Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: CO
Solvent: O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 61.9 %

Procedure:
Esomeprazole magnesium trihydrate (20 g) was dissolved in methanol (200 ml) at 25-30° C. Any undissolved material was filtered off and triethylamine (0.2 ml) was added to the filtrate. The clear solution thus obtained was subjected to spray drying with an inlet temperature of 65-68° C. and an outlet temperature of 22-42° C. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 11.5 g of esomeprazole magnesium of amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(C)OC(=O)NCCCN
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: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCNC(=O)OC(C)(C)C)c2n1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 200 mg, 0.560 mmol) and HATU (255 mg, 0.672 mmol) in DMF (2 mL) was added DIEA (292 μL, 1.68 mmol), followed by dropwise addition of tert-butyl 3-aminopropylcarbamate (117 mg, 0.672 mmol) at ambient temperature. After stirring for 3 hours, the reaction was directly purified by reverse-phase chromatography (5 to 70% acetonitrile/water) to yield the final product as white solid (250 mg, 87%). LCMS (apci) m/z=414.1 (M+H-Boc).
Reaction SMILES: C(O)(=O)C.[OH-].[Na+].[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11].[Br:19]Br>O>[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][C:15]([Br:19])=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)c1cccc(C)c1N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Br)cc(C)c1N
Temperature: 55 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A 1000-mL flask equipped with a mechanical stirrer, thermocouple, condenser and Teflon® fluoropolymer tubing ( 1/16″ (0.16) cm I.D.×⅛″ (0.32 cm) O.D.) (positioned such that the end of the tubing was submerged below the surface of the reaction mixture) was charged with acetic acid (226 mL). A solution of aqueous sodium hydroxide (50%, 25 g) in water (85 g) was added over 15 minutes, and then 2-amino-N,3-dimethylbenzamide (50 g, 0.305 mol) (see PCT Patent Publication WO 2006/062978 for a method of preparation) was added and the mixture was heated at 55° C. A two-necked 200-mL flask fitted on one neck with a Teflon® tubing dip tube was charged with liquid bromine (50.1 g), and the other neck was connected to the Teflon® tubing on the 1000-mL flask. Nitrogen gas was then flowed through the dip tube below the surface of the liquid bromine at a rate of about 0.012 m3 (0.4 cu ft) per h for 2.5 h, during which time all of the bromine evaporated and the bromine vapor entrained in the nitrogen gas flowed out of the two-necked 200-mL flask and entered the reaction mixture through the Teflon® tubing. The reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes thereafter, and then cooled to 45° C. and stirred overnight. A solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute. After about 10% of the total volume of the sodium hydroxide solution had been added, the addition was stopped and the reaction mixture was stirred for 1 h at 45° C. After 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute. After the addition was complete, the reaction was stirred for 30 minutes at 45° C., and then cooled to 10° C. and stirred for 1 h. The mixture was filtered and the solid collected was washed with methanol (130 mL) and water (260 mL), and then dried to a constant weight in a vacuum-oven at 45° C. to give the title compound as a solid (67 g, 99.4 area % purity by HPLC, 89.7% yield) melting at 133-135° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:13]([NH:17][C:18]1[O:19][C:20]([C:27](Cl)=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH3:14][C:13]([NH:17][C:18]1[O:19][C:20]([C:27]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])[CH3:15]
Reactant: CC(O)CN
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CNC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Yield: 46.1 %

Procedure:
By the procedure of Example 38, a stirred mixture of 70 ml methylene chloride, 1.80 g (24 mmol) of 1-amino-2-propanol, 2.68 g (13.2 mmol) of triethylamine, and 6.50 g (24 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride was reacted for 16 hours at ambient temperature. The product was separated and then recrystallized to yield 3.42 g of a white solid product (m.p.=105°-107° C.) identified in Table I.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.C(O)(=O)C(O)=O.[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(N(CC)CC)C>C(O)CC>[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(CO)CCN
Agent: Clc1ncnc2nc[nH]c12
Agent: O=C(O)C(=O)O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CC(CO)CCNc1ncnc2c1ncn2C1CCCCO1
Yield: 75 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2318 mg) 4-hydroxy-3-methylbutylamine oxalate, and 5 mL of triethylamine was refluxed in n-propanol for 3 hours and subsequently 24 hrs at laboratory temperature. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of hexane. The solid residue was filtered off and the crude product crystallized from methanol. Yield 75%, white solid. TLC (CHCl3:methanol (4:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (400 MHz, DMSO): 0.88d (3H, J=6.6 Hz); 1.34m (1H); 1.56m (3H); 1.70m (1H); 1.71m (1H); 1.93m (2H); 1.94m (1H); 2.26m (1H); 3.25m (1H); 3.52bs (2H); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.42t (1H, J=5.1 Hz); 5.61d (1H, J=10.6 Hz); 7.70bs (1H); 8.20s (1H); 8.30s (1H). MS (ES): [M+H]+=306 (100).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](O)=[O:26].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:25](=[O:26])[CH2:24][N:20]2[CH2:21][CH2:22][CH2:23][C:19]2=[O:18])=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: O=C(O)CN1CCCC1=O
Reactant: Clc1nn(-c2cccnc2)cc1NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CCCN1CC(=O)N(CC1CC1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 7 mL vial was added 3-chloro-N-(cyclopropylmethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.124 g, 0.500 mmol) (prepared according to the U.S. Publication No. 2012/0110702), DMAP (0.183 g, 1.50 mmol), 2-(2-oxopyrrolidin-1-yl)acetic acid (0.143 g, 1.00 mmol), EDCI (0.240 g, 1.25 mmol) followed by CH2Cl2 (1 mL). The reaction mixture was stirred at a temperature of about 25° C. for 18 hours before it was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to afford the title compound F98 as a light yellow oil (0.131 g, 70%).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:4]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][CH2:10][O:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH2:4][CH2:5]2)[CH2:31][CH2:30]1
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN([C@H]1CC[C@H](OCCC(=O)N2CCC(O)CC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
100 mg (0.24 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 3 mL of CH2Cl2 were treated with 21.3 mg (0.36 mmol, 1.5 eq) of 4-hydroxypiperidine and 0.40 mL (0.36 mmol, 1.5 eq) of NMM. The solution was cooled to 0° C. and 60.9 mg (0.31 mmol, 1.3 eq) of EDCI and 7.5 mg (0.05 mmol, 0.2 eq) of HOBT were added. The mixture was stirred at RT over night, and was then partitioned between CH2Cl2 and a saturated aqueous solution of Na2CO3. The organic phase was washed with a solution of KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 98:2 gave 97.1 mg (81%) of trans-N-{4-[3-(4-hydroxy-piperidin-1-yl)-3-oxo-propoxy]-cyclohexyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as white powder, MS: 493 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc(COC(=O)CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CNCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a cold (0°-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3) δ1.41 (s, 9H), 1.61 (quint, J=7 Hz, 2H), 2.63 (t, J=7 Hz, 2H), 3.17 (q, J=6 Hz, 2H), 3.38 (s, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 6.86 (m, 2H), and 7.26 (m, 2H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCc1c(F)cc(OC)cc1F
Agent: CCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of ethyl 3-(2,6-difluoro-4-methoxyphenyl)propanoate (1.17 g, 4.79 mmol), aluminum chloride (1.9 g, 14.2 mmol) and 1-octanethiol (1.7 mL, 9.80 mmol) in dichloromethane (20 mL) was stirred for 4 hr while raising the temperature from under ice-cooling to room temperature. The reaction mixture was poured into ice water, and the mixture was stirred for 1 hr. The mixture was extracted with dichloromethane. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.0 g, yield 91%) as a colorless oil. MS: m/z 231 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)=[O:29])=[CH:23][CH:22]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in chloroform (0.5 mL) at 20° C. was treated with 4-chlorophenyl isocyanate (11 mg,0.07 mmol). The mixture was shaken at room temperature for 18 hours then concentrated under reduced pressure. The compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 429 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.55 (s, 1 H), 8.52 (d, 1 H), 8.45 (d, 1 H), 7.83 (s, 1 H), 7.57 (d, 1 H), 7.41 (d, 2 H), 7.26 (d, 2 H), 6.70 (s, 1 H), 6.31 (d, 1 H), 3.78 (s, 1 H), 3.71 (s, 1 H), 1.63-1.93 (m, 8 H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=1)[C:4]([OH:6])=[O:5].[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>>[Cl:19][CH:20]([Cl:24])[C:21]([O:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=1)[C:4]([OH:6])=[O:5])=[O:22]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CS(=O)(=O)Nc1cc(C(=NO)C(=O)O)ccc1O
Product: CS(=O)(=O)Nc1cc(C(=NOC(=O)C(Cl)Cl)C(=O)O)ccc1O
Yield: 98.7 %

Procedure:
2-Hydroxyimino-2-(3-mesylamino-4-hydroxyphenyl)acetic acid (syn isomer) (1.37 g.) and dichloroacetyl chloride (0.9 g.) were treated according to similar manners to those of Preparation 5(1) to 5(3) to give 2-dichloroacetoxyimino-2-(3-mesylamino-4-hydroxyphenyl)acetic acid (syn isomer) (1.9 g.), which was used as a starting material for the following acylating reaction without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)=[O:11])[C:20]1=[O:21])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCS(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.33 g (0.98 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.287 g (74.8%, yellow oily substance) of the desired product.
Reaction SMILES: C(S(N1CCC(C2[C:20]3[C:15](=[C:16](C(N)=O)[CH:17]=[C:18](C4SC(CNCC(C)CC)=CC=4)C=3)[NH:14]C=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.CC(N)CCC.[BH3-]C#N.[Na+]>>[CH3:20][CH:15]([NH:14][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCCC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCC(C)NCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 35.2 mg of the title compound (60%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 2,5-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 130. 1H NMR (CDCl3) δ: 7.98 (s, 1H), 7.82 (d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=8.1 Hz), 6.37 (d, 1H, J=2.5 Hz), 6.18 (d, 1H, J=2.5 Hz), 4.58 (ABq, 2H, JAB=14.1 Hz), 4.51 (s, 2H), 4.18 (app d, 1H, J=12.5 Hz), 3.90 (m, 1H), 3.74 (app t, 1H), 3.36-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.20-3.08 (m, 2H), 3.03 (dd, 1H), 2.93-2.85 (m, 2H), 2.64 (app t, 1H), 2.46 (dd, 1H, J=12.1, 10.6 Hz), 2.00-1.80 (m, 2H). LRMS (ES)+: 472.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14](Cl)Cl.CO>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was dissolved in 1 ml of SOCl2. The solution was refluxed for 1 hour. Excess SOCl2 was removed under reduced pressure and 5 ml of CH2Cl2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. Excess MeOH and TEA were removed and the residue was purified by column chromatography with ethyl acetate/hexane (1/3) to yield the title compound as a yellow solid (316 mg). 1H NMR δ 7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.67 (dd, J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>N1C=CC=CC=1>[F:15][C:4]1[CH:3]=[C:2]([NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 76.5 %

Procedure:
To a solution of ethyl 3-(4-amino-2-fluorophenyl)propanoate (9.89 g, 46.8 mmol) in pyridine (70 mL) was added 2-nitrobenzenesulfonyl chloride (11.4 g, 51.5 mmol) by small portions, and the mixture was stirred at room temperature for 70 hr. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue. The mixture was stirred with heating at 80° C. for 15 min and filtrated through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (14.2 g, yield 76%) as pale-yellow prism crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C:28]3[CH:41]=[CH:40][C:31]([O:32][CH2:33][C:34](N(OC)C)=[O:35])=[CH:30][CH:29]=3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:35][CH:34]([CH3:43])[CH2:33][O:32][C:31]1[CH:30]=[CH:29][C:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)=[CH:41][CH:40]=1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(=O)N(C)OC)cc2)c2ccnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)O)cc2)c2ccnn12
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-N-methoxy-N-methylacetamide (0.44 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.6 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (4 mL), and sodium borohydride (0.030 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.30 g, 73%).