Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:21][C:22]1[S:26][C:25]([C:27](SC)=[NH:28])=[CH:24][CH:23]=1>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:21][C:22]1[S:26][C:25]([C:27](=[NH:28])[NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH2:12]3)=[CH:24][CH:23]=1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Reactant: CSC(=N)c1ccc(C)s1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)CCCN3CCCN2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a stirred solution of 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in ethanol (6 ml) was added methyl 5-methylthiophene-2-carbimidothioate hydroiodide (265 mg, 0.887 mmol). The resulting suspension was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane. The combined organics were dried, filtered and concentrated, then chromatographed on silica gel with ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane as eluent to give the desired 5-methyl-N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (98 mg, 0.256 mmol, 57.8% yield). 1H NMR (DMSO-d6) δ 7.45 (d, J=3.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.53 (m, 2H), 6.45 (s, 1H), 6.13 (brs, 2H), 3.26-3.16 (m, 4H), 2.68-2.63 (m, 2H), 2.43-2.39 (m, 6H), 2.41 (s, 3H), 1.86-1.82 (m, 2H), 1.68-1.64 (m, 6H). ESI-MS (m/z, %) 383 (MH+, 39), 272 (49), 192 (100). ESI-HRMS calculated for C22H31N4S (MH+), calculated: 383.2264, observed:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][S:8][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1)[CH3:14]
Reactant: CCOC(=O)CSc1nccc(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nccc(NCc2ccc(Cl)cc2)n1
Yield: 38.4 %

Procedure:
A stirred mixture of 10.0 g of (4-chloro-2-pyrimidinylthio)acetic acid, ethyl ester, 6.0 g of p-chlorobenzylamine and 4.5 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to induce crystallization. After cooling in ice the precipitate was collected on a filter. Recrystallization from benzene-petroleum ether afforded 5.5 g of product, mp. 175-178°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: NO
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=O)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=NO)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(4-chloro-3-formyl-2-oxopyridin-1(2H)-yl)-3-fluorobenzonitrile obtained in Step C (2.70 g), hydroxylamine hydrochloride (814 mg), sodium acetate (1.60 g) and methanol (60 mL)/water (15 mL) was stirred at room temperature for 1 hr. The reaction solution was poured into ice water. The resulting solid was collected by filtration, and washed successively with water, 2-propanol and diethyl ether to give the title compound (2.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1cccc(Oc2cnccn2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2cnccn2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(2-pyrazinyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9- [3-(2-pyrazinyloxy)phenyl]-1,8-(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale brown crystalline solid of melting point 204-207° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH2:12][S:13]([CH2:16][S:17]([CH2:20][C:21](O)=O)(=[O:19])=[O:18])(=[O:15])=[O:14])(O)=O>C(O)(=O)C>[CH:12](/[S:13]([CH2:16][S:17](/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18])(=[O:15])=[O:14])=[CH:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccccc1)CS(=O)(=O)/C=C/c1ccccc1
Yield: 77 %

Procedure:
A solution of benzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 77% yield. m.p. 128-130° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+].CC(C)=O>O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:13]([OH:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1S(=O)O

Procedure:
10.7 g (0.04 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonyl chloride are introduced into a solution of 15 g of Na2SO3 and 4 g of NaOH in 100 ml of water. After adding a little acetone, the mixture is heated on a steam bath for 30 minutes, then filtered and the pH is adjusted to 2-3 with concentrated hydrochloric acid.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([OH:34])=[CH:27][C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1.I[CH3:39]>CN(C=O)C.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][C:28]([O:34][CH3:39])=[CH:27][C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(C(C)C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Sodium hydride (7 mg, 0.3 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (99 mg, 0.2 mmol) in DMF (2 ml), the mixture was heated at 60° C. for 10 minutes, and iodomethane (43 mg, 0.3 mmol) was dropped thereinto followed stirring for 30 minutes. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, hexane:acetone 5:3) to provide 44 mg (yield 43%) of the desired compound as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:28]1[CH2:30][C@H:29]1[CH2:31]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:31][C@@H:29]2[CH2:30][O:28]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: OC[C@@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OC[C@@H]2CO2)cn1
Temperature: 0 °C
Reaction time: 30 h
Yield: 59.5 %

Procedure:
In a 250 mL round-bottomed flask, 6-chloropyridin-3-ol (2.116 g, 16.3 mmol), triphenylphosphine (5.14 g, 19.6 mmol) and (R)-oxiran-2-ylmethanol (1.21 g, 1.08 ml, 16.3 mmol) were combined with THF (75.0 ml) to give a colorless solution. Cooled to 0° C. DEAD (3.41 g, 3.1 ml, 19.6 mmol) was added. The reaction mixture was allowed to come to 25° C. and stirred for 30 h. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 80 g, 5% to 25% EtOAc in hexanes) followed by flash chromatography (silica gel, 40 g, 0.5% to 1% MeOH in DCM) to afford the desired product (1.8 g, 59%) as a white solid. (M+H)+=186 m/e.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O[C:26]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([C:38]#[N:39])[CH:32]=2)([CH3:28])[CH3:27]>O>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]2[C:20](=[O:21])[C:37]3[C:36]4[C:31](=[CH:32][C:33]([C:38]#[N:39])=[CH:34][CH:35]=4)[NH:30][C:29]=3[C:26]([CH3:28])([CH3:27])[C:18]=2[CH:17]=1
Reactant: CC(C)(O)c1cc2ccc(C#N)cc2[nH]1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
(Method 3) To nitrobenzene (5 ml) and aluminum chloride (400 mg, 3 mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was added. After stirring for 30 min at room temperature, 2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound AA6, 200 mg, 1 mmol) was added followed by stirring at room temperature for 3 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (127 mg, 40%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+].CN(C)C=O>O>[CH3:16][C:3]1[C:2]2[O:15][CH2:14][CH2:13][NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1nc2ccccc2c(NCCO)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2c2c1OCCN2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-N-(2-hydroxyethyl)-2-methyl-4-quinolinamine (11.5 g), potassium-tert-butoxide (3.7 g) and 100 ml of dimethylformamide (DMF) was stirred at 80° C. for 3 hours. The mixture was cooled and diluted with 600 ml of water and thereafter kept in a refrigerator for 2 days. The resultant solid was filtered and recrystallized from isopropanol. The yield was 3.3 g, mp 203°-204° C.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[C:4]([OH:6])=[O:5])C.[CH2:17]([CH:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:17]([CH:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5])=[O:41])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCC(CCOc1ccccc1N)C(=O)O
Product: CCCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.01 g of compound 43 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.54 g of ethyl 4-(2-aminophenoxy)butyric acid and 1.30 g of 3-[1-(α-pentylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:19]2([CH3:23])[CH2:22][O:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: CC1(CBr)COC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(C)COC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (3.0 g) and K2CO3 (5.5 g) in N,N-dimethylformamide (10 mL) is added 3-(bromomethyl)-3-methyloxetane (2.95 g). The mixture is stirred for 12 hours at room temperature and then partitioned between saturated aqueous NaHCO3 solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→70:30) to give the title compound. Yield: 3.5 g; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=4[F:36])[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([C@@H:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=4[F:36])[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](CC(=O)O)C4CC4)cc3)ccc2C(C)(C)C)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a solution of 22.1 (0.040 g, 0.082 mmol) in THF/MeOH (2/1) (1.5 mL) was added a 1 M solution of LiOH (0.50 mL, 0.500 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford a 22 (0.019 g, 50% yield). MS ESI (neg.) m/e: 475.3 (M−H)+.
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[F:29][C:30]1[C:35]([CH:36]=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:36]([C:35]1[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=1)[OH:37]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: O=Cc1cccnc1F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cccnc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.9 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (400 mg, 1.4 mmol) in anhydrous toluene (16 mL), TMEDA (240 uL, 2.8 mmol) was added followed by nBuLi (1.0 mL, 1.7 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and 2-fluoro-3-pyridine-carbaldehyde (0.70 g, 5.6 mmol) was added. The mixture was stirred for 12 hrs during which the mixture warmed up to room temperature, quenched with 1M HCl (2 mL) and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated and purified by silical gel column chromatography (gradient of DCM/MeOH=98/2 up to 90/10) to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(2-fluoro-pyridin-3-yl)-methanol (Compound 24-1) (0.12 g) in 26% yield. MH+=331.0.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2[CH2:16][O:17][CH:18]2[CH2:24][CH:23]3[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([O:17][CH2:16][C:5]1[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])=[N:7][O:8][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[CH2:24]2
Reactant: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The previous amine, tert-Butyl 3-((5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 3.65 mmol) was dissolved in trifluoroacetic acid in dichloromethane (30 mL, 20% solution) at RT. The solution was stirred for 1 hour at RT and the solvent was evaporated. The residue was dissolved in ethyl acetate (125 mL), washed with a saturated solution of sodium bicarbonate (100 mL), the organic layer was dried with magnesium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-20% ethanol/dichloromethane to afford the desired product as a colorless oil. 1H-NMR (DMSO-d6, 400 MHz) δ 8.44 (bs, 1H), 7.43-7.34 (m, 2H), 7.32-7.28 (m, 2H), 4.21 (s, 2H), 3.83 (bs, 2H), 3.55 (t, J=4.0 Hz, 1H), 2.35-2.28 (m, 1H), 2.20 (s, 3Hc-1.70 (m, 8H), 1.16-1.06 (m, 4H). MS m/z 339.2 (M+1).
Reaction SMILES: C(N[C:6]([C@:8]1([N:25]([C@H](C2C=CC=CC=2)C)C(=O)C)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][CH2:15][B:16]1[O:20]C(C)(C)C(C)(C)[O:17]1)=[O:7])(C)(C)C.N.[Li].[O:39]1CCCC1>>[NH2:25][C@@:8]1([C:6]([OH:7])=[O:39])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17]
Reactant: CC(=O)N([C@@H](C)c1ccccc1)[C@@]1(C(=O)NC(C)(C)C)CCC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: C1CCOC1
Agent: N
Agent: [Li]
Product: N[C@@]1(C(=O)O)CCC[C@@H]1CCCB(O)O
Temperature: -45 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A cold (−50° C.) solution of (1S,2S)—N-(tert-butyl)-1-(N—((S)-1-phenylethyl) acetamido)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentane carboxamide (0.400 g, 0.802 mmol) in anhydrous tetrahydrofuran (5 mL) under an inert atmosphere of nitrogen was gradually combined (in small portions), with liquid ammonia (20 mL) and lithium wire (0.14 g, 20 mmol) over a time interval of several minutes. After stirring for 1.5 h at −40 to −50° C., the deep blue reaction was quenched with solid ammonium chloride, warmed slowly to room temperature, and residual ammonia driven off using nitrogen. Water (3 mL) was then added to the reaction flask and the mixture extracted with methylene chloride (3×30 mL). The combined organic layer was dried using Na2SO4 and concentrated in vacuo prior to purifification by HPLC to afford the subject compound (100 mg, 50%) as a white foam. NMR (D2O) δ 2.32 (m, 1 H), 2.00 (m, 2 H), 1.77-1.90 (m, 2 H), 1.70 (m, 1 H), 1.35-1.50 (m, 3 H), 1.24 (m, 1 H), 1.12 (m, 1 H), 0.60-0.75 (m, 2 H). MS (M+1): 216.3; MS (M−H2O+1): 198.2; MS (M−2H2O+1): 180.3.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH2:26]([NH2:29])[C:27]#[CH:28]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:29][CH2:26][C:27]#[CH:28])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: C#CCN
Product: C#CCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 82.9 %

Procedure:
3-Acetyl-6-chloro-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (351 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (284 mg, yield: 83%).
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:7][CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH3:1])=[O:15]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCCCC(C)O
Agent: Cl
Product: CCCCC(C)OC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From 2-hexanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after ca. 4 h. The yield was 1.0 g (66%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]1[C:22]2[NH:21][C:20](=[O:23])[CH2:19][O:18][C:17]=2[C:16]([C:24](=[O:27])[CH2:25]Cl)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[N:1]([CH2:25][C:24]([C:16]1[C:17]2[O:18][CH2:19][C:20](=[O:23])[NH:21][C:22]=2[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)=[O:27])=[N+:2]=[N-:3]
Reactant: O=C1COc2c(C(=O)CCl)ccc(OCc3ccccc3)c2N1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Reaction time: 2 h
Yield: 94 %

Procedure:
Sodium azide (1.18 g) was added to a suspension of 5-(benzyloxy)-8-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (4.8 g) in DMF (50 mL) and stirred for 2 h. The mixture was poured onto ice/water and the resulting solid filtered off, washed with water and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid (4.6 g). 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.43-7.29 (m, 3H), 6.97 (m, 1H), 5.31 (s, 2H), 4.69 (s, 2H), 4.63 (s, 2H).
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([NH2:7])[C@H:4]([NH2:8])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:7][C@@H:5]1[CH2:6][CH2:1][CH2:2][CH2:3][C@H:4]1[NH:8][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N[C@@H]2CCCC[C@H]2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A mixture of (1R,2R)-cyclohexane diamine (20 g, 175 mmol) and sodium triacetoxyborohydride (25 g, 120 mmol) in dichloromethane (550 mL) was added with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.4 g, 92 mmol) in dichloromethane (800 mL) dropwise over a period of 45 minutes and stirred at room temperature overnight. An aqueous solution of sodium bicarbonate (5%, 200 mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the crude product which was purified by dry column vacuum chromatography to give the title compound as a pale yellow oil (18.0 g, 66%). 1H NMR (300 MHz, METHANOL-D4): δ ppm 3.99 (td, J=13.3, 3.3 Hz, 2H), 2.95-2.70 (m, 3H), 2.40-2.15 (m, 2H), 2.05 (m, 1H), 1.95-1.85 (m, 2H), 1.85-1.65 (m, 3H), 1.44 (s, 9H), 1.95-1.35 (m, 6H)