Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.O[C:17]1[N:22]=[CH:21][C:20]2[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][C:19]=2[CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:17]2[N:22]=[CH:21][C:20]3[C:23](=[O:29])[N:24]([CH:26]([CH3:27])[CH3:28])[CH2:25][C:19]=3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Reactant: CC(C)N1Cc2cc(O)ncc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1Cc2cc(OCc3c(-c4ccc(F)cc4)nnn3C)ncc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (251 mg, 1.21 mmol) in THF (30 mL) was added 6-hydroxy-2-isopropyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (232 mg, 1.21 mmol) and triphenylphosphine (413 mg, 1.58 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (624 μL, 1.58 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (87 mg, 19%) as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)([S:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:36]2
Reactant: COc1ccc(C(C#N)(Cc2cccc(CCl)c2)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C#N)(Cc2cccc(N3CCc4cc(OC)c(OC)cc4C3)c2)Sc2ccc(C)cc2)cc1OC
Temperature: 85 °C
Yield: 65.8 %

Procedure:
A mixture of 0.21 g of 3-(chloromethyl)-α-(3,4-dimethoxyphenyl)-α-[(4-methylphenyl)thio]benzene propane nitrile, 0.091 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 0.3 g of anhydrous potassium carbonate in 2.0-mL of N,N-dimethylformamide is heated at 85° C. for 4 hours, cooled, poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield an oil. This oil is purified by flash chromatography with 1.5% methyl alcohol in chloroform to yield 0.18 g of the desired product as a yellow glassy solid. MS(FAB): m/z 595(M+H).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][NH2:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[OH:17][N:18]=[C:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[C:20]1N1CCOCC1.C(O)(=O)C.O>C(O)C>[CH:10]([N:6]1[C:5]2[CH:13]=[C:14]([N:15]3[N+:18]([O-:17])=[C:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:16]3)[C:2]([F:1])=[CH:3][C:4]=2[S:8][C:7]1=[O:9])([CH3:12])[CH3:11]
Reactant: ON=C1CCCC=C1N1CCOCC1
Reactant: CC(C)n1c(=O)sc2cc(F)c(NN)cc21
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Yield: 43.8 %

Procedure:
6-Fluoro-3-(1-methylethyl)-2(3H)-benzothiazolon-5-ylhydrazine (1.11 g) and 4-(3-hydroxyimino-1-cyclohexen-2-yl)morpholine (0.90 g) were dissolved in ethanol (20 ml), a catalytic amount of acetic acid was added thereto, and the resultant mixture was heated under reflux for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and combined with a mixture of 15% aqueous pyridine (30 ml), tetrahydrofuran (20 ml) and cupric sulfate pentahydrate (2.2 g), followed by refluxing for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture. The organic layer was separated from the water layer, washed with dilute hydrochloric acid, dried and concentrated. The residue was crystallized from ether to give 2-[3-isopropyl-6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 3; 0.7 g). m.p., 92.5° C.
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[N:10]1([C:16]2[CH:27]=[C:20]3[C:21]([O:23][C:24](=O)[NH:25][C:19]3=[CH:18][CH:17]=2)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C[N:29](C)C=O>O>[NH2:29][C:24]1[C:4]([C:5]#[N:6])=[C:21]([OH:23])[C:20]2[C:19](=[CH:18][CH:17]=[C:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:27]=2)[N:25]=1
Reactant: O=c1[nH]c2ccc(N3CCOCC3)cc2c(=O)o1
Reactant: CN(C)C=O
Reactant: N#CCC(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 g of malonitrile is dissolved in 50 mL of dimethylformamide. To the solution, in several portions, 2.4 g of 60% oily dispersion of sodium hydride are added. To the clear solution 8 g of 5-(morpholin-4-yl)isatoic anhydride is added and the mixture is stirred at room temperature for 10 hours. The reaction mixture is diluted with 70 mL of water and extracted with 2×30 mL of ethyl acetate. The aqueous phase is evaporated in vacuum, the solid residue is dissolved in 20 mL of water, the pH is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water. After drying 6.5 g of the title compound is obtained, m.p.: 291° C.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([CH:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])[CH3:8].[F:15][C:16]([F:50])([F:49])[C:17]1[CH:18]=[C:19]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:20][N:21]([C@@H:28]1[C:34]2=[CH:35][C:36]3[CH2:37][O:38][CH2:39][C:40]=3[CH:41]=[C:33]2[NH:32][CH2:31][CH2:30][CH2:29]1)[C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1.O>ClCCl>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:18]=[C:19]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:20][N:21]([C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1)[C@@H:28]1[C:34]2=[CH:35][C:36]3[CH2:37][O:38][CH2:39][C:40]=3[CH:41]=[C:33]2[N:32]([C:10](=[O:11])[CH:9]([CH2:13][CH3:14])[CH2:7][CH3:8])[CH2:31][CH2:30][CH2:29]1
Reactant: CCC(CC)C(=O)Cl
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Add pyridine (0.35 mmol) followed by 2-ethyl-butyryl chloride (0.35 mmol) to a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (0.17 mmol) in dichloromethane (3 mL). After stirring at room temperature for 14 h, dilute the reaction with dichloromethane (10 mL) followed by water (10 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent in vacuo. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-50%) to elute to obtain the title compound as a colorless foam. MS (ES+): 611 (M+H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CCCCCCCC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and octanoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(octanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(octanoyloxy)-alpha-(isopropylaminomethyl) benzyl alcohol hydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)CCl.[NH2:28][C:29]1([CH2:35][OH:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[OH:36][CH2:35][C:29]1([NH:28][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:15])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: NC1(CO)CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2(CO)CCOCC2)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.59 mmol) in CH2Cl2 (5 mL) was added EDC (0.14 g, 0.72 mmol), 4-(dimethylamino)pyridine (0.088 g, 0.72 mmol), and (4-aminotetrahydropyran-4-yl)-methanol (0.094 g, 0.72 mmol). The reaction mixture was stirred at room temperature overnight then diluted with H2O and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (60% EtOAc/hexanes) to obtain 0.15 g (57%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1C(=C2SC(=Nc3cccc(NS(=O)(=O)c4ccccc4)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (0.18 g, 0.40 mmol), anhydrous CHCl3 (7 mL), benzenesulfonyl chloride (56 μL, 0.44 mmol), and TEA (0.10 mL, 0.80 mmol). The solution was stirred at 50° C. for 20 h. The yellow precipitates were collected by filtration under reduced pressure, washed with hexanes (30 mL), and dried under vacuum to give the title compound (49 mg, 21%) as a yellow solid. 1H-NMR (DMSO-d6): δ 7.97 (1H, s), 7.76 (2H, d), 7.53 (2H, m), 7.45 (2H, t), 7.37 (2H, d), 7.09–7.31 (8H, m), 6.81 (1H, d), 6.74 (1H, s), 6.57 (1H, d), 4.99 (2H, s), 3.72 (3H, s); MS(ESI): 585 (MH+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (8.7 grams), the diethyl acetal of 2-allylaminoacetaldehyde (8.0 grams) and benzene (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and thermometer. The reaction mixture was then warmed with stirring until the reactants dissolved. After this time the reaction mixture was stripped of benzene to yield an oil. This oil was dissolved in an ether-pentane mixture and was treated with diatomaceous earth and filtered. The filtrate was then stripped of solvent to yield the desired product the diethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as a dark red oil.
Reaction SMILES: [CH:1]1([C:7]2([CH2:22][OH:23])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]1([C:7]2([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(CO)(C1CCCCC1)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (3-3) (0.870 g, 2.69 mmol) in methylene chloride was added diisopropylamine (0.562 mL, 3.23 mmol), dimethylaminopyridine (32.5 mg, 0.269 mmol), and methanesulfonyl chloride (0.229 mL, 2.97 mmol). The mixture was stirred at room temperature for four hours and diluted with methylene chloride, washed with water, a saturated aqueous solution of NaHCO3, and 1 N HCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated to give (3-4) as a colorless oil.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[S:11][CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.CN(C)[CH:14]=[O:15].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[N:3]=[C:4]2[S:11][CH2:10][CH2:9][N:5]2[C:6](=[O:8])[C:7]=1[CH:14]=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=c1cc(O)nc2n1CCS2
Product: O=Cc1c(Cl)nc2n(c1=O)CCS2
Temperature: 0 °C
Yield: 69 %

Procedure:
In 40 ml of phosphorus oxychloride was dissolved 10.0 g (58.8 mmol) of 2,3-dihydro-7-hydroxy-5-oxo-5H-thiazolo[3,2-a]pyrimidine [J. Am. Chem. Soc., 64, 2709 (1942)], and 6.0 ml of dimethylformamide was added dropwise to the solution with stirring under ice-cooling. Then, the reaction mixture was heated under reflux for 30 minutes. After concentration of the reaction mixture to dryness under reduced pressure, the oily residue was poured by portions into ice water. The precipitated crystals were collected by filtration, and recrystallized from chloroform to give 8.8 g (69%) of the desired compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3].[OH-].[Na+]>CO.O>[NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: COC(=O)c1ccc2cc(C(N)=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1cc2ccc(C(=O)O)cc2o1
Temperature: 50 °C
Yield: 92.3 %

Procedure:
Methyl 2-(aminocarbonyl)-1-benzofuran-6-carboxylate(164 mg, 0.75 mmol) is dissolved in MeOH (5 mL) and water (1 mL), treated drop-wise with 2N NaOH (450 μL, 0.9 mmol) and monitored by TLC. The volatiles are removed in vacuo, and the resulting tan solid is dissolved in water (5 mL) and acidified to pH 3 with concentrated HCl. The resulting solid is collected via filtration and dried in a vacuum oven with heat 50° C. to afford 142 mg (93%) of 2-(aminocarbonyl)-1-benzofuran-6-carboxylic acid as an orange solid. HRMS (EI) calcd for C10H7NO4: 205.0375, found 205.0378 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.80 g (15.7 mmol) of N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (racemic diastereomer mixture) and 5.01 g (18.9 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 40 ml of DMF and 10 ml of pyridine, and 6.58 g (17.3 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 5.34 g of the target product (61.5% of theory, diastereomer ratio about 2.5:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH2:15][CH3:16])[C:8]([CH2:17]O)=[CH:7]2)[CH3:2].O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:17][C:8]1[C:9]([NH:14][CH2:15][CH3:16])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:13][CH:12]=2
Reactant: CCNc1nc2ccc(OCC)cc2cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCNc1nc2ccc(OCC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a stirred solution of (6-ethoxy-2-(ethylamino)quinolin-3-yl)methanol SLA 41040 (0.457 g, 1.86 mmol) in dry CH2Cl2 (40 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (2.63 mL, 37.1 mmol). The mixture was stirred for 4 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 as a yellow solid (552 mg, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 20 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
A solution of 2,5-dichloronicotinic acid (20 g, 0.10 mol) [OChem, 782D853] in dichloromethane (520 mL) was treated with 2 M oxalyl chloride in dichloromethane (160 mL, 310 mmol) followed by a few drops of N,N-dimethylformamide and stirred at 20° C. for 15 hours. The reaction mixture was concentrated, diluted with dichloromethane (200 mL), cooled to 0° C., treated with methanol (110 mL, 2.7 mol), and stirred at 0° C. for 5 minutes. The reaction mixture was concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0-80%) gave the desired product (19 g, 89%). LCMS calculated for C7H6Cl2NO2 (M+H)+: m/z=206.0, 208.0. found: 205.8, 207.7.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[C@@H:9]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.CCOC(C)=O>O.C1COCC1>[Cl:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[C@@H:9]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Yield: 1.7 %

Procedure:
LiOH (1.40 g, 58.3 mmol) was dissolved in water (50 mL) and added to (S)-ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21a, 5.71 g, 11.7 mmol) in THF (50 mL). The reaction mixture was stirred at rt for 75 min EtOAc (150 mL) was added. Washed with HCl (1 M, 100+50 mL) and brine (50 mL). The organic phase was dried over Na2SO4 and after filtration the solvents were evaporated in vacuo to yield the crude the title compound (82 mg, 107%) which was used further in the synthesis of Example 5a.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[N:19][N:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnnn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ncnn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (2.15 g, 10.0 mmol) was reacted with 1H-tetrazole (2.10 g, 30 mmol) to give 1-tert-butoxycarbonyl-4-(2H-tetrazol-2-ylmethyl)piperidine as pale yellow oily substance (1.35 g, 50%) and 1-tert-butoxycarbonyl-4-(1H-tetrazol-1-ylmethyl)piperidine as pale yellow solid substance (1.23 g, 46%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](=[O:35])[CH2:33][Br:34].CC#N>C(Cl)(Cl)Cl>[Br-:34].[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](=[O:35])[CH2:33][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: O=C(CBr)c1cc2ccccc2o1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2)c1cc2ccccc2o1
Product: [Br-]
Temperature: 60 °C

Procedure:
1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.022 g, 0.075 mmol) was diluted in CHCl3 (1.8 mL) and dispensed directly into a 1 dram vial containing 1-(1-benzofuran-2-yl)-2-bromoethanone (0.027 g, 0.112 mmol). Added CH3CN (1.2 mL), the vial was fitted with stirring bar and capped. The reaction was stirred and heated at 60° C. for 24 h and then concentrated under vacuum to give a white solid.