Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][C:21]([CH2:25][NH:26]C(OC(C)(C)C)=O)([OH:24])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:34]>C(Cl)Cl.O1CCOCC1>[ClH:34].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][CH2:20][C:21]([CH2:25][NH2:26])([OH:24])[CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCC1(O)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 1.5 h

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-4-hydroxy-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (42.0 mmol, 19.0 g) in DCM (50 mL) was treated with 4 N HCl in dioxane (80 mL) and stirred for 90 minutes. The solvents were removed under reduced pressure, and the crude salt was triturated with diethyl ether, filtered, and dried to provide 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:30])[CH3:29]>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][C:4]2[CH:11]=[CH:12][C:29]([C:28]#[N:30])=[CH:6][CH:5]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture contaiing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--g see Preparation 13), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.25 g.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:34])([F:33])[C:22]1[N:23]=[C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:25][CH:26]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[S:25][CH:26]=[C:22]([C:21]([F:34])([F:20])[F:33])[N:23]=3)[CH2:28][CH2:29]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc(C(F)(F)F)cs3)CC2)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 71%). MS (m/e): 504.0 (M+H+, 100%).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C(OCC)(=O)C>[OH-].[Na+]>[C:14]1([S:20]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2nnn(OS(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
In 1 N aqueous sodium hydroxide (45 ml) is dissolved 1-hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g). To the solution is added dropwise benzenesulfonyl chloride (7.0 g) with stirring at room temperature and further are added thereto water (50 ml) and ethyl acetate (100 ml) and the mixture is stirred for 1 hour. The ethyl acetate layer is separated, dried over magnesium sulfate-charcoal, filtered and concentrated until it becomes about 30 ml. n-Hexane (50 ml) is thereto added and the mixture is allowed to stand. The precipitated crystals are separated by filtration and dried to give faint yellow prisms of 1-benzenesulfonyloxy-6-nitro-1,2,3-benzotriazole (6.8 g), melting point: 122°-124° C. The product is recrystallized from ethyl acetate-n-hexane to give a pure product: melting point: 124° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][OH:27]>[O-2].[O-2].[Mn+4].O1CCOCC1>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[N:4][C:3]=1[CH:26]=[O:27]
Reactant: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-methanol (4.0 g), manganese dioxide (activated) (40 g) and dioxan (225 ml) was stirred at room temperature overnight. The suspension was filtered and the solid was washed with hot chloroform (1 l). The combined filtrates were evaporated in vacuo to leave a solid (4.0 g) which was purified by FCC eluting with chloroform to give a solid which was triturated with hexane (ca. 50 ml) to give the title compound (2.99 g), m.p. 184°-188° (decomp.).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[C@@H:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)[NH:5][C:4]1=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[C@@H:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)[NH:5][C:4]1=[O:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CO)NC2=O)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1NC(=O)[C@@H](Cc2cn(C)c3ccccc23)NC1=O
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of (3R,6R)-3-hydroxymethyl-6-(1-methylindol-3-ylmethyl)-piperazine-2,5-dione (0.10 g), dry pyridine (1.0 ml) and acetic anhydride (0.08 g) was heated at 100° C. for 1 hour. After the mixture was cooled to ambient temperature, the pricipitated mass was collected, washed with pyridine and then ethanol, and dried to give (3R,6R)-3-acetoxymethyl-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (61.8 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH:25]=[O:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[BH4-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:16])([F:15])[F:17])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 0 °C

Procedure:
5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridine-2-carbaldehyde (33 mg, 0.091) was dissolved in dichloromethane (2 mL) and cooled to 0° C. The mixture was treated with sodium borohydride (8.6 mg, 0.23 mmol, 2.5 equiv) and after 2 hours, the mixture was diluted with ethyl acetate (30 mL), washed with sodium bicarbonate (2×30 mL, aqueous saturated), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography, providing the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([S:13](Cl)(=[O:15])=[O:14])=[C:7]([O:17][CH3:18])[CH:6]=1)[C:2]#[CH:3].[OH:19][CH2:20][C@:21]([OH:71])([CH3:70])[C:22](=[O:69])[C@@H:23]([NH:28][C:29](=[O:68])[C@@H:30]([NH:38][C:39](=[O:67])[C@@H:40]([NH:45][C:46](=[O:66])[C@@H:47]([NH:56][C:57](=[O:65])[CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:6]=[C:7]([O:17][CH3:18])[C:8]=1[S:13]([O:19][CH2:20][C:21]([OH:71])([CH3:70])[C:22](=[O:69])[C@H:23]([CH2:24][CH:25]([CH3:26])[CH3:27])[NH:28][C:29](=[O:68])[C@H:30]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:38][C:39](=[O:67])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:45][C:46](=[O:66])[C@H:47]([CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[NH:56][C:57](=[O:65])[CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)(=[O:15])=[O:14]
Reactant: C#CCOc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Product: C#CCOc1cc(OC)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(OC)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethoxybenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:43]([C:41]2[CH:40]=[N:39][N:38]([S:35]([C:33]3[CH:32]=[CH:31][C:22]4[N:23]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:19]([C:15]([CH3:14])([CH3:18])[CH2:16][CH3:17])=[N:20][C:21]=4[CH:34]=3)(=[O:37])=[O:36])[CH:42]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Yield: 42.3 %

Procedure:
Following the same procedure in Example 24, Step A, using cyclopropylamine (21 mg, 25 uL, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 38 mg (42%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.54-0.61 (m, 2 H), 0.74-0.82 (m, 5 H), 1.42-1.58 (m, 4 H), 1.60 (s, 6 H), 1.96 (q, J=7.55 Hz, 2 H), 2.22-2.36 (m, 1 H), 2.73-2.80 (m, 1 H), 3.26-3.36 (m, 2 H), 3.86-3.95 (m, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.34 (d, J=1.76 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=500.0; Anal. Calcd for C25H33N5O4S+0.6 TFA+1.0H2O (586.07): C, 53.70; H, 6.12; N, 11.95. Found: C, 53.65; H, 5.98; N, 12.02.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>C(OCC)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:16]=1
Reactant: Fc1ccc(Br)cc1
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1ccc(-c2cccc(F)n2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
Butyl lithium (105.0 ml, 0.26 mol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-fluoro benzene (34. 3 ml, 0.31 mol) in anhydrous diethyl ether (200 ml) at -20° C. The mixture is stirred for 60 min and then chilled to -40° C. 2,6-Difluoropyridine (22.7 ml, 0.25 mol) is added and the reaction mixture is allowed to warm to ambient temperature. Subsequently, the mixture is washed with saturated aqueous ammonium chloride (300 ml). The layers are separated and the aqueous layer is washed with diethyl ether 3 times (100 ml each). After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, hexane/AcOEt 8/2) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-pyridine (19.8 g, 41.0% of th.) with mp 34° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[N:16]3[CH2:32][C:33]([F:36])([F:35])[F:34])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 93.6 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.146 mmol), lithium (bis-trimethylsilyl)amide (49 mg, 0.292 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.2 mL, 0.876 mmol) was prepared ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (58 mg, 95% yield) as a yellow oil. 1H NMR (CDCl3) δ 8.54 (s, 1 H), 7.37 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.97 (m, 2 H), 4.83 (m, 2 H), 4.49 (m, 2 H), 4.13 (s, 2 H), 1.46 (m, 3 H); MS m/z 425 M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2nc(Cl)nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution washed with water (2×20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquours were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1)→ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 12%). 1H NMR (250 MHz, CDCl3): δ 1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 (m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, 1H), 5.61 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 7.18 (s, 1H). MS (ESP): 423.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CC([O:29]O)(C)C.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: CC(C)(C)OO
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 30 h
Yield: 37 %

Procedure:
At room temperature, 1.307 g of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole, 0.059 g of tetrabutyl ammonium bromide as an interphase transfer catalyst, and 0.157 g of Mo(acac)2 oxidation catalyst were mixed in 15 ml of IPA. Next, 1.36 g of TBHP (70% aqueous solution) was added into the mixture in about 5–10 minutes. The reaction was carried out for about 30 hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 37% (HPLC purity>96%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)[C@H]1C[C@H]1C(=O)O
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2ccc(Cl)cc2)C2CC12
Yield: 79.8 %

Procedure:
6.0 g (26.7 millimoles) of cis-2-(p-chlorobenzoyl)-cyclopropanecarboxylic acid, 1.47 g (29.4 millimoles) of hydrazine hydrate and 150 ml of ethanol are refluxed for 6 hours. The mixture is concentrated to about 20 ml and the product is filtered off at 0° C. and recrystallized from methanol. 4.7 g (80% of theory) of 2-(p-chlorophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 199°-200° C.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:28]1CCN2C(=NCCC2)CC1.C=O>C1COCC1>[C:18]1([CH2:17][C:11](=[CH2:28])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.92 g of lithium chloride was suspended in 50 ml of dry THF, and 15 g of ethyl 2-diethylphosphono-3-(1-naphthyl)propionate was dropwise added thereto. Then, 16 ml of a 50% dry THF solution of DBU was dropwise added thereto, and 2.01 g of paraformaldehyde suspended in dry THF was added thereto. The mixture was stirred at room temperature for 3 hours, and the insolubles were removed by filtration and washed with a small amount of diethyl ether. The washing solution and and the filtrate were put together, and the solvent was distilled off. The resulting syrup was dissolved in 180 ml of diethyl ether. The diethyl ether layer was washed sequentially with a 10% citric acid aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate. The solvent was distilled off, and the syrup thereby obtained was purified by silica gel column chromatography (n-hexane/diethyl ether=20/1) to obtain 6.48 g of ethyl 2-(1-naphthyl)methyl-2-propenoate as colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]2[N:23]=[C:22]3[NH:24][CH:25]=[C:26]([C:27](=[O:29])[CH3:28])[C:21]3=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C1COCC1>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:24]1[C:22]2=[N:23][C:18]([NH:17][CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:31][CH:30]=3)=[CH:19][CH:20]=[C:21]2[C:26]([C:27](=[O:29])[CH3:28])=[CH:25]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CNc2ccc3c(C(C)=O)c[nH]c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc3c(C(C)=O)cn(CC(=O)OC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Tert-butyl bromoacetate (27 μL, 0.18 mmol) was added to a suspension of 1-[6-(4-methoxy-benzylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone (0.17 mmol) and potassium carbonate (27.5 mg, 0.20 mmol) in CH3CN (0.33 mL) and THF (0.33 mL). The reaction mixture was stirred at RT for 7 h. Potassium carbonate (27.5 mg, 0.20 mmol) and tert-butyl bromoacetate (27 μL, 0.18 mmol) were added again and stirring was continued overnight, this operation was repeated the next day. The suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 98:2). TLC, Rf (CH2Cl2/MeOH 9:1)=0.9; MS (UPLC/MS): 410.2 [M+H]+, 819.4 [2M+H]+, 841.3 [2M+Na]+, 454.1 [M+HCOO]−; tR (HPLC conditions f): 2.30 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc2oc(CC3CCCCN3)cc12
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(Br)cccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (0.45 g) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.89 g) and 2-(4-bromo-benzofuran-2-ylmethyl)-piperidine, D72 (0.88 g) by a procedure similar to that described for Example 1.