Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[C:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[C:9]([C:12]#[N:13])[C:10]#[N:11]>ClCCl>[Cl:2][C:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[C:9]([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CC(C#N)=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of PCl5 (16.6 g, 80 mmol) in dichloromethane (500 mL) was added dropwise to a suspension of Example 96A (8.6 g, 40 mmol) in dichloromethane (80 mL). The resulting mixture was heated to reflux for 20 hours, cooled to room temperature, and concentrated. The residue was dissolved in a minimal amount of dichloromethane and filtered through a plug of silica gel. The plug was washed with dichloromethane and the filtrate was concentrated. The concentrate was recrystallized from dichloromethane/hexanes to provide 5.4 g (57% yield) of the desired product. Rf=0.7 (5% methanol/dichloromethane).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@H]1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
Into a reaction vessel were put potassium phthalimide (5.00 g, 27.0 mmol), benzyltrimethylammonium chloride (0.50 g, 2.70 mmol) and DMF (50 ml) and then thereto was added (R)-epichlorohydrin (5.00 g, 54.0 mmol). The mixture was stirred at room temperature for 16 hours and the solvent was removed. To the residue was added ethyl acetate (30 ml), the mixture was washed with water (20 ml) and ethyl acetate was removed to give crude (R)-glycidylphthalimide (4.48 g, yield: 82%, optical purity: 63% e.e.) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C([Cl:50])C=1.ClC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:50])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: Nc1cccc(Cl)c1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-chloro-phenylamine (3.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 30:70 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16]O)[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].P(Br)(Br)[Br:23]>O1CCCC1>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16][Br:23])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: BrP(Br)Br
Reactant: O=C(Nc1cnc2[nH]c(CO)cc2c1)c1ccccc1Br
Solvent: C1CCOC1
Product: O=C(Nc1cnc2[nH]c(CBr)cc2c1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
A flask is charged successively with 1 g (2.89 mmol) of 2-bromo-N-(2-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (Example 16), 100 mL of tetrahydrofuran and 408 μL (4.34 mmol) of phosphorus bromide (PBr3) under argon atmosphere. It is stirred at room temperature for 18 hours. The solvent is then evaporated under reduced pressure, and the residue is taken up in 150 mL of ethyl acetate. The organic phase is washed with 3×50 mL of water, dried over sodium sulphate and evaporated under reduced pressure. The precipitate obtained is dried under vacuum for 1 h, finally obtaining 957 mg of a brown solid (raw yield 81%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:11]=1[N:12]1[CH2:43][CH2:42][C:15]([CH3:44])([O:16][CH2:17][CH:18]=[CH:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[CH:41]=[C:32]3[CH:31]=[CH:30][CH:29]=2)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:10]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[CH:41]=[C:32]3[CH:31]=[CH:30][CH:29]=2)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CCOc1ccccc1-c1cccc-3c1
Agent: [Pd]
Agent: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OC/C=C/COc1ccccc1-c1cccc-3c1
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCOc1ccccc1-c1cccc-3c1
Yield: 93.5 %

Procedure:
A mixture of example 20 (30 mg, 0.050 mmol), 10% Pd/C (5.35 mg, 5.03 μmol) in MeOH was stirred under a H2 balloon for 3 h. It was then filtered and concentrated to obtain 28 mg (93%) of the desired product as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.51 (br. s., 1H), 7.70 (d, J=7.1 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.40 (d, J=6.6 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.04 (d, J=7.1 Hz, 2H), 6.81 (s, 1H), 6.01 (br. s., 1H), 4.59 (t, J=11.9 Hz, 1H), 4.13 (br. s., 2H), 3.91 (t, J=11.5 Hz, 1H), 3.53 (d, J=3.5 Hz, 1H), 3.42 (d, J=4.9 Hz, 2H), 2.84 (d, J=9.9 Hz, 1H), 2.63 (br. s., 3H), 2.36 (br. s., 1H), 2.16 (br. s., 1H), 2.10-2.02 (m, 1H), 1.93 (d, J=12.5 Hz, 1H), 1.80 (d, J=9.0 Hz, 2H), 1.70-1.54 (m, 2H), 1.36-1.20 (m, 12H). LCMS (M+1)=599.38.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccc(F)cc2N1S(=O)(=O)c1cccc(O)c1
Yield: 22.9 %

Procedure:
The title compound was prepared from 3-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (350 mg, 0.91 mmol), cyclohexene (1.85 mL, 18 mmol), and 1.0 M solution of boron tribromide in dichloromethane (5.5 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane, to afford the desired compound (77 mg, 30%) as a solid, m.p. 164-167° C.;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([NH:22][C@H:23]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]2)=[N:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][C:16]([NH:22][C@H:23]3[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]3)=[N:17]4)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1
Reactant: NCC1CC1
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(NCC2CC2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-Fluoro-N-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-benzenesulfonamide (product example 1, 0.175 g, 0.404 mmol) was suspended in 2 mL cyclopropanemethylamine. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptan/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a white solid (46 mg, 24%), MS: m/e=485.5 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[N:20]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[N:24][C:19]2=[N:18][CH:17]=1)CCC>>[CH3:10][O:9][CH2:8][C:4]1[N:3]=[C:2]([C:16]2[N:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[N:24][C:19]3=[N:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COCc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: COCc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 3.6 %

Procedure:
2-Bromo-6-methoxymethylpyridine (0.27 g, 1.34 mmol; prepared according to Shawcross et al. in J. Heterocyclic Chem., 1993, 33(2), 563-565) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.34 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 3-(6-methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (15 mg) as a yellow solid: δH (400 MHz, CDCl) 3.54 (3H, s), 4.68 (2H, s), 7.34 (1H, d, J 7), 7.39 (1H, d, J 7), 7.73 (1H, d, J 7), 7.84 (1H, t, J 7), 8.52 (1H, s), 10.51 (1H, d, J 7); m/z (ES+) 309 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.[C:27]1([C:33]2[N:37]3[CH2:38][CH2:39][NH:40][CH2:41][C:36]3=[N:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.O1CCOCC1.C(OCC)C>[ClH:1].[C:27]1([C:33]2[N:37]3[CH2:38][CH2:39][N:40]([C:4]([C:3]4[C:7]([Cl:12])=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[O:6])[CH2:41][C:36]3=[N:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: c1ccc(-c2cnc3n2CCNC3)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N1CCn2c(-c3ccccc3)cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
2,4,6-Trichlorobenzoic acid (0.169 g, 0.750 mmol), EDC (0.144 g, 0.750 mmol) and 1-hydroxybenztriazole (0.115 g, 0.750 mmol) were stirred in dichloromethane (DCM) (5 mL) for 15 minutes. 3-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (100 mg, 0.5 mmol, Intermediate 3) and diisopropylethylamine (0.175 mL, 1.000 mmol) were added and the solution stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 ml) and washed with saturated sodium bicarbonate (25 ml), water (3×25 ml), brine, dried over anhydrous sodium sulfate and concentrated to a crude oil. The crude oil was twice purified by mass-directed automated preparative HPLC to afford an oil. The purified product was dissolved in dichloromethane (3 ml) and treated with 4N HCl in dioxane (500 uL). The solvents were removed in vacuo and the solid tritruated with diethyl ether to afford product 3-phenyl-7-[(2,4,6-trichlorophenyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (0.018 g, 0.041 mmol, 8.12% yield)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[CH3:26]I.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:26])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-4-(2,2,2-trichloro-ethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (420 mg, 1 mmol) and methyl iodide (0.18 mL, 3 mmol) in DMF (10 mL) cooled at 0° C. under argon was added sodium hydride (44 mg, 1.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2×25 mL), the organic phases were joined, washed with 1N HCl then brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 436 [M+H]+, 434 [M−H]−; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[I-].[K+].II>C(O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: Sc1ccccc1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Brc1cccc2[nH]cc(Sc3ccccc3)c12
Temperature: 45 °C
Yield: 99.6 %

Procedure:
A stirred solution of 4-bromo-1H-indole (4.69 g, 23.9 mmol) in ethanol (110 mL) was added thiophenol (2.46 mL, 23.9 mmol). A solution of potassium iodide (3.97 g, 24 mmol) and iodine (6.07 g, 24 mmol) dissolved in water (5 mL) and ethanol (5 mL) is added over 5 minutes and the reaction was heated at 45° C. for 12 hours. The brown reaction is concentrated in vacuo to a dark brown oil and diluted with ethyl acetate (250 mL). The organic layer is washed with water (80 mL×2), saturated Na2S2O3 (80 mL), and brine (80 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (20-30% ethyl acetate/petroleum ether) gave the title compound as a white solid (7.24 g, 99.5%). Mp: 137-139° C. MS (ES−): 302 (M−H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[O:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[K+].[K+].[NH3:25]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:9])[NH:25][CH:8]=2)=[CH:3][CH:2]=1
Reactant: N
Reactant: O=c1occ(-c2ccncc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]cc(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Pyridin-4-yl)isocoumarin (4.9 g) was suspended in ethanol and 28% aqueous ammonia, and the mixture was heated under reflux for 1 hr. Concentrated hydrochloric acid was added to acidify the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. After the completion of the reaction, aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent (chloroform:methanol=10:1). The organic layer was dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was collected by filtration to give 4-(pyridin-4-yl)-2H-isoquinolin-1-one (2.9 g).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CC[O:34][CH2:33]C1>>[CH3:24][C:23]1[O:22][N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[C:16]1[O:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([N:1]3[CH2:2][CH2:33][O:34][CH2:4][CH2:5]3)=[O:7])=[CH:9][CH:10]=2)=[N:18][N:17]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)N3CCOCC3)cc2)o1
Yield: 94 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using morpholine instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 196 mg, 94%) which was obtained as a colorless foam. MS: m/e=417.3 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][CH:12]([O:16][CH2:17][CH3:18])[CH2:11][NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:15]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(CN[C@H](C)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of (R)-(+)-1-phenylethylamine 66.6 g (550 mmol) in acetonitrile 300 ml, 2-bromo-1,1-diethoxyethane 41.3 ml (270 mmol) and potassium carbonate 70.7 g (405 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 300 ml and washed with water 500 ml and brine 500 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=5:1 and 1:1) to obtain the title compound 46.0 g (70%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(C(C)C)C(C)C.C(Cl)Cl>[Pd].CCO>[CH3:9][S:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][CH3:1])[CH2:4]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCCNC1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CNC1CCCN(S(C)(=O)=O)C1

Procedure:
1-(Methanesulfonyl)-3-(methylamino)piperidine was prepared from N3-Cbz protected 3-methylamino-piperidine: i) CH3S(O)2Cl, i-Pr2NEt, CH2Cl2; ii) H2 (1 atm), 10% Pd/C, EtOH. (m/z): [M+H]+ calcd for C7H16N2O2S: 193.10; found, 193.0. 1H-NMR (DMSO-d6; TFA salt): δ (ppm) 3.4 (dd, 1H), 3.2 (m, 2H), 3.10 (s, 3H), 3.0-2.9 (m, 2H), 2.8 (s, 3H), 1.85-1.75 (m, 2H), 1.6-1.4 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2([C:2]1[CH:3]=[C:4]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[OH:26]
Reactant: COc1ccc(C2OCCO2)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(C2OCCO2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 43.8 %

Procedure:
With 30.0 g of the compound obtained in Step 196-1 and 17.52 g of 5-chloroisatin as starting materials, 15.3 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH2:11][CH3:12]
Reactant: CO
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCc1cc(Br)ccc1C(=O)OC
Temperature: 90 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoic acid (1.35 g, 5.89 mmol) in MeOH (40 mL) was added H2SO4 (1 drop). The mixture was stirred at 90° C. for 48 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in Et2O, washed with satd NaHCO3 and brine, dried over MgSO4, and concentrated to a clear oil (1.01 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][C:11](=O)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[NH2:21])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][C:11]1[NH:21][C:14]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(NC(=O)CCN(C)C(=O)OC(C)(C)C)c1N
Solvent: CC(=O)O
Product: COc1cccc2nc(CCN(C)C(=O)OC(C)(C)C)[nH]c12
Yield: 75.6 %

Procedure:
A solution of 2.1 g of crude [2-(2-amino-3-methoxy-phenylcarbamoyl)-ethyl]-methyl-carbamic acid tert.-butyl ester in 10 mL acetic acid was heated at 65° C. for 2 h. The reaction mixture was concentrated and purified by CC with EtOAc to yield 1.5 g of [2-(7-methoxy-1H-benzoimidazol-2-yl)-ethyl]-methyl-carbamic acid tert.-butyl ester as orange foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[CH:20]1([N:23]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)(=[O:26])=[O:25])[CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].O>C(C(C)=O)C.CCOC(C)=O>[CH:20]1([N:23]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:11][CH2:10][O:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:39][CH2:38]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)(=[O:25])=[O:26])[CH2:22][CH2:21]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccc(C(OCCI)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
1-[Bis(4-fluorophenyl)-methoxy]-2-iodoethane (36) (294 mg, 0.79 mmol) was dissolved in 5 mL of methyl ethyl ketone and the mixture was added to N-cyclopropyl-N-(4-piperidinyl)-3-(trifluoromethyl)benzenesulfonamide (200 mg, 0.57 mmol) and K2CO3 (157 mg, 1.1 mmol). The mixture was then heated at 80° C. overnight. Water was added to the mixture, and EtOAc was used to extract the product. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by silica gel column eluting with CH2Cl2 and CH2Cl2/EtOAc (4:1) to afford the title compound 38 as a yellow oil. 1H NMR (CDCl3): δ 8.127 (s, 1H), 8.061-8.042 (d, 1H), 7.856-7.833 (d, 1H), 7.694-7.655 (t, 1H), 7.282-7.233 (m, 4H), 7.035-6.972 (m, 4H), 5.302 (s, 1H), 3.882-3.806 (t, 1H), 3.551-3.491 (t, 2H), 2.965-2.887 (d, 2H), 2.670-2.605 (t, 2H), 2.127-2.064 (t, 2H), 1.986-1.939 (m, 3H), 1.531-1.493 (d, 2H), 0.992-0.952 (m, 2H), 0.794-0.760 (m, 2H). LC: 100%. MS (e/z): 596 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3F)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 379(MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11](N)[CH3:12])=[CH:7][CH:6]=1.F[C:17](F)(F)COC1C=CC(C#N)=CC=1>>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([NH2:10])[CH3:17])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(OCC(F)(F)F)cc1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Product: CC(N)c1ccc(OCC(F)(F)F)cc1

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine, step B, starting from 4-(2,2,2-trifluoroethoxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28-7.34 (m, 2 H) 6.94-7.00 (m, 2 H) 4.70 (q, J=8.78 Hz, 2 H) 3.95 (q, J=6.53 Hz, 1 H) 1.21 (d, J=6.78 Hz, 3 H). MS (ESI) m/z: 220 [M+H]