Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[C:5]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(O)C(Nc1ccccc1)c1cc2ccccc2s1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A mixture of 2-(benzo[b]thiophen-2-yl)-2-(phenylamino)acetic acid (I30) (796 mg, 2.81 mmol), (R)-quinuclidin-3-ol (429 mg, 3.37 mmol), HOBT (516 mg, 3.37 mmol), and DCC (696 mg, 3.37 mmol) in THF (30 ml) was stirred at r.t. overnight. THF was evaporated, and the crude product was partitioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-2-yl)-2-(phenylamino)acetate (361 mg, 32.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5](C(OC)=O)=[C:4]([O:12][CH:13]([CH3:18])[C:14]([O:16]C)=O)[CH:3]=1.[H-].[Na+].[Cl-].[NH4+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:14](=[O:16])[CH:13]([CH3:18])[O:12][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1Oc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A mixture of the compound of Example 7, Step A, (6.7 g) and sodium hydride (60% in oil, 1.5 g) was heated to reflux in tetrahydrofuran (50 ml). It Was then allowed to cool to room temperature over 1.5 hrs. The cooled mixture was treated with aqueous ammonium chloride solution and ether. The ether solution was dried over magnesium sulfate and then evaporated. The oil was subjected to chromatography on silica gel with hexanes/ethyl acetate (25:1) as the eluent. The desired product (1.99 g) was obtained as a low melting solid. NMR: 7.6 (d, 1H), 7.1 (m 2H), 4.7 (q, 1H), 1.55 (d, 3H).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)[CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl>C(O)C>[N:21]1([C:17]2[CH:16]=[C:15]([N:12]3[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]3)[CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc(-n3ccnn3)c2)CC1
Agent: Cl
Solvent: CCO
Product: OC1CCN(c2cccc(-n3ccnn3)c2)CC1
Reaction time: 6 h

Procedure:
To an ethanol (18 mL) solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-(1H-1,2,3-triazol-1-yl)phenyl]piperidine (1.83 g, 5.12 mmol) was added concentrated hydrochloric acid (1030 μL, 12.5 mmol). After 6 hours, the reaction mixture was quenched with saturated aqueous sodium hydrogencarbonate solution (30 mL) and charged with ethyl acetate (30 mL). The reaction mixture was stirred vigorously for 10 minutes. The aqueous layer was extracted with more ethyl acetate (2×30 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.83 (s, 1H), 7.37 (s, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.97-3.87 (m, 1H), 3.66 (dt, J=12.7, 4.7 Hz, 2H), 3.05 (ddd, J=12.7, 9.7, 3.1 Hz, 2H), 2.07-1.98 (m, 2H), 1.75-1.66 (m, 2H); LC-MS: m/z 245.2 (M+H).
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH2:22])[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4].CC(C)([O-])C.[Na+].Br[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.[Na].Cl>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC>[ClH:1].[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH:22][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=2)[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4]
Reactant: Cc1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 85 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
A mixture of (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride (for a preparation see intermediate 61) (250 mg, 0.700 mmol), sodium tert-butoxide (336 mg, 3.50 mmol), 2-bromo-5-methylpyridine (132 mg, 0.770 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (55.0 mg, 0.140 mmol) and tris(dibenzylideneacetone)dipalladium(0) (64.1 mg, 0.070 mmol) was stirred in toluene (12 mL) at 75° C. under nitrogen for 5 h. An extra portion of sodium tert-butoxyde (81 mg, 0.84 mmol), Davephos (55.0 mg, 0.140 mmol) and tris(dibenzylideneacetone)dipalladium(0) (64.1 mg, 0.070 mmol) was added after having cooled the mixture down and the resulting mixture was stirred at 85° C. for 60 h under nitrogen, then cooled to room temperature and filtered through celite. The insoluble material was rinsed with DCM, stirred in 5% MeOH in DCM (100 mL) then filtered off. The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 20 G silica cartridge (gradient:0 to 3% MeOH in DCM) gave a residue which was dissolved in AcOEt. The resulting solution was treated with HCl (1.0M in Et2O, 3 mL) then concentrated in vacuo. Trituration of the residue with Et2O gave (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (143 mg, 0.347 mmol, 50%) as an off white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([C@@H:30]1[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[C@H:32]([C:48]([C:50]2[N:51]=[CH:52][N:53]3[CH:57]=[C:56]([Sn](CCCC)(CCCC)CCCC)[S:55][C:54]=23)=[O:49])[CH2:31]1)=[N+:28]=[N-:29]>>[N:27]([C@@H:30]1[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[C@H:32]([C:48]([C:50]2[N:51]=[CH:52][N:53]3[CH:57]=[C:56]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:55][C:54]=23)=[O:49])[CH2:31]1)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@H](N=[N+]=[N-])CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@H](N=[N+]=[N-])CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12

Procedure:
A crude compound (261 mg) of 4-nitrobenzyl (1S,5R,6S)-2-[7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared in the same manner as in Example, except that 157 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 321 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:13]([CH3:12])[CH:14]=1)=[O:9]
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: Cc1cc(C)cc(NC(=O)c2cc(Br)ccc2O)c1
Yield: 58.1 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dimethylaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH:11]=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C=O.[CH2:15](NCCCC)CCC.C(O)(=O)CCCCC>>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:8])([OH:9])[CH3:7])[C:10](=[CH2:15])[CH:11]=[O:12]
Reactant: CCCCNCCCC
Reactant: CC(CC=O)CCCC(C)(C)O
Agent: C=O
Solvent: CCCCCC(=O)O
Product: C=C(C=O)C(C)CCCC(C)(C)O
Temperature: 95 °C
Yield: 1341.5 %

Procedure:
A 3 L four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 1032 g (6.0 mol) of hydroxycitronellal, 520 g (6.4 mol) of a 37% by mass formaldehyde aqueous solution, 53 g (0.41 mol) of dibutyl amine and 10 g (0.09 mol) of hexanoic acid, and the contents in the flask were stirred while heating at 95° C. After the elapse of 40 min, it was confirmed that no hydroxycitronellal was present in the raw mixture, and then the mixture was cooled and separated into two layers. The thus separated organic layer was subjected to distillation treatment, thereby obtaining 1058 g (5.5 mol) of 3,7-dimethyl-2-methylene-7-hydroxyoctanal (purity as measured by gas chromatography: 95%) (yield based on theoretical amount: 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[F:12][C:11]([F:14])([F:13])[S:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1cccc(Br)c1)C(F)(F)F
Product: O=S(=O)(c1cccc(N2CCNCC2)c1)C(F)(F)F

Procedure:
Beginning with 3-bromo-trifluoromethanesulfonyl-benzene and piperazine, the titled cmp was recovered by the procedure described in Preparation 17. MS m/z (rel. intensity, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104 (10), 56 (15). (45).
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:49]1[C:57]2[C:52](=[N:53][CH:54]=[CH:55][CH:56]=2)[N:51]([CH2:58][CH2:59]O)[CH:50]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:4]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][N:31]([CH2:59][CH2:58][N:51]3[C:52]4=[N:53][CH:54]=[CH:55][CH:56]=[C:57]4[N:49]=[CH:50]3)[S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:33])=[O:34])([CH3:10])[CH3:11])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: OCCn1cnc2cccnc21
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCn2cnc3cccnc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reaction time: 2 h
Yield: 299.4 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-2,4-dinitrobenzenesulfonamide (0.415 g in 6 mL benzene) was added 0.20 g 2-imidazo[4,5-b]pyridin-3-yl-ethanol followed by 0.32 g triphenylphosphine and 0.189 mL of diethyl azodicarboxylate added dropwise. After 2 hours, the mixture was concentrated and the crude reaction product purified by flash chromatography on silica gel (methylene chloride:methanol, 98:2; then 95:5) to give the title compound (1.51 g).
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)[CH:9]=2)=[CH:5][CH:4]=1.O>Br.C(O)(=O)C>[C:10]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:24][CH:23]=2)[CH:9]=1
Reactant: COc1ccc(Oc2cccc(Oc3ccc(OC)cc3)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Oc2cccc(Oc3ccc(O)cc3)c2)cc1
Yield: 102.1 %

Procedure:
22 g of the above-described compound from Example 20 are dissolved, under argon, in a mixture of 60 ml of hydrobromic acid (48% solution) and 150 ml of hydrogen bromide in glacial acetic acid (33% solution), and the mixture is heated, adjusted to the evolution of gas, at reflux. After a total of 5 hours, 300 ml of water are added dropwise, with cooling. The batch is extracted several times with a total of 400 ml of diethyl ether. The combined organic phases are washed four times using 400 ml of water each time, dried over magnesium sulfate and filtered. The solvent is removed in vacuo. 20.5 g of a crystalline solid are obtained, which was purified over a column with silica gel (0.063-0.20 mm) (eluant: n-hexane/ethyl acetate 3:1). The solvent is removed and the product is dried in vacuo. 15.8 g of a beige solid are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH:13]([CH:16]([CH3:18])[CH3:17])[NH:12]1)[CH2:8]2.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:12]1[CH:13]([CH:16]([CH3:18])[CH3:17])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)=[O:23]
Reactant: CC(C)C1NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)N1C(C(C)C)C(=O)N1C1C2CC3CC(C2)CC1C3

Procedure:
2-(Adamantan-2-yl)-4-(propan-2-yl)-1,2-diazetidin-3-one prepared in Process 3 of Example 10 and 2-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [I:1][C:2]1[S:3][C:4]([C:7]2[S:8][C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][CH:11]=2)=[CH:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>CO>[I:1][C:2]1[S:3][C:4]([C:7]2[S:8][C:9]([C:12]3[S:13][C:14]([Br:17])=[CH:15][CH:16]=3)=[CH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Ic1ccc(-c2ccc(-c3cccs3)s2)s1
Solvent: CO
Product: Brc1ccc(-c2ccc(-c3ccc(I)s3)s2)s1
Reaction time: 12 h
Yield: 95 %

Procedure:
100 mg (0.27 mmol) of 2-iodo(5,2′:5′,2″-terthiophene) (1) obtained above in the first step of example 1 were diluted in 100 ml of methanol at 0° C. 2 equivalents of N-bromosuccinimide (NBS, 95 mg, 0.53 mmol) were then added. The mixture was left stirring, in the dark for 12 h. The solvent was then evaporated under reduced pressure. The crude product of the reaction was then purified by column chromatography using, as eluent, petroleum ether then a petroleum ether/dichloromethane (5/1: v/v) mixture. The expected product was isolated in the form of a yellow powder (115 mg; yield=95%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>[Pd].CCCCCC>[F:21][C:19]([F:20])([F:22])[S:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)Sc1ccc(C#Cc2ccc(SC(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CCCCCC
Product: FC(F)(F)Sc1ccc(CCc2ccc(SC(F)(F)F)cc2)cc1
Yield: 103.6 %

Procedure:
1,2-bis(4-trifluoromethylthiophenyl)acetylene (200 mg, 0.53 mmol) was hydrogenated over 10% palladium on carbon (20 mg) in hexane (30 mL) at rt for 2 hours. The reaction was filtered and the filtrate was concentrated to give 0.21 g (100%) of 1,2-bis(4-trifluoromethylthiophenyl)ethane. 1HNMR (360 MHz, DMSO-d6) δ 7.61 (d, J=8.3 Hz, 4H), 7.40 (d, J=8.3 Hz, 4H), 2.97 (s, 4H, CH2CH2). MS-EI m/z 382 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2ccccc2)CC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichloro-phenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and benzoyl chloride (0.038 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-benzoylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (103 mg, 80%) as a white solid, mp 63-66° C. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.94 min, m/z 471.32 (65), 469.31 (M++H, 100). HPLC tr=2.35 min (98.01%) 1H NMR (270 MHz, CDCl3) δ 1.35 (2H, m, CH2), 1.55 (2H, m, CH2), 1.76 (6H, m, 3CH2), 2.00 (2H, m, CH2), 2.87 (2H, m, CH2), 3.17 (1H, m, ½CH2), 3.87 (1H, br t, ½CH2), 4.19 (1H, m, CH), 4.43 (1H, m, ½CH2) 6.79 (1H, d, J=8.6 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.25 (1H, m ArH), 7.35 (1H, br d, NH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 23.81, 29.36, 32.26, 33.17 (CH2), 39.60 (CH), 40.78 (CH2), 43.70 (CH), 47.79 (CH2), 118.00, 120.65, 124.43, 124.88, 126.21, 128.57, 130.85, 130.87, 132.74, 133.06, 148.97, 153.09 (ArC), 163.63 and 174.71 (C═O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:15][P:16]([OH:31])([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:15][P:16]([OH:31])([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)C(Cc1ccc(-c2ccccc2)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1
Yield: 97.6 %

Procedure:
The process is performed according to the operating conditions in 5.4., starting with 1.7 g (3.32 mmol) of ethyl 3-(4-bromophenyl)-2-[[hydroxy[1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]methyl]propanoate and 4.05 g (3.32 mmol) of phenylboronic acid. 1.65 g of product are recovered (yield=97.6%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:46])([F:44])[F:45])[N:33]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:32]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: N#Cc1ccc([C@@H](CC(=O)O)c2ccc(F)c(F)c2)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@H](c2ccc(C#N)cc2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (50 mg, 0.16 mmol) and the product from step 4 of Example 89 (78 mg, 0.16 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.02 mL, 0.18 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=650.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(CC)CC.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([C:9]([OH:11])=[O:10])=[C:6]([NH:20][C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2nc(Cl)nc(Cl)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine-5-carboxylic acid (5.69 g, 25.02 mmol) in DMF (60 mL) was added Et3N (8 mL, 57.4 mmol) and m-toluidine (3.2 mL, 29.5 mmol) at 0° C. The mixture was stirred at RT for 12 h. To the mixture was added 1N HCl. The mixture was extracted with EtOAc. The organic layers were basified with saturated aq NaHCO3 and the aqueous layers were washed with EtOAc. The washed aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were washed with 1N HCl, water, and brine, were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure, triturated with hexane, and filtered to give a first batch of the title compound (4.36 g). The filtrate was concentrated, triturated with hexane, and filtered to give a second batch (0.36 g) of the title compound (total 4.72 g, 63%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 7.00-7.02 (m, 1H), 7.25-7.28 (m, 2H), 7.33-7.35 (m, 2H), 10.13 (s, 1H), 1H not detected. [M+H] calc'd for C12H10Cl2N3O2, 298. found, 298.