Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH2:33]([SH:36])[CH:34]=[CH2:35]>>[CH2:33]([S:36][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:34]=[CH2:35]
Reactant: C=CCS
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccc(OC)cc3)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 4-methoxyphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 10 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@H:13]2[N:18]3[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][CH2:22][C:23](=[O:24])[N:17]3[CH2:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:48]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:48][C:11]([C@H:13]3[N:18]4[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:21][CH2:22][C:23](=[O:24])[N:17]4[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCC(=O)c3ccc(Br)cc3)N2C1=O)OCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O)OCc1ccccc1
Temperature: 110 °C
Yield: 34.1 %

Procedure:
In a 10 ml, seal tube, benzyl (4S,7S)-4-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (200 mg, 350 μmol) was combined with 1,4-dioxane (5 ml) to give a light yellow solution. Ammonium acetate (270 mg, 3.5 mmol) was added and the reaction mixture was heated at 110° C. for 12 hr. It was cooled and diluted with EtOAc (2×30 ml). The combined organic layers were washed with brine and H2O, dried with MgSO4 and concentrated in vacuo to afford a viscous oil. The crude was purified on a silica gel column (CH2Cl2, 2%, 4%, 6%, 8% MeOH/CH2Cl2) to afford benzyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a yellow solid (66 mg, 34.1%). ESI-LRMS m/e calcd for C26H26BrN5O4 [M+] 552. found 553 [M+H+].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32]([CH2:31][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 185.5 %

Procedure:
To a suspension of sodium hydride (452 mg, 13 4 mmol, 60% in mineral oil) in DMF (25 ml) under nitrogen was added dropwise a solution of 6 (3.7 g, 10.35 mmol) in DMF (50 ml) and the mixture was stirred at 60° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of tert-butyl bromoacetate (2.62 g, 13 4 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 3 h. The DMF was removed under high vacuum and the crude product was suspended in water (100 ml) and the mixture was extracted by ethyl acetate (2×100 ml). The combined ethyl acetate phases were washed by water (1×50 ml), brine (1×50 ml), dried over sodium sulphate filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (9/1) to give the title compound 7 (3.5 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:21]([CH3:24])[O:22][N:23]=3)[C:6](=[O:20])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([N-]C)[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.[CH2:35]([N:37](CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:21]([CH3:24])[O:22][N:23]=3)[C:6](=[O:20])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:35][NH:37][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=4)[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCN(CC)CC
Reactant: C[N-][C@@H]1CCC[C@H](n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](CNC(=O)c3cccnc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R, 3S) 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl methyl amide (700 mg, 2.0 mmol) in 35 mL of dichloromethane was added 440 mg (2.4 mmol) of nicotinoyl chloride hydrochloride, 0.85 mL (6.0 mmol) of triethylamine and 5 mg of 4-dimethylaminopyridine. The reaction mixture was stirred overnight at ambient temperature, then washed with 1 N hydrochloric acid. The aqueous layer was extracted with 20% isopropanol/chloroform. The combined organics were washed with saturated sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was chromatographed on silica gel using methanol/chloroform as eluent to yield 740 mg (82%) of the desired isomer as a white solid. MS (ion spray) 451.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:63])([F:62])[C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:52][NH:51][CH2:50][CH:49]([NH:53][C:54](=[O:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:48]2)=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:55]1([C:54]([NH:53][CH:49]2[CH2:48][CH:47]([C:44]3[CH:43]=[CH:42][C:41]([C:40]([F:63])([F:39])[F:62])=[CH:46][CH:45]=3)[CH2:52][N:51]([C:12]([C:9]3([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]3)=[O:14])[CH2:50]2)=[O:61])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
125 mg (0.62 mmol) of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid together with 295 mg (0.78 mmol) of HATU and 127 mg (1.03 mmol) of 4-dimethylaminopyridine were initially charged in 8 ml of DMF, and 180 mg (0.52 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 179 mg (65% of theory)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[O:25]=[C:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCCC2=O)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)c1n[nH]c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 50 mg 1H-Indazole-3-carboxylic acid in 2 mL DCM and 0.2 mL NEt3, 108 mg 1-(4-Amino-phenyl)-pyrrolidin-2-one and 79 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CO[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:18])[CH:12]=4)[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(I)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cccc(N3C(=O)[C@@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 85 starting from 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O2: 471, observed (M+H)+: 472.2 1H NMR (400 MHz, MeOD-d4) δppm 2.22-2.35 (m, 2 H) 2.98 (s, 3 H) 3.35-3.39 (m, 1 H) 6.17 (d, J=7.58 Hz, 1 H) 6.83 (t, J=7.58 Hz, 1 H) 6.96 (d, J=8.08 Hz, 1 H) 7.13-7.21 (m, 1 H) 7.27-7.33 (m, 2 H) 7.34-7.40 (m, 2 H) 7.60-7.65 (m, 1 H) 7.68-7.80 (m, 3 H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:18]=[N:17][C:6]2[NH:7][C:8](=[O:16])[CH2:9][N:10]([CH2:12][C:13]([OH:15])=O)[CH2:11][C:5]=2[CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Br:2][C:3]1[CH:18]=[N:17][C:6]2[NH:7][C:8](=[O:16])[CH2:9][N:10]([CH2:12][C:13]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:15])[CH2:11][C:5]=2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CN1CC(=O)Nc2ncc(Br)cc2C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A suspension of (7-bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid hydrochloride (1.66 g, 4.45 mmol) in CH2Cl2 (50 mL) was treated sequentially with (i-Pr)2EtN (3.1 mL, 18 mmol), N-methyl piperazine (0.54 mL, 4.87 mmol), HOBt (0.66 g, 4.88 mmol), and EDC (0.95 g, 4.96 mmol). After stirring overnight, the mixture was diluted with CH2Cl2 (100 mL) and then washed with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 95:5) gave the title compound (1.42 g, 83%) as an off-white solid: MS (ESI) m/e 382 (M+H)+.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@@H:41]1[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@@H:41]3[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]3)=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: COC(=O)[C@H]1CC[C@@H](N)C1
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@@H]2CC[C@H](C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 5 from 2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and methyl (1S,3R)-3-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1.[O:20]=[C:21]1[NH:25][CH2:24][CH2:23][N:22]1[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29]([O-:31])=[O:30]>>[F:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[F:18])[CH2:11][N:25]1[CH2:24][CH2:23][N:22]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=2)[C:29]([O:31][CH3:2])=[O:30])[C:21]1=[O:20]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: Fc1ccc(CBr)cc1F
Product: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Yield: 66 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with 4-(bromomethyl)-1,2-difluorobenzene to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 66% yield: 1H NMR (300 MHz, CDCl3) δ 8.86-8.85 (m, 1H), 8.37 (dd, J=5.1, 0.6 Hz, 1H), 7.47-7.45 (m, 1H), 7.16-7.01 (m, 3H), 4.43 (s, 2H), 4.05 (t, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.38 (t, J=8.0 Hz, 2H); MS (ES+) m/z 348.0 (M+1).
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[Cl-].[C-:31]#[N:32].[K+]>C(Cl)(Cl)(Cl)Cl.O>[C:31]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:32]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octlymethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>COCCOC>[CH:1]1([C:4]2[NH:12][C:7]3=[N+:8]([O-:18])[CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]c(C3CC3)cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: [O-][n+]1cccc2cc(C3CC3)[nH]c21
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a stirred solution of 2-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (7.6 g) in DME (100 ml) was added a solution of m-chloroperoxybenzoic acid (17.9 g) in DME (50 ml), under an atmosphere of nitrogen, keeping the temperature between 20 and 25° C. The resulting suspension was stirred at 20° C. for 45 min and then sodium metabisulphite solution (20 ml, 40%) was added. The mixture was concentrated in vacuo to ˜80 ml. Water (100 ml) was added and the mixture basified by the addition of aqueous potassium carbonate solution. The suspension was stirred for 14 h and then the precipitate was collected by filtration, washed with water and dried to give the title compound (4.1 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>O1CCOCC1>[Cl:17][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:21][CH2:18][CH2:19][CH3:20])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCCN
Reactant: O=C(Nc1cccnc1Cl)c1cccnc1Cl
Solvent: C1COCCO1
Product: CCCNc1ncccc1C(=O)Nc1cccnc1Cl
Temperature: 150 °C
Reaction time: 6 h

Procedure:
26.8 g (0.1 mol) of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide were dissolved in 200 ml of dioxane, and the resulting solution was admixed with 21.4 g (0.362 mol) of propylamine. Thereafter, the mixture was shaken in a stainless steel pressure vessel at 150° C. for 6 hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel, successively using dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/cyclohexane/ethyl acetate 1/2/1 (v/v/v) as eluents. The product obtained by evaporation was a highly viscous resin that had a satisfactory quality for the following reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N:15]=1.C(Cl)(Cl)Cl>CS(C)=O.CCCCCC>[Cl:21][C:18]1[CH:17]=[C:16]([CH3:22])[N:15]=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:19]=1[CH3:20]
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,4,6-trimethylphenol (405 mg, 3.31 mmol) in 2 ml of DMSO was treated with NaH (60% in oil, 180 mg, 4.5 mmol). After 5 min, 2,4-Dichloro-3,6-dimethyl-pyridine (528 mg, 3 mmol) was added. The mixture was heated in the oil bath of 130° C. for 6 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give 812.5 mg of crude material with two regioisomers. After silica gel column chromatography using 1:1 of CHCl3:hexane as eluent, the title compound was isolated as white crystals (141 mg), mp 57-62° C.; high MS for C16H18ClNO: calc, 275.1072, found 275.70172; IR(KBr) 2951, 2920, 1592, 1564 cm−1; 1H NMR (CDCl3) δ 6.87 (s, 2H), 6.77 (s, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 2.03 (s, 6H) ppm. The regiochemistry was determined by X-ray structural analysis of the undesired regioisomer, 2-chloro-3,6-dimethyl-4-(2,4,6-trimethyl-phenyoxy)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)CCc2ccc(Cl)cc2)cc1
Yield: 77 %

Procedure:
from 2-(4-chlorophenyl)-ethanesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate; colorless oil; yield 77% of theory, and from this, by hydrolysis:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCC4=O)cc3F)CC2)c(C)c1
Yield: 70.3 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and pyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (142 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:17])[CH:4]=1)=[O:2].[Si]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(C(C)(C)C)(C)C>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][C:5]=2[CH3:17])=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: Cc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Product: Cc1cc(C=O)ccc1-c1ccc(O)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 4-formyl-2-methyl-phenyl ester (9.3 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (2.35 g, 9.3 mmol) according to Method B to yield 1.12 mg (57%, over two steps) of yellowish solid: mp 94-96° C.; 1H NMR (DMSO-d6): ): δ 2.33 (3H, s), 6.86 (2H, d, J=8.55 Hz), 7.22 (2H, d, J=8.51 Hz), 7.39 (1H, d, J=7.81 Hz), 7.61 (1H, d, J=7.82 Hz), 7.81 (1H, s), 9.65 (1H, s), 10.00 (1H, s); IR 1670 cm−1; MS (ESI) m/z 211 (M−H)−, 213 (M+H)+.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:37])[F:36])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Reaction time: 18 h
Yield: 89.5 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.012 mL, 0.17 mmol) was added to a solution of 2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (13) (27 mg, 0.056 mmol) in MeOH (2 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 15 minutes at room temperature before sodium triacetoxyborohydride (47 mg, 0.22 mmol) was added in one portion and stirring was continued at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) then dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 14 as a white solid (25 mg, 90%); 1H NMR (400 MHz, d4-MeOH) δ 8.77 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 8.18 (dd, J=8.6, 2.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.21-7.15 (m, 3H), 3.67 (s, 2H), 3.20-3.14 (m, 2H), 3.14-3.08 (m, 2H), 3.04 (d, J=11.7 Hz, 2H), 2.71 (tt, J=11.9, 3.9 Hz, 1H), 2.35 (s, 3H), 2.21 (td, J=12.0, 2.5 Hz, 2H), 1.96 (d, J=11.0 Hz, 2H), 1.92-1.80 (m, 2H). LCMS-A: rt 4.635 min; m/z 499 [M+H]+.