CO)c1
Product: COc1cccc(COCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1
Yield: 64 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3-anisyl alcohol, the title compound was isolated as a yellow solid in 64% yield (92% purity by HPLC).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][CH2:4][NH:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:14][CH3:15])=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:17]1.[Cl:29][C:30]1[C:43]([N:44]=[C:45]=S)=[C:42]([Cl:47])[CH:41]=[CH:40][C:31]=1[CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].CC(C)N=C=NC(C)C>CC#N>[F:28][C:2]([F:1])([F:27])[CH2:3][CH2:4][NH:5][C:6]([C:7]1[C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[CH2:17]2)=[CH:9][C:10]2[N:14]([CH3:15])[C:45]([NH:44][C:43]3[C:42]([Cl:47])=[CH:41][CH:40]=[C:31]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]=3[Cl:29])=[N:13][C:11]=2[CH:12]=1)=[O:26]
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(3,3,3-trifluoro-propyl)-2-[3-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoic acid amide (93 mg, 0.22 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (71 mg, 0.22 mmol), DIC (35 μL) and MeCN (2.0 mL).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O.C(OCC)(=O)C>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: Cc1ccn(C(=O)NC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)n1ccc(CBr)n1
Yield: 32 %

Procedure:
To N-tert-butyl-3-methyl-1H-pyrazole-1-carboxamide (609 mg, 3.36 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (849 mg, 4.77 mmol) and benzoyl peroxide (114 mg, 0.470 mmol). The mixture was heated to reflux overnight and then diluted with water and ethyl acetate. The organic layer was separated, dried and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluting with 10% ethyl acetate in heptane) to give the title compound (280 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:20]>>[Br:20][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Reactant: BrC(Br)(Br)Br
Product: O=C(OCc1ccccc1)N1CCCC(CBr)C1

Procedure:
The title compound was prepared by the method of Preparation 9 from benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate [Preparation 59] and carbon tetrabromide. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 80:20, by volume ethyl acetate:hexane, in 10% increments, to afford benzyl 3-(bromomethyl)-1-piperidinecarboxylate as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:9][N:8]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])C.[BH4-].[Li+]>O1CCCC1>[OH:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:9][N:8]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29]
Reactant: CCOC(=O)CC[C@H]1CC[C@@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)N[C@@H]2CC[C@H](CCCO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of tert-butyl cis-2-(3-ethoxy-3-oxopropyl)-5-{[(1-isopropyl-1H-indazol-3-yl) carbonyl]amino}piperidine-1-carboxylate (300 mg, 0.617 mmol, step 7 of Example 5) in tetrahydrofuran (7 mL) was added at 0° C. a solution of lithium borohydride (2M in tetrahydrofuran, 1.54 mL, 3.08 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 282 mg (quant.) of the title compound as a colorless oil. The resulting residue was used for the next reaction without purification.