Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([Cl:16])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccc1C(F)(F)F
Yield: 90.1 %

Procedure:
4-Trifluoromethylnicotinic acid (50.09 g, 0.262 mol) was suspended in benzene (250 ml), and thionyl chloride (38.2 ml, 0.524 mol) and N,N-dimethylformamide (0.1 ml) were added. The mixture was refluxed for 3 hours. The reaction mixture was concentrated, and the residue was distilled under reduced pressure to obtain 49.45 g (yield 90.1%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[CH:15]1([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]4[CH:35]=[C:36]([C:38]5[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][N:39]=5)[S:37][C:30]=34)=[C:24]([F:46])[CH:23]=2)=[O:20])[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.CC(O)=O>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:36]3[S:37][C:30]4[C:31](=[N:32][CH:33]=[CH:34][C:29]=4[O:28][C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][CH:15]5[CH2:16][CH2:17]5)=[O:20])=[CH:23][C:24]=4[F:46])[CH:35]=3)=[N:39][CH:40]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (1.34 g, 6.69 mmol) was added to a solution of the aldehyde 47 (2.0 g, 4.46 mmol) in a mixture of NMP (20 mL) and glacial AcOH (0.250 mL). The reaction mixture was stirred for 30 min. NaBH(OAc)3 was then added and the reaction mixture was stirred for an additional 2.5 hours. The reaction mixture was then poured into a saturated aqueous NaHCO3 solution. A precipitate was formed which was collected by filtration, washed with water and air-dried. The crude material was purified by column chromatography using a 5 to 20% gradient of MeOH in EtOAc as eluent to afford the title compound 343 (1.45 g, 51.4% yield). MS (m/z): 633.6 (M+1)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:18])=[N-]>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Reactant: C=[N+]=[N-]
Product: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1

Procedure:
2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) and diazomethane (1.5 g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Preparation (5-3) (b) to give crystals of methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[C:22]1([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ccc2ccc(-c3ccccc3)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(-c3ccccc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 57.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-phenyl-1,8-naphthyridine (1.6 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 160° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenyl-1,8-naphthyridin-2-yl)-3-chlorobenzamide (1.5 g), m.p. 175° C., is obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)CCN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 87.4 %

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (10 g), β-alanine methyl ester monohydrochloride (5.99 g), acetic acid (4 mL) and sodium triacetoxyborohydride (10.9 g) in dichloroethane (400 mL) was stirred overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (12.0 g, 87%) as a colorless oil.
Reaction SMILES: [C:1]([C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[K+].O.[OH-].[K+].[H][H]>[Ni].C(O)(C)C>[NH2:2][CH2:1][C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](C#N)CC(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of potassium (S)-3-cyano-5-methylhexanoate (20 g, 103.5 mmol), water (50 mL), 45% KOH (12 g), isopropanol (12 g), and Raney Nickel were shaken overnight in a Parr Shaker under 50 psi of hydrogen. The mixture was filtered, heated to approximately 50° C., treated with acetic acid (6.5 mL) and stirred overnight at room temperature. The mixture was then adjusted to slightly above pH 7 with 45% KOH and concentrated under vacuum to remove most of the isopropanol. Isopropanol (20 mL) was added to the mixture, which was then acidified with acetic acid, stirred overnight at room temperature, and filtered to give 4.3 g of (S)-3-aminomethyl-5-methylhexanoic acid as a white crystalline solid. The enantiomeric purity was determined to be 100% e.e. by preparing a derivative of (S)-3-aminomethyl-5-methylhexanoic acid using Marfey's reagent (Nα-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) and analyzing by HPLC on a BDS Hypersil C18 column (250×4.6 mm, 5μ) eluted with acetonitrile:1% triethylamine (pH 3) (38:62, v/v).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:32][NH:33][CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:33]([CH3:34])[CH3:32])=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CC(C)(C)Oc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a large capacity microwave tube containing 2-(6-chloropyridin-3-yloxy)-2-methylpropanal (354 mg, 1.77 mmol) and sodium triacetoxyborohydride (940 mg, 4.43 mmol) in dry dichloromethane (4 ml) was added glacial acetic acid (0.81 ml, 14.2 mmol) followed by a 2 M solution of dimethylamine (14.2 ml, 28.4 mmol, in tetrahydrofuran). The tube was capped and heated to 50° C. (oil bath) with vigorous stirring for 16 hours. The mixture was cooled to ambient and the contents poured into a separatory funnel containing an aqueous solution of saturated sodium bicarbonate (30 ml). Dichloromethane (30 ml) was added and the mixture was shaken. The contents were filtered through a plug of celite, washing well with dichloromethane. The filtrate was collected and washed with a brine solution (40 ml). The dichloromethane phase was collected and the aqueous phase was back extracted with methylene chloride (2×40 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The material was purified by preparative thin layer chromatography (2 plates), eluting with 1.8% methanol/dichloromethane. The plates were then re-developed with 2.6% methanol/dichloromethane, and the product band was collected which provided the desired as a light yellow mobile oil, which slowly solidified on standing (255 mg). (M+H)+=229 m/e.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].[CH3:17][NH:18][C:19]([NH2:21])=[S:20]>C(O)(=O)C>[CH3:17][NH:18][C:19]1[S:20][C:2]2[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]=2[N:21]=1
Reactant: CC1(C)CC(=O)C(Br)C(=O)C1
Reactant: CNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
82 g of 2-bromo-5,5-dimethylcyclohexane-1,3-dione, 40 g of sodium acetate and 50 g of N-methylthiourea are dissolved in 500 ml of acetic acid. The mixture is stirred at room temperature until the weakly exothermic reaction has subsided, and then refluxed for 3 hours. The reaction mixture is then concentrated to one third of its volume in a rotary evaporator, poured into 100 ml of water and cooled to 0° C. The precipitate is collected by filtration and dried in vacuo at 80° C., affording 64 g of 2-methylamino-5,5-dimethyl-7-oxo-4,5-dihydro-6H-benzthiazole with a melting point of 217°-218° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24].[F:42][C:43]([F:49])([F:48])[CH2:44][C:45](O)=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH:39][C:45](=[O:46])[CH2:44][C:43]([F:49])([F:48])[F:42])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Reaction time: 1 h
Yield: 28.2 %

Procedure:
TBTU (2.09 g, 6.50 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (1.30 g, 4.33 mmol), 3,3,3-trifluoropropionic acid (0.574 mL, 6.50 mmol) and DIPEA (2.97 mL, 17.3 mmol) in CH2Cl2 (43 mL). The mixture was stirred for 1 h, and CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl, aq. 10% Na2CO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 60:40) yielded the title compound (500 mg, 28%). LC-MS: tR=1.12 min; ES+: 410.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:33]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:32])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:31])[C:20]=2[N:21]2[CH2:26][CH2:25][NH:24][C@@H:23]([C:27]([F:30])([F:29])[F:28])[CH2:22]2)[N:13]=1.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:33][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:31])[C:20]=1[N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([C:27]([F:29])([F:30])[F:28])[CH2:22]1)=[O:32]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCN[C@@H](C(F)(F)F)C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCN[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-Butyl (R)-2-(2,6-difluorophenyl)-4-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (80 mg, 0.126 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at ambient temperature for 3 hours. The pH of the mixture was adjusted to about 8˜9 by addition of ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to afford 169 formic acid salt (40 mg, 73%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.84 (s, 1H), 7.50-7.55 (m, 3H), 7.37 (s, 1H), 7.25-7.28 (m, 2H), 3.47 (s, 3H), 3.36-3.48 (m, 1H), 3.07-3.16 (m, 3H), 2.94-2.96 (m, 2H), 2.78-2.80 (m, 1H), 1.24 (s, 1H); MS (ESI) m/z=488.1 (M+1+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:12][C:13]1[CH:44]=[CH:43][CH:42]=[CH:41][C:14]=1[CH2:15][NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:40])[C@@H:27]([OH:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:18]>CCOC(C)=O>[CH3:12][C:13]1[CH:44]=[CH:43][CH:42]=[CH:41][C:14]=1[CH2:15][NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:40])[C@@H:27]([OH:39])[C@@H:28]([NH:38][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=1[Cl:11])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[O:18]
Reactant: Nc1cccc(C(=O)O)c1Cl
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(N)c2Cl)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
DPP-Cl(68 μl) and TEA(50 μl) were added to a solution of 3-amino-2-chlorobenzoic acid (56 mg) in EtOAc (2 ml), and the mixture was stirred for one hour. After the addition of the compound obtained in Step 2 of Example 1 (141 mg) and TEA (50 μl), the mixture was stirred overnight. The reaction mixture was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4. After filtration and concentration, the residue was purified by silica gel column chromatography (CH2Cl2—MeOH), and reprecipitated from a mixture of CH2Cl2 and n-hexane to obtain the title compound (153 mg, 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:3]2[C:4]([NH:8][S:9]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[N:5][CH:6]=[N:7][C:2]=2[O:29][CH2:28][CH2:27][OH:30])=[CH:21][CH:22]=1
Reactant: OCCO
Reactant: O=S(=O)(C=Cc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Product: O=S(=O)(C=Cc1ccccc1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
6.20 g of 2-phenyl-ethenesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide was added to a solution of 7.65 g of potassium-tert.-butylate in 100 ml of ethylene glycol. The resulting solution was heated to 110° C. and stirred for 17 h. The ethylene glycol was evaporated under high vacuum and the remaining residue was treated with 250 ml of cold water. The suspension was acidified by adding 10 g of citric acid monohydrate and stirred at 0° C. for 15 min. The precipitate was collected, washed with water and dried to give 6.71 g of 2-phenyl-ethenesulfonic acid [5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide as a white powder. LC-MS: tR=4.55 min, [M+H]+=432.00 (ES+), [M−H]−=429.98 (ES−).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:4])=[O:3]
Reactant: Cc1c(-c2cccnc2)n(CCO)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2cccnc2)n(CCOS(C)(=O)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.70 ml) is added dropwise to a solution of 7.5 g 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole and 10.34 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated NaHCO3 solution, dried over MgSO4 and evaporated in vacuo. There is obtained 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole which is used directly in the above reaction.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15].[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[NH4+]>O>[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.83 h
Yield: 81.5 %

Procedure:
To 98% sulfuric acid (4.93 kg, 49.3 mol), 2,3,5-trimethylpyridine1-oxide (1.38 kg, 10.1 mol) was added. After 97% nitric acid (1.44 kg) was added dropwise thereto over 50 minutes, the mixture was heated at 85° C. for 4 hours. The reaction mixture was poured to a mixture of ammonium hydrogen carbonate (10.6 kg) and water (9.0 L). The mixture was extracted with ethyl acetate (3.0 L×3). The obtained organic layer was concentrated and dried under vacuum overnight to obtain a desired product (1.50 kg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[CH3:30][C:31]([NH2:34])([CH3:33])[CH3:32]>>[C:31]([NH:34][C:20]([C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:11]3[S:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:9]([C:26]([NH:27][CH3:28])=[O:29])[C:10]=3[CH:16]=2)[CH:25]=[CH:24][CH:23]=1)=[O:21])([CH3:33])([CH3:32])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12

Procedure:
5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 2-methylpropan-2-amine (0.016 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.42 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.96 (s, 2H), 7.82 (s, 3H), 7.66 (s, 2H), 7.57 (s, 1H), 7.37 (s, 2H), 2.78 (s, 3H), 1.42 (s, 9H). LCMS: retention time: 3.218 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 461 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=1[O:39][CH3:40])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=3[O:39][CH3:40])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCCBr
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(4-amino-5-chloro-2-methoxyphenyl)-l-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-amino-5-chloro-2-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[CH:19]([OH:21])=[O:20].[C@@H:12]12[CH2:14][C@@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3)cc1
Yield: 216.6 %

Procedure:
Title compound 207 (0.32 g, 0.878 mmol) and Pd/C (0.093 g, 0.088 mmol) were combined in methanol (16.73 mL) and formic acid (0.836 mL). The reaction mixture was stirred at reflux for 2 h. The mixture was filtered and concentrated to afford title compound 208 (0.278 g, 99%) as a clear oil. LRMS: (calc) 246.14. (found) 247.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13](Cl)[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15].C(O)C>[H][H].[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: [H][H]
Reactant: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC(C)(C)[N+](=O)[O-])c(OC)c1OC
Yield: 89.1 %

Procedure:
A mixture of 5 g of 1-(2,3,4-trimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane, 2 g of 10% palladium-carbon and 50 ml of ethanol is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the uptake of hydrogen is completed, insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. 3.95 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropane are thereby obtained as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:35][CH2:36][CH3:37])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH2:29]C)[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=O)[CH3:2].Cl.[NH2:39][OH:40]>N1C=CC=CC=1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([C:1](=[N:39][OH:40])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:35][CH2:36][CH3:37])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2CC)C(=O)N1Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCNc1ccc(C(C)=NO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 38 was added hydroxylamine hydrochloride (2 equiv) and pyridine. The resulting mixture was heated at 80° C. for 24 h, cooled, concentrated and chromatographed (TEA-washed silica gel, 0-50% EtOAc/Hex) to give the title compound. 1H-NMR (DMSO-d6): δ 11.07 (1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m), 7.21-7.33 (5H, m), 7.09-7.14 (1H, m), 5.05 (2H, s), 3.92 (2H, q), 3.27 (3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).