Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[N:4][CH:3]=1.[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1>>[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])(=[O:28])=[O:27])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1

Procedure:
Prepared according to Preparation 207 using 5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208) and 5-chloro-2,4-difluorobenzenesulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[C@@H:10]2[C@H:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8][CH2:9]2)[CH2:4][CH2:3]1>C(N(CC)CC)C>[O:1]=[C:2]1[C@@H:10]2[C@@H:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:8][CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=C1CC[C@H]2CN(C(=O)OCc3ccccc3)CC[C@H]12
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]12

Procedure:
Azabicycles of general formula (98), (99), (100) and (101), wherein R is aryl or heterocycle, R′ is alkyl and R1 is as defined in formula (I), may be prepared as described in Scheme 24. Benzyl (trans)-5-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate, prepared as described in Eur. J. Med. Chem. (1991) 26, 889–906, may be epimerized with a base such as, but not limited to, triethylamine to provide benzyl (cis)-5-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate. Benzyl (cis)-5-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate may be processed as described in Schemes 2–8 to provide azabicycles of general formula (98), (99), (100) and (101).
Reaction SMILES: [CH:1]([C:4]1[C:16]([N:17]2[CH2:21][CH2:20][N:19]=[C:18]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([CH:28]([CH3:30])[CH3:29])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+]>C(#N)C.ClCCl>[CH:1]([C:4]1[C:16]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([CH:28]([CH3:30])[CH3:29])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(oc3ccccc32)c(C(C)C)c1N1CCN=C1c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)c1cc2c(oc3ccccc32)c(C(C)C)c1-n1ccnc1-c1ccccc1
Yield: 72 %

Procedure:
1-(2,4-diisopropyldibenzo[b,d]furan-3-yl)-2-phenyl-4,5-dihydro-1H-imidazole (7.4 g, 18.66 mmol) was dissolved in 200 mL of acetonitrile and 100 mL of dichloromethane. Potassium Permanganate (5.90 g, 37.3 mmol) and Clay K10 (12 g, 30.7 mmol) were ground in a mortar. The solid was then added carefully to the solution. Heat was generated after a few minutes. The reaction was monitored by TLC. The reaction was quenched with methanol after 1.5 h. The reaction mixture was filtered through Celite. The solvent was evaporated and the residue was purified by column. 5.3 g (72% yield) of pure product was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:9]=[N:10][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Clc1cc2nc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3cc(Cl)ncc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 6-chloro-3H-imidazo[4,5-c]pyridine (3.50 g, 22.79 mmol) in THF (50 mL) at 0° C. was slowly added sodium hydride (60% dispersion in mineral oil, 1.82 g, 45.58 mmol) in several portions. After stirring at RT for 30 min, 1-(chloromethyl)-4-methoxybenzene (4.30 g, 27.48 mmol) was added and the mixture was stirred at RT for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by SiO2 chromatography eluting with hexane/EtOAc (1:1) to afford 5.0 g (80%) of 6-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine as a white solid. MS (ESI): m/z=274.2 [M+1]+.
Reaction SMILES: C(N([C:12]1[S:13][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:16]=1)C(=O)OC(C)(C)C)(C)C.Br[C:27]1[CH:28]=[C:29]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:30]2[N:31]([CH:33]=[C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:35]=2)[CH:32]=1>>[CH:34]([NH:35][C:14]1[S:13][C:12]([C:27]2[CH:28]=[C:29]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:30]3[N:31]([CH:33]=[C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:35]=3)[CH:32]=2)=[N:16][CH:15]=1)([CH3:36])[CH3:33]
Reactant: COC(=O)Cc1cn2cc(Br)cc(-c3ccccc3)c2n1
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Product: COC(=O)Cc1cn2cc(-c3ncc(NC(C)C)s3)cc(-c3ccccc3)c2n1

Procedure:
Prepared in an similar fashion as Example 34, step #4 from tert-butyl isopropyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate and Methyl 2-(6-bromo-8-phenylimidazo[1,2-a]pyridin-2-yl)acetate. LCMS 407.4, HPLC Tr 2.02 min (Conditions C).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=O)=[CH:4][CH:3]=1>CC(O)=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]3[CH:13]=[C:14]([O:17][CH2:18][CH3:19])[CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(NC(=O)COc2ccc(Cl)cc2)c(NCC(C)C)c1
Solvent: CC(=O)O
Product: CCOc1ccc2nc(COc3ccc(Cl)cc3)n(CC(C)C)c2c1
Yield: 89.9 %

Procedure:
A solution of 58a (3.5 g, 0.0093 mol) in AcOH (50 mL) was heated at 100° C. for 1 hr. The reaction mixture was concentrated in vacuo, and to the residue was added CH2Cl2 (100 mL) and 37% aqueous ammonia (15 mL). The organic phase was washed with saturated NaHCO3 (2×75 mL) and brine (1×75 mL), filtered through phase separation filter paper, and concentrated in vacuo to give 3.0 g of a pink solid. The solid was chromatographed on 50 g of silica gel with 10 g anhydrous sodium sulfate on top packed with hexanes. The column was eluted with 25 mL portions of hexanes for fractions 1-4, 25% EtOAc in hexanes for fractions 5-8, and 35% EtOAc in hexanes for fractions 9-20. The product eluted in fractions 11-20 to give 2.5 g (70%) of Compound #7 as a tan solid. HPLC analysis showed a purity of 97%. 1H NMR (300 MHz, CDCl3): δ 7.7 (d, 1H), 7.3-6.8 (m, 6H), 5.35 (s, 2H), 4.1 (m, 4H), 2.3 (m, 1H), 1.45 (t, 3H), 1.0 (d, 6H) ppm.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11]CO1)C)[CH2:3][OH:4].[CH2:14](I)CCC.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:8]([O:7][CH2:5][C@H:2]([CH3:1])[C@@H:3]([OH:4])[CH3:14])[CH2:13][CH2:12][CH3:11]
Reactant: C[C@H](OC1CCCCO1)[C@@H](C)CO
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC[C@H](C)[C@H](C)O
Reaction time: 2 h
Yield: 59.7 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 5.0 g of the (2S,3S)-2-methyl-3-(2-tetrahydropyranyloxy)butanol obtained in Example 1 i) and 24.5 g of butyl iodide. Thereto was added 1.22 g of oily sodium hydride (about 60%) in small portions with ice-cooling. The mixture was stirred for 2 hours with ice-cooling. The reaction mixture was poured into 300 ml of ethyl acetate and the resulting mixture was stirred. The insoluble materials were removed by filtration. The filtrate was washed with water three times. The organic layer was dried and concentrated. The residue, i.e. crude (2S,3S)-4-butoxy-3-methyl-2-(2-tetrahydropyranyloxy)butane was dissolved in 150 ml of methanol. To the solution was added 6.0 g of a nonaqueous strongly acidic cation exchange resin (Amberlist 15), and the mixture was stirred for 6 hours at room temperature. The cation exchange resin used was removed by filtration and the filtrate was concentrated. The residue was subjected to Kugelrohr distillation under reduced pressure to obtain 2.54 g of (2S, 3S )-4-butoxy-3-methyl-2-butanol.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=3)[N:16]=[C:15]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:39].Cl.O.C(OCC)(=O)C>C1COCC1.C(O)C.[OH-].[Na+]>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]#[C:19][C:17]2[CH:18]=[C:13]([S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[C:7]([CH3:39])[CH:8]=3)[CH:14]=[C:15]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=3)[N:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)nc(C#Cc3ccc(CO)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(CO)cc3)nc(C#Cc3ccc(CO)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[2,6-Bis-(4-hydroxymethyl-phenylethynyl)-pyridin-4-ylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (150 mg; 0.27 mmol) was dissolved in a mixture of THF and ethanol (1:1) (10 ml) and 1N sodium hydroxide (1.5 ml) was added. The reaction mixture was stirred for about 1 h and 1N aqueous hydrogen chloride (3 ml), water (10 ml) and ethyl acetate (20 ml) was added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (10 ml). The pooled organic phases were washed with water (10 ml), dried and evaporated. During the evaporation a solid was formed which was filtered off and dried to give {4-[2,6-bis-(4-hydroxymethyl-phenylethynyl)-pyridin-4-ylsulfanyl]-2-methyl-phenoxy}-acetic acid. Yield: 51 mg.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]2)=[C:9]([CH:13]=1)[C:10](N)=[O:11].Cl.S(Cl)([Cl:24])=O.C(N(CC)CC)C>O>[Cl:24][CH2:18][CH2:19][CH:15]1[CH2:16][N:17]([CH3:20])[C:10](=[O:11])[C:9]2[CH:13]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=2[O:14]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC2CCN(C)C2)c(C(N)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)C(=O)N(C)CC(CCCl)O2
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 19.2 g (0.48 mole) of sodium hydroxide in 500 ml of water was added 60 g (0.24 mole) of 5-methoxy-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was cooled and the pH adjusted to 6.8 with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was boiled in isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 500 ml of chloroform and to this solution was added 114 g (0.96 mole) of thionyl chloride. The mixture was heated at reflux for 48 hr, then cooled with an ice/acetone bath. To the mixture was added dropwise 97 g (0.96 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction solution was washeed in sequence with water, 3N hydrochloric acid solution, water, 15% aqueous sodium hydroxide and water and finally dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a black solid. The solid was purified on a silica gel column using ethyl acetate as the eluting solvent to give on isolation 15 g (23%) of beige colored product, m.p. 98°-100° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[C:7]([C:9]#[N:10])[N:8]=1)([CH3:3])[CH3:2].[Cl:21][Sn]Cl.C(O)(C(F)(F)F)=O.[Sn]>Cl.O.C(#N)C.CC(O)C>[ClH:21].[CH:1]([C:4]1[S:5][C:6]2[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:9]([NH2:10])[C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: Cl[Sn]Cl
Reactant: CC(C)c1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Temperature: 60 °C
Yield: 95.9 %

Procedure:
Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile (35.1 g, 122 mmol) and IPA (525 mL) stir under N2 and heat to 60° C. to dissolve. Add a solution of SnCl2 (70.0 g, 369 mmol, 3.0 eq.) in aqueous 5M HCl (525 mL) dropwise over 30 min. Heat the reaction mixture at reflux (80–85° C.) for 1 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). Cooling the reaction to 50° C. Remove most of the solvent in vacuo. Treat the aqueous solid residue (188 g) with IPA (500 mL) and heat to 60–70° C. for a few minutes to form a homogenous slurry. Cool the slurry to rt, then 0–5° C. for 1–2 h. Isolate the product by vacuum filtration and dry in a vacuum oven at 60° C. to afford 45.9 g (128%) of crude product that was heavily contaminated with residual tin. Suspent the crude product in aqueous 1N HCl (2.25 L) and heat to reflux (95° C.) for 1 h, during which time most of the solids dissolve. Cool to rt, isolate the product by vacuum filtration, rinse with aqueous 1N HCl, and dry in a vacuum oven at 70° C. to afford 34.5 g (97%) of the title compound as a yellow/orange solid. Analytical analysis: Sn (9.0%), H2O (1.2%). 1H NMR (300 MHz, DMSO-d6) δ 10.96 (bs, 1H), 10.15 (bs, 1H), 8.94 (bs, 2H), 7.10–6.95 (m, 2H), 6.93–6.82 (m, 2H), 3.10 (dq, 1H, J=6.95 Hz), 1.28 (s, 3H), 1.26 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 164.42, 159.24, 158.94, 137.01, 128.58, 127.11, 125.09, 122.87, 120.14, 119.23, 32.41, 21.98(2). IR(KBr) 3301, 3249, 2964, 1653, 1614, 1553, 1509 cm−1. HRMS (ES) M/z calculated for C13H15N4S 259.1017 (M+−Cl), found 259.1010.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH2:28]([O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:38][C:37]1[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=1[O:35][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
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: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
6.38 g of sodium triacetoxyborohydride (30.1 mmol) was added to a solution of 4.68 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (25.0 mmol), 5.0 g of 2-benzyloxyaniline (25.0 mmol) and 1.44 ml of acetic acid (25.0 mmol) in methylene chloride (250 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 8.50 g of the title compound (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]([C:7]2[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[OH:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Brc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2Br)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a cold (−78° C.) solution of 2-bromo pyridine (800 mg, 5.06 mmol) in freshly distilled THF (15 mL) was added LDA (2.0 M, 2.8 mL, 6.5 mmol). The mixture was stirred under N2 for 30 min. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was added slowly to maintain the bath temperature below −70° C. The reaction was stirred at below −70° C. for 30 min, warmed to −20° C. within 60 min, and quenched with saturated aqueous NH4Cl (10 mL). Work-up and purification gave 4-[(2-bromo-pyridin-3-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 50%) as a colourless oil.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].[S-:19][S-].[Na+].[Na+]>O>[SH:19][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)c1cccc(N)c1C(=O)O
Reactant: [S-][S-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc(S)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
10.2 g of 2-amino-6-acetylbenzoic acid was converted into a diazonium salt with a mixture of 14.2 ml of concentrated hydrochloric acid, 40 ml of water and 4.3 g of sodium nitrite, and the diazonium salt was gradually added dropwise at a temperature of 0° to 5° C. to a sodium disulfide aqueous solution (prepared from 14.3 g of sodium sulfide.9H2O, 1.9 g of sulfur, 4.6 g of sodium hydroxide and 30 ml of water). After adding dropwise, the reaction liquor was stirred for 2 hours at room temperature to complete the reaction. The reaction liquor was poured into a large amount of water, and after adding concentrated hydrochloric acid thereto, the product was extracted with ethyl acetate. To the ethyl acetate layer, was added sodium hydrogencarbonate aqueous solution, and the content soluble in sodium hydrogencarbonate was extracted. To the resultant aqueous solution, was added 14.8 g of sodium pyrosulfate, and the mixture was refluxed for 30 minutes to complete the reaction. To the reaction liquor, was added concentrated hydrochloric acid, and the product was extracted with ethyl acetate. The extracted liquor was dried, and the solvent was distilled off under reduced pressure to obtain 10.1 g of 2-mercapto-6-acetylbenzoic acid at a yield of 90%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.FC(F)(F)C(O)=O.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>CS(C)=O>[C:41]([C:40]1[CH:43]=[CH:44][C:37]([NH:36][CH2:35][CH2:34][NH:33][C:2]2[N:7]3[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:3]=2)=[N:38][CH:39]=1)#[N:42]
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(NCCNc3ccc(C#N)cn3)n2n1

Procedure:
200 mg (0.52 mmol) of ethyl 5-chloro-7-(4-trifluoromethylphenyl)[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 149A) and 123 mg (0.62 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 13A) are introduced into DMSO (2 ml), 0.54 ml (3.1 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 90° C. for 30 min. The reaction mixture is purified by preparative HPLC. 98 mg (38% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CC(O)=O>C1COCC1.[Zn]>[CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: COCC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCC(C)(C)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
1-(2-Methoxy-1,1-dimethyl-ethyl)-4-nitro-benzene (1 eq) was dissolved in THF (40 mL/mmol) at 0° C. and HOAc (20 eq) was added, followed by Zn dust (30 eq). The mixture was stirred at RT until the starting material was consumed and was filtered on silica pad. Solvent was evaporated, the residue was dissolved in CH2Cl2 and washed with NaOH 1M. The organic phase was dried, filtered and evaporated to give the amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(O)C=CC=1.[C:24]1([CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:33]2([OH:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]([CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]2=[O:41])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 3-(benzyloxy)phenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (75%): MS (ES+) m/z 496.0 (M−17).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:37])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC(=O)[C@H](C)O)c(F)cc43)c(C)c2C1=O
Yield: 50.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (37 mg, 50.3%) as an orange solid.