Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(SC2C3C(=CC(C)=CC=3)[NH:12]C=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.C(Cl)(=O)C(Cl)=O.N>>[Cl:32][C:30]1[CH:29]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][CH2:45][CH2:46][C:47]([NH2:12])=[O:49])[CH:27]=[C:26]([Cl:25])[CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCCC(=O)O)[nH]c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCCC(N)=O)[nH]c2c1
Yield: 17 %

Procedure:
Following the method used to prepare 24a, the use of 50 (135 mg, 0.34 mmol) and oxalyl chloride (43 μL, 0.51 mmol) followed by reacting the intermediate acid chloride with aqueous ammonia (2 mL) provided 23 mg (17%) of product 24c as a pale yellow solid, mp 163-164° C. 1H NMR (300 MHz, CDCl3) δ 1.92-2.01 (q, J=7 Hz, 2H), 2.25 (t, J=7 Hz, 2H), 2.46 (s, 3H), 2.96 (t, J=7 Hz, 2H), 5.42 (brs, 2H), 6.84 (d, J=2 Hz, 2H), 6.96-7.00 (m, 2H), 7.21 (s, 1H), 7.38 (d, J=8 Hz, 1H), 9.34 (brs, 1H). LC-MS (CI): m/z 393.0, 395.0 [(M+H)+ C19H18Cl2N2OS requires 392.05]. Purity (100%). Calcd for C19H18Cl2N2OS: C, 58.02; H, 4.61; N, 7.12; S, 8.15; Cl, 18.03. Found: C, 58.06; H, 4.79; N, 6.88; S, 7.90; Cl, 17.75. The low yield for amide preparation in this case was due to the significant formation of a six membered lactam via cyclization of the intermediate acid chloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)COCC[Si](C)(C)C)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[N:21]([CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([O:31][CH3:30])[CH:33]=3)[N:20]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1

Procedure:
Was prepared by alkylation of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) with 3-methoxybenzyl bromide and potassium carbonate in DMF as above. LCMS (System A) RT=1.25 min, ES+ve m/z 464/466 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11]1>N1C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:13][CH2:14][N:10]([CH2:9][CH2:8][NH:7][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:11]2)=[CH:23][CH:24]=1
Reactant: Brc1nccs1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Solvent: c1ccncc1
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)C3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of 12.8 parts of 2-bromothiazole, 22 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2 -amine and 250 parts of pyridine was stirred and refluxed for 6 hours. After cooling, 12.8 parts of 2-bromothiazole were added and stirring was continued overnight at reflux temperature. The mixture was cooled and evaporated. The residue was taken up three times in methylbenzene and the latter was evaporated each time. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane, methanol and ammonium hydroxide (45:45:10:1 by volume) as eluent. The pure and the less pure fractions were collected and the eluent was evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (96:3:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 2.0 parts (7.3%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl]-3-pyrrolidinyl]-1H-benzimidazol-2-amine; mp. 127.1° C. (compound 168).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29]2)[C:25]([CH3:34])([CH3:33])[CH2:24][CH2:23][N:22]3[CH:21]=1)=O>>[CH3:33][C:25]1([CH3:34])[C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]3[CH2:23][CH2:24]1)[CH:29]=[C:28]([F:32])[CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cccc(F)c45)C(=O)NC3=O)c3cc(F)cc1c32

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].O[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:11][CH:12]=1)[CH3:15]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Yield: 51 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-diethylamino-ethoxy)-phenylamine (775 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (557 mg, 51%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 2-(N,N-diethylaminomethyl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 118°-119° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([Si:5]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]1[O:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[CH3:4]>CO>[OH:12][CH2:11][C:9]1[CH:10]=[C:6]([Si:5]([CH2:13][CH3:14])([CH2:15][CH3:16])[CH2:3][CH3:4])[O:7][CH:8]=1
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[Si](CC)(CC)c1cc(CO)co1
Reaction time: 1 h

Procedure:
Sodium borohydride (353 mg, 0.93 mmol) was added portionwise to a solution of 2-triethylsilyl-4-furaldehyde (Compound 11, 1.64 g, 7.79 mmol) in methanol (10 ml) at 0°. After 1 hour, most of the methanol was evaporated and the residue dissolved in a minimum amount of dilute hydrochloric acid. Extraction (ethyl acetate), drying (magnesium sulfate) and evaporation gave an oil, which was purified by flash chromatography on silica using 20% ethyl ether/hexane. Fractions with Rf of about 0.07 (10% ethyl ether/hexane) gave after evaporation the title alcohol as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH:33]1[CH2:37][O:36][C:35](=[O:38])[O:34]1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:32][CH:33]3[CH2:37][O:36][C:35](=[O:38])[O:34]3)[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1OCC(CCl)O1
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CC3COC(=O)O3)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 65 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
To a solution of 6.5 g of the compound of Example 1 in 50 ml of dimethylformamide are added 4.1 g of potassium carbonate and 4.1 g of 4-chloromethyl-2-oxo-1,3-dioxolane, and the mixture is stirred at 65° C. for 4 hours. After completion of the reaction, the reaction mixture is poured into ice-cold water, and the precipitate is extracted with ethyl acetate. The extract is washed with water, dried and concentrated, and then the obtained residue is recrystallized from isopropyl ether to give 6 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-oxo-1,3-dioxolan-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 140°-141° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18]>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH:8][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:18]
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)ncn1)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 174.3 %

Procedure:
A solution of 6-chloro-pyrimidin-4-ylamine (997 mg, 7.7 mmol) and 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) in THF (20 mL) is refluxed for 4 h. A further amount of 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) is added and the reaction mixture is refluxed for 28 h. The reaction mixture is cooled to RT, the precipitate is filtered to afford the title compound (1.9 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[CH3:14][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=O)[O:17]C1=O.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[C:4]([NH:5][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:15][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: Nc1cccc(Br)c1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CNc1ccccc1C(=O)Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A mixture of 3-bromo-2-chloroaniline [prepared according to the procedure described in U.S. Pat. No. 8,242,260] (240 mg, 1.162 mmol) and toluene (10 mL) at 0° C. was slowly treated with 2 M trimethylaluminum in toluene (0.99 mL, 1.98 mmol). The mixture was allowed to warm to room temperature and stirred for 15 min. A partial suspension of 1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (300 mg, 1.52 mmol) in toluene (4 mL) was added slowly. The resulting mixture was heated at 50° C. for 4 h, cooled to 0° C., and treated dropwise with 1M aqueous HCl until no more gas evolution was observed. The mixture was stirred for 2 h while warming to room temperature, then was extracted with EtOAc. The organic phase was washed sequentially with NaHCO3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide as a yellow solid (110 mg, 28% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.78 (dd, J=7.9, 1.5 Hz, 1H), 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.57 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.38 (ddd, J=8.4, 7.1, 1.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.68-6.61 (m, 1H), 2.79 (d, J=5.1 Hz, 3H).
Reaction SMILES: [O:1]([C:8]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])C1C=CC=CC=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC>[C:8]([NH:10][C@H:11]([C:19]([O:21][C:19](=[O:20])[C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:10][C:8]([OH:1])=[O:9])=[O:20])[CH2:12][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:9])=[O:1]
Reactant: Oc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)[C@H](Cc1ccccc1)NC(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, a solution prepared by dissolving 571 mg (2 mmol) of N-phenoxycarbonyl-L-phenylalanine and 184 mg (2 mmol) of phenol in 20 mL of 2-butanone was charged into a two-necked round bottom flask having a volume of 100 mL and mounted with a Dimroth condenser, and was then stirred at 80° C. for 8 hours. The fact that N-carboxy-phenylalanine anhydride was obtained in a yield of 99% or more was confirmed by subjecting the reaction mixture to NMR determination.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:16].[CH3:17][N:18](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]#[N:18])=[C:3]([CH3:16])[CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C#N
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-N-tert-butyl-3-methylbenzenesulfonamide (1.207 g) and zinc cyanide (0.976 g) in DMF (8 ml) was purged with N2 for 20 min. Then PdCl2(dppf) was added. The reaction mixture was heated at 120° C. for 4 hours and showed no reaction. Pd(PPh3)4 was added and the reaction mixture was stirred at 120° C. over the weekend. The reaction mixture was diluted with EtOAc and washed with 5% LiCl solution (2×). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel column chromatography to give 1.227 g N-tert-butyl-4-cyano-3-methylbenzenesulfonamide as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cccnc1
Product: COc1cc(OC)c(-c2cccnc2)cc1C=O
Yield: 68 %

Procedure:
Ex-104A: 2,4-Dimethoxy-5-pyridin-3-yl-benzaldehyde was prepared in a similar manner as described in Ex-3A from pyridine-3-boronic acid and 5-bromo-2,4-dimethoxybenzaldehyde, 68% yield. 1H-NMR (CDCl3) δ 10.33 (s, 1H), 8.71 (d, J=1 Hz, 1H), 8.51–8.53 (m, 1H), 7.81 (s, 1H), 7.74–7.78 (m, 1H), 7.27–7.31 (m, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.91 (s, 3H). HMRS (EI) calcd. for C14H13NO3: 243.0895; found: 243.0888.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (35 mg, 0.077 mmol) and methoxyethylamine (5 eq) in DMF (0.5 ml) was added K2CO3 (5 eq). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (10 mg, 26%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH2:40]([O:39][CH:38]([O:42][CH2:43][CH3:44])[C@@H:37]([N:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH3:45])[CH3:41]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1.[H][H]>C(O)C.[Pt]=O>[CH3:26][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Yield: 15.6 %

Procedure:
5-Dimethylamino-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (86.0 g) is dissolved in ethanol (800 ml), and thereto is added platinum oxide (10 g). The mixture is subjected to hydrogenation at ordinary temperature under atmospheric pressure of hydrogen for 4 hours. The catalyst is removed by filtration, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=200:1→100:1), and further purified by silica gel thin layer chromatography (developer; chloroform:methanol=10:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (Rf: 0.52, 27.4 g) and 5-dimethylamino-1-(2-methyl-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (Rf: 0.48, 12.3 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[O:13]=[C:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Br:12][C:10]1[N:11]=[C:7]([C:14]2([OH:13])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17]2)[S:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1csc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2nc(Br)cs2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
n-Butyllithium (1.6 M in THF, 6.3 mL, 10.1 mmol) was added dropwise to a −78° C. solution of 2,4-dibromothiazole (2.00 g, 8.30 mmol) in tetrahydrofuran (50 mL), and the mixture stirred at −78° C. for 1 h. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (2.83 g, 16.55 mmol) in tetrahydrofuran (5 mL) was added, and the resulting mixture stirred for 1 h at room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20% with ethyl acetate/petroleum ether) to afford tert-butyl 3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate (0.890 g, 32%) as a white solid. MS (ESI, pos. ion) m/z 335, 337 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](SC)[N:6]=1>CCO>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:2][NH2:3])[N:6]=1
Reactant: NN
Reactant: CSc1nccc(C)n1
Solvent: O
Solvent: CCO
Product: Cc1ccnc(NN)n1
Temperature: 0 °C
Reaction time: 50 h
Yield: 21562.2 %

Procedure:
Based on a reported procedure (Vanderhaeghe, Claesen, Bull. Soc. Chim. Belg. 1959, 68, 30). Hydrazine monohydrate (334.7 ml, 6.90 mmol) was added in one portion to a solution of 4-Methyl-2-methylsulfanyl-pyrimidine (357.9 g, 2.55 mol) in abs. EtOH (890 ml). The resulting mixture was refluxed for 50 h, then hydrazine monohydrate (200 ml) was added and refluxing was continued for 50 h (the reaction was monitored by 1H NMR). Then it was cooled to 0° C. to crystallize and 213 g of crude product was isolated by filtration. Recrystallization from ethanol gave the title compound (184.7 g, 59%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2nnc(C)o2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2nnc(C)o2)c(C)[nH]c1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 42.5 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)pyridine (95 mg, 0.408 mmol) and sodium iodide (182 mg, 1.21 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (3 mL) followed by chlorotrimethylsilane (156 μL, 1.24 mmol). The reaction mixture is stirred at 50° C. under nitrogen for 2.5 hr. The reaction mixture is allowed to cool and then quenched with water (0.5 mL). After stirring for 30 min the mixture is evaporated. The residue is partitioned between water and dichloromethane and the mixture treated with a little sodium bisulfite to decolorize. The dichloromethane layer is separated and the aqueous layer is extracted with five portions of dichloromethane. The combined dichloromethane layer is washed with two portions of aqueous sodium hydroxide (1M), then dried over magnesium sulfate and evaporated to give an orange residue. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (30:1). The clean fractions containing the product are combined and evaporated to give 3-ethyl-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyridin-2-one (38 mg, 43% yield) as a white solid. LC/MS: RT: 2.10 min, MS: m/e=220 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 12.24 (1H, s), 7.76 (1H, s), 2.76 (3H, s), 2.61 (2H, q), 2.61 (3H, s), 1.25 (3H, t).