Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](SC)[N:8]=2)=[C:5]([CH3:15])[O:4][N:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[C:22]([O-])(O)=O.[Na+]>CO>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:18]([CH3:22])(=[O:20])=[O:17])[N:8]=2)=[C:5]([CH3:15])[O:4][N:3]=1
Reactant: CSc1nccc(-c2c(C)noc2C)n1
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1-c1ccnc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A solution of 4-(3,5-dimethyl-isoxazol-4-yl)-2-methylsulfanyl-pyrimidine (638 mg, 2.88 mmol) in MeOH (23 ml) was cooled at 0° C. and then an aqueous solution of oxone (5.31 g, 8.64 mmol in 23 ml of water) was slowly added. After stirring 1.5 hours at room temperature, the mixture was basified with solid NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 666 mg of the title compound that was used in the next step without further purification (91% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.O.C(#N)C>CN(C=O)C>[CH:27]1([NH:31][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30][CH2:29][CH2:28]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: NC1CCC1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (10 g, 26.5 mmol) in DMF (150 mL) was added cyclobutanamine (15.10 g, 212 mmol) at rt. Then the mixture was stirred at 70° C. for 15 h. After the reaction was done, the reaction mixture was poured into water/ACN (200 mL, 7:3). The suspension was filtered and rinsed with ACN to give the title compound (8.5 g, 78%). ESI-MS m/z [M+H]+ 412.1.
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](C)[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].[N:17]1[NH:18][N:19]=[CH:20][CH:21]=1>CN(C=O)C>[CH3:11][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)=[CH:7][CH:6]=1
Reactant: c1cn[nH]n1
Reactant: Cc1cnc(C#N)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C#N)n1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
To 3-bromo-5-methylpicolinonitrile (2.2 g, 11 mmol) in DMF (28 mL) was added K2CO3 (1.7 g, 12 mmol) and 2H-1,2,3-triazole (650 μL, 11 mmol). The mixture was heated to 100° C. for 36 h, cooled to rt and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. Purification via silica gel chromatography (10-100% EtOAc in hexanes) gave the title compound (1 g, 48%).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5](P(OCC)(OCC)=O)[O:6]CC)C.C([N-]C(C)C)(C)C.[Li+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[CH:34]=O)=[CH:29][CH:28]=1.S(=O)(=O)(O)O>O1CCCC1.O1CCCC1.CCCCCCC.C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[CH2:34][C:5](=[O:6])[C:4]([OH:3])=[O:17])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(OCC)P(=O)(OCC)OCC
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(CC(=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
A solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 50 ml of tetrahydrofuran is mixed while being cooled with ice within 20 minutes with 30 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene, and it is stirred for 15 minutes at 0° C. Within 30 minutes, a solution of 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran is added in drops thereto at 0° C. After 20 hours at room temperature, 2N sulfuric acid is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. The crude product is saponified with 200 ml of 2 M sodium hydroxide solution/400 ml of ethanol. 13.8 g of acid, which is refluxed for 3 hours with 300 ml of 2N sulfuric acid and 100 ml of glacial acetic acid while being stirred vigorously, is obtained. After extraction with ethyl acetate and washing with water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained as a red oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=O.[C:16]([NH:19][C:20]([NH2:22])=[NH:21])(=[O:18])[CH3:17]>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[NH:22][CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Yield: 25.5 %

Procedure:
To a stirred solution of 2-bromo-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol). The reaction mixture was stirred and refluxed for overnight. The solvent was evaporation under reduced pressure and diluted with water and extracted with ethyl acetate (75 ml×3) and organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2% methanol in chloroform to obtain 1.15 g of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 2.07 (s, 3H), 7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).
Reaction SMILES: [Cl:1]CC=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg:11].C(O[CH2:15][CH3:16])C>>[CH:15]([Mg:11][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:16].[Cl-:1]
Reactant: [Mg]
Reactant: CCOCC
Reactant: ClCC=Cc1ccccc1
Product: C=C[Mg]Cc1ccccc1
Product: [Cl-]

Procedure:
In diethylether under reflux, 15.2 parts of chloromethylstyrene and 2.5 parts of metallic magnesium were reacted to obtain a diethylether solution of vinylbenzylmagnesium chloride. To 1000 parts of tetrahydrofuran (hereinafter referred to as THF), were added 117 parts of this solution under an atmosphere of dry nitrogen, and cooled to -78 degrees C. Then, 157 part of dimethylaminoethyl ethacrylate were added thereto and polymerized for 24 hours at -78 degrees C. After stopping polymerization with a small amount of methanol, the polymerizate was precipitated into hexane, filtered and then dried to obtain a polydimethylaminoethylmethacrylate acromer (Mn 2500).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[NH:50][C:49]([NH2:52])=[N:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:37]1[CH:38]=[CH:39][N:35]=[C:36]1[NH:40][C:41]([C:43]1[C:51]2[N:50]=[C:49]([NH:52][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1)=[O:42]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc(Cl)cc1
Yield: 19.7 %

Procedure:
70 mg (0.45 mmol) of 4-chloro-benzoic acid 170 mg (0.45 mmol) of HBTU in a mixture of 3 ml of DMF and 1 mL of DIEA was reacted with 100 mg (0.4 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide synthesized above as described in general procedure A and 2-(4-chloro-benzoylamino)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (30 mg, 17.24%) was isolated. LCMS: 382 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 11.99 (d, 1H), 8.16 (d, 2H), 7.94 (d, 1H), 7.70 (dd, 3H), 7.30 (t, 1H), 6.81 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl

Procedure:
8.10 g (37.6 mmol) of (2-chloro-4-nitrophenyl)acetic acid is suspended in 40 mL of thionyl chloride and refluxed for 2 hours. The product is reacted further without any more purification. Crude yield: 8.80 g (100% of theory); C8H5Cl2NO3.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[O:19])[CH2:11]1)=[O:7])(C)(C)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)=[O:19])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: Cn1cc(C(=O)NCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethyl)-1-methyl-1 H-indole-3-carboxamide (2.16 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (1.1 g) to give N-(2-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)ethyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)cc1
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-methylphenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (90 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 33 as a yellow solid (65 mg, 78%). ESI-MS m/z: 334 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.31 (d, J=7.2 Hz, 1H), 8.24 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 2H), 7.38 (d, J=7.2 Hz, 2H), 2.84 (s, 3H), 2.54-2.52 (m, 1H), 2.39 (s, 3H), 1.06-1.03 (m, 2H), 0.77-0.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:46][C:47](=[NH:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C>[C:48]([C:47]1[N:52]=[C:4]([C:3]2[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=2[Cl:1])[O:6][N:46]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)C(=N)NO
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1noc(-c2cc(I)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
To a solution of 2-chloro-5-iodobenzoic acid (1.0 g, 3.54 mmol) in 40 mL DMF was added diisopropylethyl amine (1.23 mL, 7.08 mmol) followed by HATU (2.02 g, 5.31 mmol). After stirring the reaction at room temperature for 10 min, N-hydroxy-2,2-dimethylpropanimidamide (0.82 g, 7.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then at 110° C. for 16 h. After cooling to room temperature the reaction was quenched with water and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography (2-5% EtOAc in hexanes) to yield 660 mg of intermediate US1-2.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1)=[O:4].C(O[CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=O)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][CH:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CNC(=O)N1CCCC(N)C1
Solvent: Cc1ccccc1
Product: CNC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Reacting 1-(N-methylcarbamoyl)-3-aminopiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-[1-(N-methylcarbamoyl)-3-piperidinyl]-9-xanthenylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: Nc1ccc(Cl)cc1
Product: CSc1ccc(C(=N)Nc2ccc(Cl)cc2)cc1
Yield: 83.26 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (11.7 g, 78 mmol) and 4-chloroaniline (10 g, 78 mmol) by following the procedure described in preparation 10 (18.06 g, yield 83.26%, purity 98.9% by HPLC). MS m/z:277.1/278.7 (M+).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH3:22])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:5]=2[C:6]=1[CH3:19])=[O:10]
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 85 °C
Yield: 69.3 %

Procedure:
A solution of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone (50 mg, 0.13 mmol) in toluene (1.5 mL) and ethanol (1.5 mL) was degassed with argon for 15 min. At this time, 3-methyl benzene boronic acid (21.2 mg, 0.16 mmol, 1.2 eq) was added followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), complex with dichloromethane (1:1) (10.6 mg, 0.01 mmol, 0.1 eq) and 2M aqueous Na2CO3 (0.21 mL, 3 eq). The reaction was bubbled with argon for another 5 min and then heated to 85° C. for 4 h. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure and purified on the pre-HPLC to afford 35.6 mg (69%) of a yellow solid as the product. 1H-NMR (CDCl3): δ 7.72 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J=1.6, 8.0 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.58 to 7.53 (m, 4H), 7.33 (t, 1H), 7.18 (d, J=7.2 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H); LC-MS (MH+=395/397).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24]([OH:26])=O)=[CH:14][CH:13]=1.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH:31]([CH2:35][NH:36][C:37]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])[CH2:30]2)[CH2:28]1>ClCCl>[Cl:47][C:44]1[CH:45]=[CH:46][C:37]([NH:36][CH2:35][CH:31]2[N:32]([C:24]([C:19]3[N:20]=[C:21]([CH3:23])[S:22][C:18]=3[C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[O:26])[CH2:33][CH2:34][C:29]3([CH2:27][CH2:28]3)[CH2:30]2)=[C:38]([CH:43]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1cc(Cl)ccc1NCC1CC2(CCN1)CC2
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NCC1CC2(CCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydroxybenzotriazole (13 mg, 0.097 mmol) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate HCl (23 mg, 0.12 mmol) in anhydrous dichloromethane (2 ml), 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (23 mg, 0.097 mmole) was added and the resulting solution was stirred 1 h at room temperature. (±) methyl 2-(6-azaspiro[2.5]octan-5-ylmethylamino)-5-chlorobenzoate (intermediate 10) (20 mg, 0.08 mmol) was added and the resulting mixture was stirred at the same temperature overnight. The mixture was washed with NaHCO3 saturated solution (3×5 ml).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].O.[NH2:13][NH2:14].ON1C=CC=CC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1ccccn1O
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1ccc(O)c(O)c1
Reaction time: 16 h

Procedure:
16.9 g (0.11 mol) of 3,4-dihydroxybenzoic acid in 170 ml of tetrahydrofuran are treated with 5 g (0.1 mol) of hydrazine hydrate and 1.1 g (0.01 mol) of 1-hydroxy-2-(1H)-pyridone. A solution of 22.7 g (0.11 mol) of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran is added to the reaction mixture at 20° within 15 minutes. The reaction mixture is stirred at 20° for 16 hours. The resulting dicyclohexylurea is filtered off and the filtrate is evaporated. The residue is stirred with 60 ml of ethanol at 20° for 2 hours and the crystalline crude product is subsequently filtered off under suction and dried firstly in a water-jet vacuum and then in a high vacuum at 40°, whereby 3,4-dihydroxybenzoic acid hydrazide is obtained as a beige powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[C:11]([O:15][C:16](=[O:35])[NH:17][C@H:18]([C:23](=[O:34])[NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28][CH2:27][C@@H:26]1[OH:33])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:11]([O:15][C:16](=[O:35])[NH:17][C@H:18]([C:23](=[O:34])[NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28][CH:27]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[C@H:26]1[OH:33])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:13])([CH3:14])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC(S(=O)(=O)c2ccccn2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
Pyridine-2-sulfonyl chloride (0.71 g, 0.4 mmol) was added to a solution of [(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (0.126 g, 0.344 mmol), sodium bicarbonate (0.87 g, 1.03 mmol) in CH2Cl2 (3 ml) and H2O (2 ml) and was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 3% MeOH/CH2Cl2) to yield the title compound (0.180 g, 70%): 1H NMR: 8.68 (m, 1H), 8.05 (1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd), 4.95–4.88 (dd), 4.20–3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d), 1.94–1.57 (m, 4H), 1.45–1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd); Electrospray mass spec: M+H+=499.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.[NH2:15][OH:16]>CO.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[N:15][OH:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: NO
Reactant: CC1(C)CC(=O)c2ccccc2O1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2ccccc2O1
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
A reaction mixture prepared from 10 mmol of 2,2-dimethyl-4-chromanone, 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated with stirring over the course of 2 hours to 80-85° C., the solvent is distilled off on a rotary evaporator and the oily residue is crystallized under water.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([OH:17])=O)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(C(C)C)C(C)C.O.ON1C2C=CC=CC=2N=N1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].Cl.CN(CCCN=C=NCC)C>ClCCl>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([NH:50][O:49][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:17])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 1.04 mmol, 1.0 eq) in dichloromethane (10 mL) under nitrogen, was added DIPEA (285 mg, 2.20 mmol, 0.384 mL, 2.12 eq) followed by the addition of 1-hydroxybenzotriazole monohydrate (307 mg, 2.00 mmol, 1.93 eq). The solution was allowed to stir for 30 minutes before being treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (163 mg, 1.39 mmol, 1.34 eq) and then dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (285 mg 1.49 mmol, 1.43 eq). The mixture was then allowed to stir for 3 hours at RT. The mixture was then absorbed onto silica gel and purified by flash chromatography eluting with 5-100% EtOAc/Hpt to give (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (230 mg, 52% yield). LC-MS M+H+426.1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]1=[O:43].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[O:33][N:32]=4)=[CH:23][CH:24]=3)[C:7](=[O:43])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethyl-1-[(2′-{4-[(2-methoxyethoxy)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}biphenyl-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15.5 g) and trifluoroacetic acid (100 mL) was stirred at 50° C. for 3 hr. To the reaction mixture was added toluene (100 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (11.7 g, 99%).