Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:24]([CH3:23])(=[O:26])=[O:25])=[C:11]([C:18]([F:20])([F:21])[F:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 5 h

Procedure:
(4-Amino-3-trifluoromethyl-5-vinylbenzyl)carbamic acid tert-butyl ester (235.6 mg, 0.75 mmol), Methanesulfonyl chloride (5 eq, 3.73 mmol, 288.40 μl), and triethylamine (3 eq, 2.25 mmol, 313.60 μl) were added to methylene chloride. The reaction mixture was stirred for 5 hr. The reaction mixture was purified according to step 5 of Example 8 to give a title product, yellow syrup (89.3 mg, 30.21%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(OCCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Yield: 27 %

Procedure:
A suspension of potassium carbonate (290 mg) and palladium tetrakistriphenylphosphine (49 mg) in a solution of 1-[3-(4-bromophenoxy)-propyl]piperidine (250 mg) and 4-methylbenzeneboronic acid (228 mg) in toluene (5 mL) is heated overnight at a temperature close to 100° C. The mixture is diluted with ethyl acetate (200 mL) washed with a saturated aqueous sodium bicarbonate solution (3 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane then dichloromethane/methanol/ammonia 99/1/0.5. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to give 70 mg of 1-{3-[(4′-methylbiphenyl-4-yl)oxy]propyl}piperidine, oxalate as a white solid melting at 195° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].CCN(C(C)C)C(C)C.[CH2:32](Br)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A suspension of (E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (500 mg, 1.55 mmol, Intermediate 1) in DCM (15 ml) was treated with DIPEA (0.33 ml, 1.86 mmol) and phenethyl bromide (0.251 ml, 1.86 mmol), and stirred at RT for 8 days. The mixture was concentrated and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester a yellow solid (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14](C(OC)=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]cc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.386 g (1 mmole) of 8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 10 ml of methanol, 1 ml of water and 0.225 g (4 mmole) of potassium hydroxide was heated to reflux for 31/2 hours under an atmosphere of nitrogen. The solvent was evaporated and the residue was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated and the residue was heated in mineral oil up to 230° for 5 min. The reaction mixture was partitioned between 1 N hydrochloric acid and methylene chloride/hexane. The acid extract was made alkaline with sodium carbonate solution and extracted with methylene chloride. The residue obtained after evaporation of the dried extracts was chromatographed over 10 g of silica gel using methylene chloride/ethyl acetate 1:2. Crystallization of the combined clean fractions from ethyl acetate/hexane yielded colorless crystals with mp 247°-250°. Uv λ max 212 mμ (ε=42250) sh 262 (10000) ir (KBr) 1695 cm-1 (CO) 3150 (NH). Nmr (CDCl3) 4.18 ppm (d, 1) and 4.88 (d, 1) (AB-system, J=12.5 Hz, C4 --H) 6.28 (d, 1, J=2 Hz, C3 --H) 6.9-7.7 (m, 5, aromatic H) 8.13 (d, 1, J=8.5 Hz, C10 --H) 10.46 (broad s, 1, NH).
Reaction SMILES: CC1C=CN=C(NC2N=C(C3OC(NCC4C=CN=CC=4)=NC=3)C=CC=2)C=1.Cl[C:29]1[O:30][C:31]([C:34]2[CH:35]=[C:36]([NH:40][C:41]3[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:32][N:33]=1.FC(F)(F)C(O)=O.[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][C:60]1=[O:65]>CC(O)C>[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][N:62]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:41]4[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=4)[CH:35]=3)=[CH:32][N:33]=2)[CH2:61][C:60]1=[O:65]
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)c2)n1
Reactant: COCCN1CCNCC1=O
Agent: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COCCN1CCN(c2ncc(-c3cccc(Nc4nccc(C)n4)c3)o2)CC1=O

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from [3-(2-chloro-oxazol-5-yl)-phenyl]-(4-methyl-pyrimidin-2-yl)-amine and 1-(2-methoxy-ethyl)-2-oxopiperazine trifluoroacetic acid salt in iPrOH. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.35 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.31-7.20 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=5.0 Hz, 1H), 4.10 (s, 2H), 3.79-3.72 (m, 2H), 3.58-3.46 (m, 6H), 3.25 (dd, J=2.7, 2.2 Hz, 3H), 2.38 (s, 3H). (ESI+) m/z 409 (M+H)+. Retention time=2.94 mins (method 1).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH:7]([N:20]1[CH2:23][CH:22]([O:24]S(C)(=O)=O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42](O)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]>CN(C=O)C>[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([O:24][CH:22]2[CH2:23][N:20]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:21]2)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2c(c1)OC(C)(C)C2
Temperature: 100 °C
Yield: 84 %

Procedure:
Cs2CO3 (1.16 g, 4.95 mmol) was added to a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (193a) (756 mg, 2.38 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (440 mg, 1.98 mmol) in DMF (6 mL). The mixture was heated to 100° C. for 4 hr, quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H2O, dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a white sold (740 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=7.07 Hz, 4 H) 7.27-7.32 (m, 4 H) 7.18-7.25 (m, 2 H) 7.04 (d, J=1.01 Hz, 1 H) 6.81 (d, J=1.01 Hz, 1 H) 4.87 (t, J=5.81 Hz, 1 H) 3.85 (s, 3 H) 3.76 (ddd, J=7.52, 5.87, 2.02 Hz, 2 H) 3.12 (ddd, J=7.33, 5.56, 1.77 Hz, 2 H) 2.99 (s, 2 H) 1.49 (s, 6 H); LCMS for C28H29NO4 m/z 444.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)([O-:15])=[O:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([O-:15])=[O:14]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 172.4 %

Procedure:
A mixture of 4-fluoroanisole-2-boronic acid (3.3 g, 19.4 mmol), 2-nitrobromobenzene (3.56 g, 17.6 mmol), triphenylphosphine (367 mg, 1.4 mmol), triethylamine (4.6 g, 45.8 mmol), and 40 mL of dimethylformamide was sparged with nitrogen for 5 minutes before adding palladium acetate (160 mg, 0.7 mmol) and heating the mixture to 100° C. for 5 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was shaken with 0.1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed by 4% ethyl acetate/hexanes to give 7.5 g of the title compound. Yield: 86%. EA. MS(FD).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=2)[CH:17]=O)([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:24]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([NH:22][CH2:17][C:16]2[CH:19]=[C:12]([C:9]([CH3:11])([CH3:10])[C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=[CH:14][C:15]=2[O:20][CH3:21])[C@@H:24]1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 68 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:37])[F:36])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:36])[F:37])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(N)cc1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of [3-(4-tert-butoxycarbonylaminobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.11 g) in dichloromethane (2.5 mL) was treated with trifluoroacetic acid (0.25 mL) and the resulting mixture was allowed to stand at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a yellow gum (0.051 g).
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[C:20](N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)[CH3:21].BrCC=CC=C>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH:3][CH:20]=[CH2:21]
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Agent: C=CC=CCBr
Product: C=CC=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Yield: 80 %

Procedure:
The compound is prepared in analogy to compound 204 from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 1-brom-2,4-pentadien in 80% yield as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:18](N)=[NH:19]>COC(O)C>[N+:11]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:18][N:19]=[C:4]2[OH:6])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: N=CN
Agent: COC(C)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (1000 g, 5 mol) and formamidine acetate (1000 g, 10 mol) were dissolved in methoxyethanol (4 L) and heated to 115° C. for 16 hours. After cooling the mixture to room temperature, ice water (5 L) was added and the mixture was stirred for 30 minutes before collecting the product (125 g, 14%) by filtration.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[CH:5]1)(=O)C.[CH3:15]I.O>C(#N)C>[CH3:15][N:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][N:4]=[CH:5]1
Reactant: CC(=O)n1cnc(-c2ccccc2)c1
Reactant: CI
Solvent: CC#N
Solvent: O
Product: Cn1cncc1-c1ccccc1

Procedure:
To 2.88 g of 1-acetyl-4-phenylimidazole in 50 ml of acetonitrile was added 5.8 ml of methyl iodide and the reaction mixture sealed in a flask over a weekend. The reaction mixture was poured into water and then decanted from insoluble oil. The pH of the decanted solution was adjusted to 9 with sodium carbonate and the solution extracted with chloroform. The extracts were combined, dried over magnesium sulfate and concentrated to give 1.02 g of crude product which was chromatographed on 50 g of silica gel using 30% ethyl acetate in chloroform as the eluent, 640 mg.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=1.[Cl-].[Na+]>CS(C)=O>[CH2:3]([O:5][C:7]1[N:12]=[N:11][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCO
Reactant: CC(C)(CO)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(C(C)(C)CO)nn1

Procedure:
1.6 g (0.053 mol) of 80% strength sodium hydride in white oil are suspended in 50 ml of dimethyl sulfoxide and 2.5 g (0.055 mol) of ethanol are added dropwise at 15°-20° C. After completion of gas evolution, a solution of 1.0 g (0.005 mol) of 2-(6-chloro-pyridazin-3-yl)-2-methylpropanol in 20 ml of dimethyl sulfoxide is allowed to run in and the mixure is warmed to 90°-100° C. for 1.5 hours. After cooling, the mixture is poured into concentrated sodium chloride solution and extracted with ether. After removing the solvent, a yellow oil remains as the crude product. Yield: 0.6 g (61% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[SH:11].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[S:11][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cc(Cl)cc(S)c1Cl
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,5-dichloro-3-methoxybenzenethiol (2.36 g) and DMF (dry) (60 mL) were added K2CO3 (1.72 g) and methyl 4-chloro-3-oxobutanoate (1.46 mL) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (3.37 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61]O)=[O:54])([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.CCCCCCC>[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: Oc1ccc(Br)cc1Sc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1ccc(Br)cc1Sc1cccc(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Bromo-2-(3-fluoro-phenylsulfanyl)-phenol (2.898 g, 9.69 mmol) and triphenylphosphine (3.558 g, 13.6 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to 0° C. under an inert atmosphere. To the solution was added DEAD (2.81 mL, 14.27 mmol)dropwise. After 25 minutes was added 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tertbutyl ester (2.504 g, 1.163 mmol) in THF (15 mL) via cannulation. The mixture was stirred at room temperature for 16 hours. Heptane (350 mL) and THF (100 mL) was added. The organic phase was then washed with water (4×50 mL) and then brine, dried (Na2SO4), filtered and the filtrate concentrated in the presence of silica gel. The crude products absorbed onto silica gel and eluted with a gradient of heptane-heptane ethyl acetate (85:15). The product was isolated after concentration of relevant fractions.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4][O:5][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOC(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOC(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: -3 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
A 20-L 4-neck round-bottom flask was flushed with N2, then charged a solution of tert-butyl 2-(1,3-dihydroxypropan-2-yloxy)ethylcarbamate (418 g, 1.8 mol, 1.0 eq) in dichloromethane (9000 mL, 21.5 v) and N,N-diisopropylethylamine (574 g, 4.4 mol, 2.5 eq). This is followed by dropwise addition of methanesulfonyl chloride (509 g, 4.4 mol, 2.5 eq) with stirring at −6-0° C. over 1 hour. The resulting mixture was stirred for 4 h at −6˜4° C., then washed with water (3×4000 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/EtOAc (1:1) to give 740 g (101.0%) of 2-(2-(tert-butoxycarbonylamino)ethoxy)propane-1,3-diyl dimethanesulfonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1cccc2c(-c3cccc(NCc4ccc5ccccc5c4)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and naphthalene-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 471.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([NH2:14])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:15]([O-])([O-:17])=[O:16].[K+].N>OS(O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cccc2nc(N)[nH]c12
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N)nc12
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
1.0 g (5.2 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid methyl ester was suspended in 10 mL of conc. H2SO4 at −15° C. and cooled to −30° C. Potassium nitrate (0.58 g, 5.72 mmol) dissolved in 10 mL of sulfuric acid and cooled to 0° C. was then added dropwise to the reaction mixture. The reaction mixture was stirred −30° C. for 15 min then warmed to −10° C. over 30 min. Then the mixture was poured into a beaker containing ice and neutralized (˜pH=8) with concentrated aqueous ammonia solution. The resulting solid was filtered. The solid obtained was washed with cold water and ether, and dried under vacuum to provide 0.85 g (70%) 2-amino-6-nitro-1H-benzoimidazole-4-carboxylic acid methyl ester as a solid. LCMS: 239 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.C(CN)O>C1(C)C=CC=CC=1>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: NCCO
Solvent: Cc1ccccc1
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 92.5 °C

Procedure:
In a clean round bottom flask, 10 gm of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthalimidopiperidine-yl) xanthine and 100 ml of toluene were charged. 10 ml of ethanolamine was added to the reaction mass and heated to 90-95° C. to complete the reaction. The reaction mass was cooled to 80° C. and the layers were separated. The organic phase was distilled under vacuum to get crude linagliptin. Dry wt: 7.50 gm HPLC purity: 97.95% Impurity X: 0.69%