Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>C1C=CC=CC=1.CCCCC>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:27])=[CH:23][CH:24]=1
Reactant: CCCCCCC(=N)N
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCCCC
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 300 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 21.9 g. 4-(trifluoromethoxy)phenyl isothiocyanate [b.p. 88° C./7 mm.; prepared from 4-(trifluoromethoxy)aniline] in 120 ml. dry acetone there was obtained 1-[4-(trifluoromethoxy)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 90°-91° C. (from benzene-n-pentane); hydrochloride (25.3 g.), m.p. 171°-172° C. (from acetonitrile).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (520 mg, 4.00 mmol, 1.00 equiv) in methanol (50 mL) was added PTSA (35.0 mg, 0.200 mmol). The resulting mixture was stirred overnight at 80° C. in an oil bath, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with 30 mL of water and extracted with 3×30 mL of DCM. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. This resulted in 500 mg (87%) of methyl tetrahydro-2H-pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH4+].[Cl-].C1C=CC2N(O)N=[N:20]C=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([NH2:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-2-thiophenecarboxylic acid (7.50 g, 43.3 mmol), NH4Cl (6.95 g, 130 mmol), HOBT (8.62 g, 56.3 mmol), and EDC (12.46 g, 65.0 mmol) were combined with DMF (100 mL) and DIEA (15.13 mL, 87.0 mmol). The reaction was stirred at room temperature overnight. The brown solution was concentrated, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. The solid residue was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:6].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].O>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:4]([CH:5]=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)CCC=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of dilsobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step. Alternatively, alkylation with ethyl bromoacetate can be conducted in the presence of toluene-acetonitrile 1/1 (v/v) as solvent. The final aldehyde can also be distilled under reduced pressure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:17]([CH:18]=1)=[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[CH3:33])=[CH:14]2)=[O:9].[C:34]([O-])(=[O:36])C.[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:17]([CH:18]=1)=[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[CH3:33])=[C:14]2[CH:34]=[O:36])=[O:9]
Reactant: COC(=O)c1ccn2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccn2c(C=O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
To phosphorus oxychloride (0.35 ml, 3.82 mmol) cooled at 0° C. under argon, was added dropwise anhydrous DMF (0.34 ml, 4.46 mmol) and the mixture was stirred for 5 min forming a precipitate. 1.5 ml of DMF were added and stirring was continued at 0° C. for 15 min. To this mixture was added dropwise a solution of the compound of step 2 (0.476 g, 1.27 mmol) in 5 ml of DMF, and the mixture was heated at 60° C. for 1.5 h and then stirred at room temperature overnight. A solution of sodium acetate (0.837 g) in 6.5 ml water was added, the mixture was heated at 50° C. for 1 h, and evaporated to dryness under reduced pressure. The residue was dissolved in EA, the solution was washed with a saturated solution of sodium hydrogencarbonate, water and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 90:10) to give 0.297 g of the title compound.
Reaction SMILES: [C:1]([C:3](=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2].[CH2:23]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]1[O:26][CH2:25]1.C>[Cl-].C[N+](C)(C)C.C(Cl)Cl>[CH2:28]([O:27][CH2:23][CH:24]([OH:26])[CH2:25][O:9][CH2:8][CH2:7][O:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:29]=[CH2:30]
Reactant: C=CCOCC1CO1
Reactant: N#CC(C(=O)OCCO)=C(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCOCC(O)COCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
Into a round bottom flask was charged 29 g. (0.1 moles) of 2-hydroxyethyl 2-cyano-3,3-diphenylacrylate, 12.4 g. (0.11 moles) of allyl glycidyl ether and 250 mg. of tetramethylammonium chloride. The flask was stoppered and the mixture was heated at 50° C. for 16 hours. Then cooled mixture was diluted with 50 ml. methylene dichloride, treated with decolonizing charcoal and filtered. The filtrate was evaporated, leaving a pale yellow oil characterized as the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]1[C:21]([O:23][CH:24]([CH2:26][CH3:27])[CH3:25])=[O:22])=[O:5])[CH3:2].C(O)(=O)C.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16][CH2:37][C:36]2[CH:39]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:41]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=2)[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]1[C:21]([O:23][CH:24]([CH2:26][CH3:27])[CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](N)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 3) (500 mg, 1.30 mmol) in anhydrous dichloroethane (30 mL) was added acetic acid (79 mg, 1.30 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (318 mg, 1.30 mmol) and sodium triacetoxyborohydride (418 mg, 1.97 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was then diluted with chloroform and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title compound (approximately 500 mg) which was used directly in Example 5.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])C)[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].C(N(C(C)C)CC)(C)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CC#N>[CH:15]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:9]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([CH3:33])=[CH:28][C:27]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([CH3:33])=[CH:28][C:27]=1[S:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)=[CH:4][N:3]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Product: Cc1cc(S(=O)(=O)Nc2ccc(Sc3ccc(S(=O)(=O)N4CCCCC4)cc3)cn2)c(Cl)cc1Cl

Procedure:
Prepared from 2-amino-5-bromopyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichloro-5-methylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.35 & 8.02 (2×1H, 2×s, A-ring CH's), 7.63, 7.42 & 7.18 (3×1H, d, s & d, J 10 Hz, B-ring CH's) 7.55 & 7.11 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 2.93-2.81 (4H, m, CH2NCH2), 2.34 (3H, s, CH3), 1.60-1.48 (4H, m, CH2CH2CH2CH2CH2), 1.39-1.27 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.77 minutes. LC/MS rt=7.44 minutes, 572/574 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)(=[O:23])=[O:22])[C:5]([C:8]([C:10]2[C:18]3[O:17][C:16](=[O:19])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=2)(=[O:23])=[O:22])[C:5]([CH:8]([OH:9])[C:10]2[C:18]3[O:17][C:16](=[O:19])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc3[nH]c(=O)oc23)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2cccc3[nH]c(=O)oc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[5-chloro-2-(2-oxo-2,3-dihydro-benzooxazole-7-carbonyl) -pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (41 mg) in THF (1 mL) and H2O (0.1 mL) was added NaBH4 (10 mg). The mixture was stirred at room temperature for 1 h, diluted by EtOAc (3 mL) and quenched by saturated aqueous NH4Cl solution (1 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 514.0.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[NH:15][CH:14]=[N:13][CH:12]=1.[H-].[Na+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1ncc(-c2ccc3c(c2)CCCC3)[nH]1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Yield: 50.1 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1H-imidazole (387 mg, 1.95 mmol), NaH (60%, 76 mg, 1.89 mmol), and SEMCl (474 uL, 2.28 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (321 mg, 52%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.92 (t, 2H, J=9.0 Hz), 1.80–1.83 (m, 4H), 2.77–2.81 (m, 4H), 3.51 (t, 2H, J=9.0 Hz), 5.28 (s, 2H), 7.08 (d, 1H, J=9.0 Hz), 7.29 (s, 1H), 7.48 (d, 1H, J=6.0 Hz), 7.54 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)c(C)c1
Yield: 32.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (574 mg) described in Preparation Example 65 and 5,5-dimethyloxazolidin-2-one (265 mg) described in Preparation Example 43, the title compound (203 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[CH2:18]([NH:26][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc(-c2ccc(CNCCc3ccccc3)cn2)c1
Reaction time: 16 h

Procedure:
To a solution of 3-(5-formylpyridin-2-yl)benzamide (40 mg, 0.18 mmol) in MeOH (2.5 mL) was added phenethylamine (27 μL, 0.21 mmol). The mixture was stirred for 16 h before adding sodium borohydride (33 mg, 0.88 mmol). After 16 h water (1 mL) was added and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 5% MeOH:DCM) gave the title compound: RT=2.32 min; m/z (ES+)=332.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:29]2[O:33]C(C)(C)[O:31][C:30]2=O)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:37][OH:38].CC#N>CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@@H:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C@H:29]([OH:33])[C:30]([NH:37][OH:38])=[O:31])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@@H]2OC(C)(C)OC2=O)cc1
Reactant: NO
Solvent: CC#N
Solvent: CC(C)O
Product: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@H](O)C(=O)NO)cc1
Reaction time: 0.75 h
Yield: 66 %

Procedure:
To a solution of (5S)-5-((1R)-4-(4-ethoxyphenyl)-1-{[4-(4-fluorophenyl)-1-piperazinyl]carbonyl}butyl)-2,2-dimethyl-1,3-dioxolan-4-one (120 mg; 0.24 mmol; 1.0 eq.) in iPrOH (1 mL) was added an aq. solution of hydroxylamine (50%, 71 μl; 1.2 mmol; 5.0 eq.) and the reaction mixture was stirred for 45 min. CH3CN (4 mL) was then added and the resulting mixture was purified by chromatography by reverse-phase preparative HPLC (gradient from 25% to 45% of CH3CN containing 0.1% TFA, in water containing 0.1% TFA). The collected fractions were lyophilized to give the title compound (19) as a white solid (75 mg, 66%). 1H NMR (CDCl3, 300 MHz) δ 7.1-6.99 (m, 6H), 6.80 (d, J=8.2 Hz, 2H), 4.26 (m, 1H), 4.06 (m, 1H), 3.96 (t, 2H, J=6.8 Hz), 3.80 (m, 1H), 3.63 (m, 2H), 3.40 (m, 1H), 3.23-3.00 (m, 4H), 2.58 (m, 2H), 1.85-1.52 (m, 4H), 1.38 (t, J=6.9 Hz, 3H). M−(ESI): 472.1; M+(ESI): 474.6. HPLC: Rt: 3.2 min (HPLC purity: 93.7%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][C:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cnc(N)c(Br)c1
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: COCCOC
Solvent: O
Product: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (40.8 mg) was added to a suspension of 3-bromo-5-methylpyridin-2-amine (220 mg), 4-phenoxyphenylboronic acid (327 mg) and sodium carbonate (249 mg) in DME (8 mL) and water (1.5 mL) and the mixture was stirred at 85° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (315 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[NH:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1)=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1Cl
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CO)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 28.1) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 407 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1.[N+]([O-])(O)=O.[CH3:29][CH2:30][O:31]C(C)=O.CCCCCC>C(O)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:30](=[O:31])[CH3:29])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)cc(OC)c1OC

Procedure:
A solution of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine in acetic acid was treated with fuming HNO3 at 0° C. for 15 min. Work-up and preparative TLC (EtOAc:hexane 1:1) gave N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide. HPLC Rt: 5.744 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 6.58 (s, 2H), 5.33 (s, 2H), 3.85 (s, 3H), 3.85 (s, 6H), 2.43 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.5 g (149 mmol) 2,3-dihydro-benzo[1,4]dioxin-6-ylamine and 25 ml (179 mmol) triethylamine in 1 l diethyl ether is added at 12° C. within 10 minutes 20 ml (164 mmol) pivaloyl chloride dissolved in 250 ml diethyl ether. The temperature is kept between 12-16° C. The reaction mixture is stirred at room temperature for 1 hour. Then it is washed with 2× with 300 ml water, 2× with 150 ml 1 N HCl and 2× with brine, dried with Na2SO4 and partially evaporated to a volume of 80 ml. This leads to a suspension. Hexane is added and the solid is filtered to give N-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,2-dimethyl-propionamide.