Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:6]2[CH:5]=[C:4]([C:11]([OH:13])=O)[N:3]=1.C1(P([Cl:28])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[NH2:31][C@@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1.[OH-].[Na+]>C1COCC1>[ClH:28].[N:34]12[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35]1)[C@@H:32]([NH:31][C:11]([C:4]1[N:3]=[CH:2][N:7]3[CH:8]=[CH:9][CH:10]=[C:6]3[CH:5]=1)=[O:13])[CH2:33]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cccn2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccn2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid hydrochloride (0.33 g, 1.66 mmol) and TEA (2.0 mL, 14.35 mmol) are dissolved in 15 mL THF. Diphenylphosphinic chloride (0.47 g, 1.99 mmol) is added dropwise. After 1 h, (R)-(+)-3-aminoquinuclidine dihydrochloride is added and the reaction is allowed to stir at RT. After 1 day, 1N NaOH is added and the mixture is extracted with CHCl3. The combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH) to afford 0.45 g (100%) of product. The hydrochloride salt is prepared and recrystallized from CH3CN/Et2O.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=[O:14].[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].Br([O-])(=O)=O.[Ba+2].Br([O-])(=O)=O>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:14])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCc1cccc(C(C)(C)C)c1
Agent: [Ba+2]
Agent: [Ce+3]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cccc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirring solution of 1-tert-butyl-3-ethylbenzene (11.15) in acetonitrile (350 ml) and water (150 ml) at room temperature was added cerium (III) sulfate (6.05 g) and barium bromate (13.5 g). The resulting suspension was heated at reflux for 16 hrs. After cooling to room temperature, the reaction mixture was filtered. Saturated aqueous sodium thiosulphate solution was added to the filtrate, and the product was extracted into DCM (3×100 ml). Combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-tert-butyl-phenyl)-ethanone as a yellow oil crude product (13.5 g). 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.39 (t, 1H), 2.61 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24]Br)=[CH:22][C:17]=2[O:16][CH2:15]1.O>CC(C)=O.C(OCC)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CSCC(=O)c1ccc2c(c1)OCO2

Procedure:
Ethyl 2-mercaptoacetate (9.68 mL, 88.3 mmol) was added dropwise to a suspension of K2CO3 (12.2 g, 88.3 mmol) and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (21.4 g, 88.3 mmol) in dry acetone (100 mL). The mixture was stirred at reflux for seven hours, cooled at an icebath and added 200 mL water. Diethyl ether (400 mL) was added and the phases were separated. The aqueous layer was extracted with diethyl ether (200 mL) and the combined organic layers were washed with brine (200 mL), dried (MgSO4) and concentrated. This afforded the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:4]1.C(N(CC)C(C)C)(C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].CCOC(C)=O>CN(C=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[S:12][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]=1[S:7]([N:5]1[CH2:6][CH:3]([CH2:2][NH:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:4]1)(=[O:8])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: NCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a stirring mixture of Example 2 (200 mg, 0.39 mmol) and N,N-diisopropyl-ethylamine (68 μL, 42 mmol) in DMF (5 mL) was added ethyl bromoacetate (43 μL, 0.39 mmol) and the mixture allowed to stir for 18 hours. After this time EtOAc (25 mL) was added to the reaction mixture which was then washed with brine (3×25 mL), dried (sodium sulfate) and then reduced in vacuo. The resulting oil was purified by column chromatography (SiO2, 50% DCM in EtOAc) to afford the title compound as a white solid (47 mg, 20%). LCMS (pH 3) RT 2.24 minutes, (ES+) 605 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.COCCOC.O>[Cl:27][C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Clc1ccncc1Br
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Fc1ccc(-n2ncc3c(-c4cnccc4Cl)ccnc32)cc1
Temperature: 105 °C
Yield: 11.3 %

Procedure:
Example 10 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 2 h, and using the following materials: Intermediate 5A (40 mg, 0.156 mmol), 3-bromo-4-chloropyridine (53.6 mg, 0.279 mmol), sodium carbonate (61.3 mg, 0.578 mmol), degassed EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.022 mmol). Example 10 was isolated as an off-white solid (5.7 mg, 11%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 35% Solvent B to 100% Solvent B over 12 min, ret. T=11.8 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.78-8.86 (2 H, m), 8.74 (1 H, d, J=5.19 Hz), 8.37 (1 H, s), 8.26-8.34 (2 H, m), 7.86 (1 H, d, J=5.19 Hz), 7.43-7.55 (3 H, m). LC/MS (Condition B): ret. T=3.8 min, (M+H)+ 325.00, 326.98. Analytical HPLC: (Condition A): >98%, ret. T=24.69 min, (Condition B): >98%, ret. T=24.45 min, (Condition C): >98%, ret. T=18.88 min, (Condition D): >98%, ret. T=15.00 min.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>CC(N(C)C)=O.[Zn].[Cu]I>[Cl:24][C:25]1[C:30]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: Clc1nccnc1Cl
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a suspension of activated zinc dust (84.4 g, 1.29 mol, 1.94 eq.) in anhydrous DMA (270 mL) was added 1,2-dibromoethane (9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period of 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (329 g, 1.06 mol, 1.59 eq.) in anhydrous DMA (670 mL) was added to the above suspension over a period of 45 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour while cooling back to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2,3-dichloropyrazine (99 g, 0.664 mol, 1 eq.), PdCl2(dppf)CH2Cl2 (16.3 g, 19.9 mmol, 0.03 eq.) and CuI (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the remaining zinc dust and added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight (19 hours). The mixture was cooled to room temperature and diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase was extracted with ethyl acetate (4 L) and organic extracts were combined, washed with brine (1 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 6:1) to give 92 g of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.C([Li])CCC.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>>[CH:1]([C:4]1[CH:5]=[C:6]([O:12][CH3:13])[C:7]([O:10][CH3:11])=[CH:8][C:9]=1[C:30]([N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[O:31])([CH3:3])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(C(C)C)cc1OC
Agent: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1cc(OC)c(OC)cc1C(C)C

Procedure:
Thirty-one grams of 4-isopropyl-1,2-dimethoxybenzene was treated with N-bromosuccinimide followed by butyllithium and diethyl carbamyl chloride as in preparation 6B to yield 15.2 g of 2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide as a viscous oil. The benzamide was treated according to preparation 18B with butyllithium and sulfur dioxide followed by sulfuryl chloride then ammonia to provide 4.5 g of the sulfonamide, mp 181°-182° C. from ether. This was cyclized in acetic acid as in preparation 18B to obtain 2.86 g of 6,7-dimethoxy-4-isopropylsaccharin, mp 210°-212° C. from ethyl acetate-hexane.
Reaction SMILES: ClC1C=CC(C([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)CCO)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)O)=[C:28]([F:41])[CH:27]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)=[C:28]([F:41])[CH:27]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 9 and 652 mg (2.56 mmol) of the compound from Example 85A in analogy to the synthesis of the compound from Example 101. 197 mg (18% of theory) of the target compound were obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3].N1C=CC=CC=1.[CH3:32][Si:33]([CH3:36])([CH3:35])Cl.O>C1(C)C=CC=CC=1>[CH3:32][Si:33]([CH3:36])([CH3:35])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O)[C@H]1[C@@H](C)C(=S)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]1[C@@H](C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (5.04 g: 13.35 mmole) in toluene (40 ml) under ice cooling, pyridine (1.51 ml: 18.69 mmole) is added and trimethylchlorosilane (2.26 ml: 17.36 mmole) is added dropwise. The mixture is stirred at room temperature for 1.5 hours. Water (80 ml) is added to the reaction mixture, and aqueous layer is extracted with toluene. The extract and the organic layer are combined, washed with water (2 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give crude (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (5.614 g) as oily residue. Yield: 94%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[SH2:9].[CH:10](Cl)(Cl)Cl>>[SH:9][C:10]1[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[N:7][N:8]=1
Reactant: ClC(Cl)Cl
Reactant: NNc1ccccn1
Reactant: S
Product: Sc1nnc2ccccn12
Yield: 88 %

Procedure:
5 g of 2-pyridylhydrazine (prepared by heating 2-chloropyridine with 85% hydrazine hydrate at 125° C. for 24 hours) is added to 12 ml of carbon disulfied in 40 ml of chloroform. A precipitate is formed, and the mixture is refluxed on a steam bath for twenty hours, with the evolution of hydrogen sulfide. The crystalline material is isolated given 6.1 g (88% yield) of title compound which has a m.p. of 209°-210° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH3:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N+:15]=1[O-]>C(Cl)Cl>[Cl:3][CH2:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1c(C)c(C)[n+]([O-])c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)c(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A solution of 1.38 g (9.04 mmols) of phosphorus oxychloride in 5 ml of methylene chloride and a solution of 913 mg (9.04 mmols) of triethylamine in 5 ml of methylene chloride were, respectively, dropped almost simultaneously in 15 minutes into a solution of 1.85 g (8.00 mmols) of the crude product of 2, 3-dimethyl-4-acetoxyquinoline oxide in 5 ml of methylene chloride, followed by stirring at room temperature for 10 minutes. The reaction solution was washed with a saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, followed by purification by silica gel column chromatography (Wako (solvent: n-hexane : ethyl acetate=5:1) to obtain 700 mg (yield 36%) of 2-chloromethyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2Cc3ccccc3C2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2Cc3ccccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 16a) (91 mg, 0.19 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (82 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CN(C1C=CC=CN=1)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(CCO)cc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g of 2-(4-cyanophenyl)ethanol are introduced into 50 ml of dimethylforamide. 2.54 g of imidazole, 5,63 g of tert-butyldimethylsilyl chloride and a spatula tip-ful of dimethylaminopyridine are added. The reaction medium is left for 2 hours at room temperature and is then added to an ice-water mixture. The mixture is extracted with ethyl acetate and the extracts dried over anhydrous sodium sulphate. The product is purified by chromatography on a column of silica gel, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give 1-cyano-4-(tert -butyldimethylsilyloxyethyl)benzene.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[CH:3]1([CH2:2][N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC2CCC2)CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
Bromomethylcyclobutane (0.200 g, 1.34 mmol, 1 eq) was suspended in DCM (2 mL). DIPEA (0.59 mL, 3.35 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (0.550 g, 2.95 mmol, 2.2. eq), and the reaction mixture was stirred at 35° C. for 2 h. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (0.030 g, 8.8%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 1.64-1.74 (m, 2H), 1.76-1.96 (m, 2H), 2.02-2.12 (m, 2H), 2.37 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.43 (d, J=7.0 Hz, 2H, NCH2), 2.55 (m, 1H, cyclobutyl CH), 3.43 (t, J=5.0 Hz, 4H, piperazine N(CH2)2); GC-MS (Cl, m/z): Rt=3.77 min—255 [(M+H)+, 100%].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].O1CCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]([C:22](=[O:23])[CH2:21][Cl:20])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1ccc(N(C(=O)CCl)c2c(F)c(F)cc(F)c2F)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylanilin (2.05 g) and chloro acetylchloride (1.99 g) is mixed without solvent and heated with stirring to 90° C. under nitrogen for 20 h. Tetrahydrofurane (10 ml) and aqueous sodium bicarbonate are added after cooling and stirring is continued for about 1 hour. The organic phase is diluted with toluene and washed with water three times and dried over magnesium sulfate. Evaporation and chromatography of the residue (silica, toluene) gave N-(2′,3′,5′,6′-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline (1.84 g) as a solid which is recrystallised from heptane, mp.: 72° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[S:27][C:17]=2[N:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Br:24][C:25]1[CH:26]=[C:27]([C:32]([OH:34])=O)[NH:28][C:29]=1[CH2:30][CH3:31].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=2)[C:46]([NH2:48])=[O:47])[CH2:39][CH2:38]1>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([C:32]([NH:36][CH:37]2[CH2:38][CH2:39][N:40]([C:43]3[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=3)[C:46]([NH2:48])=[O:47])[CH2:41][CH2:42]2)=[O:34])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: CCc1[nH]c(C(=O)O)cc1Br
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Br
Reaction time: 8 h

Procedure:
Diisopropylethylamine (0.28 ml, 1.64 mmol), EDC (0.088 g, 0.46 mmol) and HOAT (0.063 g, 0.46 mmol) were added to a stirred solution of 4-bromo-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 10, 0.1 g, 0.46 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.14 g, 0.55 mmol) in 3 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[C:15]([CH:28]=2)[O:16][CH2:17][CH:18]([O:24]C(=O)C)[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH4+].[OH-]>CO>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:32])([F:33])[F:31])=[C:15]([O:16][CH2:17][C@@H:18]([OH:24])[N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:28]=1)=[O:9]
Reactant: CC(=O)OC(COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F)N1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H](O)N2CCCC2)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid 2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethyl ester (408 mg) was dissolved in MeOH (15 ml) and NH4OH (6 ml) was added and the mixture was stirred at RT for 6 h. The reaction was concentrated in vacuo and dried under high vacuum. The residue was purified over silica gel column (8:92:0.6 MeOH: CH2Cl2:NH4OH). The purified fractions were concentrated in vacuo and dried again to provide (R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide as a white foam.