Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[C:1]1([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:20]([F:19])([F:30])[F:31])=[O:24])[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc(-c2ccc(N3CCNCC3)nn2)cc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccc3)nn2)CC1
Yield: 67 %

Procedure:
Following the procedure as described in Example 5, making variations only as required to use 3-phenyl-6-piperazin-1-ylpyridazine in place of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as an off-white solid in 67% yield (0.312 g). 1H NMR (300 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.73-7.71 (m, 2H), 7.63-7.51 (m, 2H), 7.47-7.39 (m, 3H), 7.34 (d, J=7.3 Hz, 1H), 7.06 (d, J=9.9 Hz, 1H), 4.10-3.67 (m, 6H), 3.35-3.32 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 158.2, 151.7, 135.9, 134.3, 132.4, 129.5, 129.2, 128.9, 127.3, 126.9, 126.1, 114.2, 46.5, 45.2, 44.9, 41.3. MS (ES+) m/z 413.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH:2]=1.[OH-].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1
Reactant: O=C([O-])c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccnc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 267.1 %

Procedure:
A suspension of crude ethyl 6-[3-endo-({[2-methyl-3-methyloxy)phenyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylate (4.72 g, max. 9.55 mmol) and potassium hydroxide (1.07 g, 19.10 mmol) in methanol (90 mL) and water (30 mL) was stirred at 60° C. for 2 hours. After cooling to room temperature, some of the methanol was evaporated, water was added to the resulting mixture, and the pH adjusted to 5 with 1N aqueous hydrochloric acid. The precipitate was filtered, washed with water, and dried to afford 6-[3-endo-({[2-methyl-3-methyloxy)phenyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylic acid (3.14 g, 83% yield over two steps). 1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 6.83 (br s, 1H), 8.64 (d, 1H), 8.24 (d, 1H), 7.91 (dd, 1H), 7.23 (t, 1H), 7.02 (d, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 4.60 (br s, 2H), 3.86 (m, 1H), 3.80 (s, 3H), 2.21 (m, 2H), 2.14 (s, 3H), 2.07 (m, 2H), 1.97 (m, 2H), 1.87 (d, 2H); MS (EI) for C22H25N3O4: 396 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC([N:22]1[CH2:25][C@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]1[C:32](O)=[O:33])=O)(C)(C)C>>[C:26]1([C@H:24]2[CH2:25][NH:22][CH:23]2[C:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C1C(=O)O
Reactant: NC(=O)c1ccc(N)c2cccnc12
Product: NC(=O)c1ccc(NC(=O)C2NC[C@@H]2c2ccccc2)c2cccnc12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 27 by using 5-aminoquinoline-8-carboxamide coupled with (3S)-1-(tert-butoxycarbonyl)-3-phenylazetidine-2-carboxylic acid, followed by de-Boc to afford Example 30. LC-MS (M+H=347, obsd=347).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (E)-4-(4-amino-1H-indazol-1-yl)-4-(4-chlorophenyl)hex-2-enenitrile (130 mg) and NMM (117 mg) in DCM (5 mL) was added MsCl (53 mg), Then the mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=5/1) to afford the title compound as a pale yellow solid. LC/MS m/z=415.2 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1([F:19])[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[C:23]([CH2:22][CH2:21][C:20]([NH:16][C:15]1[CH:17]=[CH:18][N:11]([C@@H:4]2[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C:3]2([F:2])[F:19])[C:12](=[O:13])[N:14]=1)=[O:26])([OH:25])=[O:24]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 105.2 %

Procedure:
Two hundred mg of 2'-deoxy-2',2'-difluorocytidine, hydrochloride, was dissolved in 2 ml of pyridine, and then 134 mg of succinic anhydride was added. The mixture was stirred at ambient temperature for 1.25 hours, and was then concentrated under vacuum. The residue was dissolved in dichloromethane/methanol, and the solution was absorbed on 1.5 g of silica gel, which was then slurried in dichloromethane and loaded on a 4 g silica gel column. The column was eluted with a gradient solvent, starting with dichloromethane and ending with methanol. The product-containing fractions were combined and freeze-dried overnight to obtain 255 mg of product mixture. It was dissolved in 3 ml of 0.01M ammonium acetate, and was chromatographed on a 22 ml mono-Q fast flow column (Pharmacia Inc.), eluting with the ammonium acetate gradient buffer which has previously been described. Evaporation of the product-containing fractions gave 81 mg of a mixture of the mono-acylated products named in the heading.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([C:50](O)=O)[CH:43]=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:50]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[C:46]([F:49])([F:47])[F:48])[O:16][N:15]=1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cnn(C)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.88 (d, J=0.9 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 5.40 (s, 2H), 4.01 (s, 3H), 2.96 (t, 2H), 1.87-1.68 (m, 2H), 1.03 (t, 3H); MS (ES) m/z 449 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)#[N:39].C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][N:11]([S:46]([C:43]1[CH:42]=[CH:41][C:40]([C:38]#[N:39])=[CH:45][CH:44]=1)(=[O:48])=[O:47])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCC(C)C)N1CCN(Cc2cccnc2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(C#N)cc1)N1CCN(Cc2cccnc2)C1=O
Yield: 74.1 %

Procedure:
Example 785A (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) and combined with p-cyanobenzenesulfonyl chloride (24 mg, 1.2 equivalents) and triethylamine (41 μL, 3 equivalents) at 25° C. for 16 h. The mixture was quenched with 1N NaHCO3 and extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified using ethyl acetate to give 49 mg (74%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:3]=1.CN1CCOCC1.ClC(OC(C)=C)=O.[CH2:44]([NH2:47])[CH:45]=[CH2:46]>C1COCC1>[CH2:44]([NH:47][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:8]=1)[CH:45]=[CH2:46]
Reactant: C=CCN
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)O)c3)ccnc2n1
Agent: C=C(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CCNC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which was added N-methyl morpholine (49 mg, 0.162 mmol), and isopropenyl chloroformate (36 mg, 0.295 mmol). This was stirred at room temperature for 1 hr at which time the allylamine (42 mg, 0.739 mmol) was added and the reaction mixture stirred at room temperature for another 1 hr. THF was then removed under a stream of N2 and then crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid. (8.0 mg, 9.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.92 (s, 3H), 2.74 (s, 2 H), 3.86 (d, J=5.15 Hz, 2 H), 5.04-5.16 (m, 2 H), 5.73-5.98 (m, 1 H), 6.73 (d, J=6.99 Hz, 1 H), 7.10 (dd, J=7.72, 2.21 Hz, 1 H), 7.27-7.43 (m, 3 H), 7.51-7.65 (m, 2 H), 7.69-7.82 (m, 2H), 8.54 (d, J=7.35 Hz, 1 H), 8.82 (d, J=8.46 Hz, 1 H); MS (ESI+) m/z 445 (M+TFA+H)+; (ESI−) m/z 443 (M+TFA−H)−.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[C:6]1([C:12]2[O:13][CH2:14][C@H:15]([CH2:17][OH:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N[C@H](C(O)=O)CO>C1COCC1.O>[CH2:4]([O:18][CH2:17][C@H:15]1[CH2:14][O:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:16]1)[CH3:5]
Reactant: OC[C@H]1COC(c2ccccc2)=N1
Reactant: CCI
Agent: N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@H]1COC(c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of sodium hydride (354 mg, 8.86 mmol) and iodoethane (0.90 ml, 11.2 mmol) in anhydrous THF (22 mL) was chilled to 0° C. A solution of (S)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (785 mg, 4.43 mmol) (Synthesis, 1993, 2, 250-262; using D-, instead of L-serine as a starting material) in 10 ml anhydrous THF was then added dropwise to the reaction mixture. The resulting mixture was allowed to warm to ambient temperature, and stirred overnight. After addition of water, the mixture was extracted with EtOAc. The combined organic extracts were dried and concentrated to afford (S)-4-(ethoxymethyl)-2-phenyl-4,5-dihydrooxazole as a clear, light-brown oil (0.981 g, 108%), which was used directly in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[NH:11][C:10](=[O:12])[CH2:9][CH:8]1[C:13]([F:16])([F:15])[F:14].F[B-](F)(F)F.[CH3:22][O+](C)C>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[CH:8]([C:13]([F:16])([F:14])[F:15])[CH2:9][C:10]([O:12][CH3:22])=[N:11]1
Reactant: O=C1CC(C(F)(F)F)C(CC2OCCO2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CC2OCCO2)C(C(F)(F)F)C1

Procedure:
The product material from Example 223 B is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3 to yield 2-[(1,3-dioxolan-2-yl)methyl]-3,4-dihydro-5-methoxy-3-(trifluoromethyl)-2H-pyrrole as a mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>O1CCOCC1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]([O:18][CH3:19])=[C:2]([N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:7]=1)([O:12][CH3:13])[CH3:9]
Reactant: C1COCCN1
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(F)(F)F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene (O3.004; 700 mg) was initially charged in dioxane (7 ml) and admixed successively with Pd(II) acetate (46 mg), cesium carbonate (2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (118 mg) and morpholine (0.27 ml). Thereafter, the reaction mixture was heated to 90° C. for 7 h and then left to stand overnight. Subsequently, it was filtered and the filtrate was concentrated by rotary evaporation. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient). 433 mg of the title compound were obtained.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([OH:3])[OH:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:25]=[CH:26][CH:27]=[CH:28]C=2N=N1.C(N(CC)C(C)C)(C)C.N1CCC1>CC#N>[N:25]1([C:8]([C:7]2[CH:6]=[CH:5][C:4]([B:1]([OH:2])[OH:3])=[CH:12][CH:11]=2)=[O:10])[CH2:26][CH2:27][CH2:28]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccc(B(O)O)cc1)N1CCC1
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A solution of 4-boronobenzoic acid (527.4 mg, 3.18 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.61 g, 4.23 mmol) and N,N-diisopropylethylamine (1.665 mL, 9.53 mmol) in CH3CN (40 mL) was stirred at room temperature for 30 min. Azetidine (0.321 mL, 4.76 mmol) was added. After stirring for 3 days, the mixture was concentrated and purified by reverse phase HPLC (Sunfire S10 30×250 mm column, 10-40% solvent B gradient) to give the expected product as white solid (361 mg, 55% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 7.68 (2H, d, J=7.70 Hz), 7.60 (2H, d, J=7.97 Hz), 4.37 (2H, t, J=7.56 Hz), 4.19 (2H, t, J=7.84 Hz), 2.36 (2H, quin); MS (ES+) m/z: 206 (M+H); LC retention time: 2.01 min (analytical HPLC Method A).
Reaction SMILES: C1(C2[O:12][C@H:11]3[CH2:13][C@H:14]([N:17]4[CH:22]=[CH:21][N:20]=[C:19]([C:23](OC)=[O:24])[C:18]4=[O:27])[CH2:15][O:16][C@@H:10]3[CH2:9][O:8]2)C=CC=CC=1.[NH3:28]>C(O)(=O)C.CO>[OH:12][C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:16][CH2:15][C@@H:14]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:28])=[O:24])[C:18]2=[O:27])[CH2:13]1
Reactant: N
Reactant: COC(=O)c1nccn([C@@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)c1=O
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1nccn([C@@H]2CO[C@H](CO)[C@@H](O)C2)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 5.0 mL of 80% aqueous solution of acetic acid was dissolved 80 mg of methyl 4-[(4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. The solution was heated at 80° C. for 2 hours and then allowed to cool, and the solvent was removed under reduced pressure. The residue was diluted with 20 mL of water and washed with diethyl ether, and water was distilled off from the aqueous layer. The residue thus obtained was dissolved in 4.0 mL of methanol, and gaseous ammonia was introduced until saturation at an ice-cooled temperature. After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:methanl=10:1] to obtain 24 mg of 4-[(3S,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)s3)ccc21
Reactant: O=CCCCCO
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 125 mg (0.35 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-thiadiazol-2-yl]piperidine and 72 mg (0.70 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:24][CH2:23][CH2:22]1.F[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[C:42]#[N:43]>O1CCCC1>[C:42]([C:41]1[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=1[C:21]1([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH2:22][CH2:23][CH2:24]1)#[N:43]
Reactant: N#Cc1ccccc1F
Reactant: COc1cc2c(cc1OC)C(C1CCC1)=NCC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3C#N)CCC1)=NCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (24.5 ml, 2M solution in hexane) was added to a solution of diisopropylamine (6.85 ml) in tetrahydrofuran (50 ml) at 0° C. The resulting solution of lithium diisopropylamide was stirred at 0° C. for 20 minutes. A solution of 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (10 g) in tetrahydrofuran (100 ml) was added. The mixture was stirred at 0° C. for 1 hour, then cooled to -70° C. and treated dropwise with 2-fluorobenzonitrile (4.42 ml). The mixture was stirred at -70° C. for 50 minutes, then allowed to warm slowly to ambient temperature. The mixture was poured onto hydrochloric acid and washed with ether. The aqueous phase was basified with ammonia solution and the product was extracted with ethyl acetate. The resulting solid (0.6 g) was collected by filtration. The filtrate was washed with brine, dried over magnesium sulphate and the solvent removed in vacuo to give further solid. The combined solids were recrystallised from acetonitrile yielding a solid which was dried in vacuo to give 1-[1-(2-cyanophenyl)cyclobutyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (5 g).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: ClCCl
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 114.4 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in dichloromethane (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.23 g) was obtained by concentrating under a reduced pressure (yield: 99.0%).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[C:17](=[O:26])[NH:18][CH:19]=[N:20]2.O>C1COCC1>[F:25][C:23]1[CH:22]=[C:21]2[C:16]([C:17](=[O:26])[NH:18][CH:19]=[N:20]2)=[C:15]([O:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:24]=1
Reactant: OC1CCOCC1
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (6.15 g) was added to a solution of 4-hydroxytetrahydropyran (2.94 g) in THF (40 ml) and the mixture was stirred at ambient temperature for 15 minutes. The resultant mixture was added to a stirred solution of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g) in THF (60 ml) that was being heated to reflux. A further portion of THF (20 ml) was added and the reaction mixture was heated to reflux for 30 minutes. A second portion of potassium tert-butoxide (6.15 g) was added and the reaction mixture was heated to reflux for 40 minutes. A third portion of potassium tert-butoxide (1.52 g) was added and the reaction mixture was heated to reflux for 20 minutes. The reaction mixture was allowed to cool to ambient temperature. Water (50 ml) was added and the bulk of the organic solvent was evaporated. The residue was acidified to pH<2 by the dropwise addition of 2M aqueous hydrochloric acid. The resultant slurry was stirred for 15 minutes. The mixture was filtered and the isolated solid was washed with water (20 ml) and dried overnight in vacuo at 40° C. There was thus obtained 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5.96 g; 96% HPLC purity using Method A, retention time 3.34 minutes); NMR Spectrum: (DMSOd6) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m, 2H), 3.85-3.95 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H), 7.05 (m, 1H), 8.0 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[Br:32]Br>ClCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:32])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: BrBr
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 134.3 %

Procedure:
The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45° C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45° C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder.