Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH2:14][C:15](=[O:17])N)=[C:9]([OH:18])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2].Cl.C(=O)(O)[O-:21].[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH2:14][C:15]([OH:21])=[O:17])=[C:9]([OH:18])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)c1ccc2c(CC(=O)O)c(O)ccc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
To 12.4 g of 6-amidino-1-carbamoylmethyl-2-naphthol was added 370 g of 25% hydrochloric acid, followed by stirring at 70° C. for 2.5 hours. After cooling with water, the precipitate was collected by filtration and washed with 80 g of 15% hydrochloric acid. The collected precipitate was added to a solution prepared by adding 200 ml of water to 10 g of sodium bicarbonate, followed by stirring for 1 hour at room temperature, and the resulting precipitate was collected by filtration and washed with water. This collected precipitate was added to a solution of 13 ml of methanesulfonic acid in 180 ml of water to dissolve the precipitate at 50° C. Furthermore, 1.0 g of active carbon was added to the solution, followed by stirring for 1 hour at room temperature. Thereafter, insoluble matter was filtered off and the filtrate was concentrated to 90 ml under reduced pressure. This solution was stirred for 24 hours under cooling with water. Then, the precipitate was collected by filtration and washed with a small amount of acetone and ether to obtain 12.3 g of the desired product.
Reaction SMILES: C(OC[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(=O)C.C1COCC1.[OH-].[Na+:30]>CO>[C:21]([NH:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([S:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[N:16]=1)(=[O:23])[CH3:22].[Na+:30]
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)COC(C)=O)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(-c2ccc(S(=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
({4-[2-(Acetylamino)-1,3-thiazol-4-yl]phenyl}sulfonyl)methyl acetate (700 mg), THF (8 ml), MeOH (4 ml) and 1N—NaOH (1.98 ml) were combined. The reaction mixture was stirred at r.t. for 1.5 hours, and concentrated in vacuo. The residual solid was washed with ethyl ether to give sodium 4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (731 mg) as a colorless solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH:26]=O)=[O:19])[CH3:16].[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O)(=O)C>ClCCCl>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH2:26][NH:47][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CC=O
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Yield: 55.4 %

Procedure:
Sodium triacetoxyborohydride (32 mg, 0.152 mmol) was added to a solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-oxo-ethyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5h (34 mg, 0.084 mmol), cyclopentylamine (12 μl, 0.118 mmol), and acetic acid (5 μl, 0.09 mmol) in 1,2-dichlorethane (2 ml) at room temperature. The reaction mixture was quenched with 1N NaOH and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with sat'd aq NaCl, dried, and concentrated in vacuo. The crude residue was purified on a 1 mm chromatotron plate using 100% EtOAc to give I-5i as a colorless oil (22 mg): +APCI MS (M+1) 472.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1F)[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[CH:7]=[O:8])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(C=O)ccc1-n1ccnc1
Yield: 83.5 %

Procedure:
3-Ethoxy-4-fluoro-benzaldehyde (0.081 g, 0.482 mmol) was dissolved in 1 ml of DMSO and treated with potassium carbonate (0.166 g, 2.5 eq.) and imidazole (0.066 g, 2 eq.), and the mixture was allowed to react under a balloon of argon for 2 h at 105° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, AcOEt) produced 0.087 g of the title compound as off-white crystals.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:22]([Cl:23])=[CH:21][N:20]([CH3:24])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:23][C:22]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[C:31]([OH:33])=[O:32])[N:7]([CH2:6][C:5]4[CH:34]=[CH:35][C:2]([N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:3][CH:4]=4)[C:11]=3[CH:12]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: C1CCNCC1
Reactant: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCCCC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions described in Example 152 using piperidine. MS (ESI): mass calcd. for C31H36ClN5O3, 562.12; m/z found, 562.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.65 (s, 1H), 7.53 (d, J=8.8, 1H), 7.03 (d, J=8.9, 3H), 6.92 (d, J=8.8, 3H), 5.44 (d, J=16.6, 1H), 5.37 (d, J=16.4, 1H), 4.98 (s, 2H), 3.81 (s, 3H), 3.60-3.49 (m, 1H), 3.14-3.09 (m, 4H), 2.91-2.79 (m, 1H), 2.40-2.28 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.63 (m, 8H), 1.62-1.53 (m, 2H), 1.53-1.37 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:17]=[CH:16][N:15]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:14]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ccc(-c3ccn(-c4ncccn4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution of 3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole (930 mg, 3.66 mmol) in 15 mL of dry THF was slowly added 240 mg (6.00 mmol) of NaH. After stirring at room temperature for 20 minutes, 500 mg (4.15 mmol) of 2-chloropyrimidine was added in one portion. The reaction was allowed to stir overnight at room temperature and concentrated to dryness. The residue was dissolved in CHCl3 and subjected to flash chromatography. Elution with 3:2 hexane/EtOAc gave 994 mg of the title compound as a solid, mp 123-125° C. 1H NMR (CDCl3): δ8.77 (d, 2H, J=4.8 Hz), 8.65 (d, 1H, J=3.0 Hz), 7.95 (d, 2H, J=8.7 Hz), 7.20 (t, 1H, J=4.9 Hz), 7.07-6.98 (m, 5H), 6.78 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Br:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of 2,3-diamino-5-bromobenzotrifluoride (150 mg, 0.612 mmol) and oxalic acid dihydrate (81 mg, 0.643 mmol, used as received) in 2N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 150 mg of crude title compound (81.9%) as a red powder. The crude compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 135 mg of title compound. Recrystallization from DMSO/H2O gave 125 mg of pure title compound (68.3%) as red microcrystals. Mp: 307°-9° C. (dec. from 290° C.). IR (KBr, cm-1) 3412, 3250, 1756, 1706, 1606; 1H NMR (DMSO-d6): δ7.514 (d, 1H, J=1.5 Hz); 7.556 (d, 1H, J=1.5 Hz); 11.342 (s, 1H); 12.220 (s, 1H). HRMS: calcd for C9H4BrF3N2O2 (M+) m/z: 307.9407; found: 307.9420.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[C:21]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]Br)=[CH:30][CH:29]=1)(=[O:23])[CH3:22]>CN(C=O)C>[C:21]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:32][CH:33]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCCOc1ccc(CCBr)cc1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(CCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)cc1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (651 mg) in DMF (15 mL) was treated with sodium hydride (84 mg) under nitrogen and stirred for 1 h. A solution of 2-[4-(2-bromoethyl)phenoxy]ethyl acetate (500 mg) in DMF (5 mL) was added and the reaction mixture was stirred for a further 2 h. This was then concentrated in vacuo and the residue was taken up in EtOAc, washed with water, brine and dried (MgSO4). The solution was concentrated in vacuo and the residue was purified by chromatography (Biotage, 90 g) eluting with cyclohexane-EtOAc (2:1) to give the title compound (355 mg). LCMS RT=3.26 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc2ncoc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2ncoc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methylbenzoxazol-6-yl)-2-pyridylamine (44) (26.6 mg, 0.12 mmol) in 2 ml DCM was added 2-fluorobenzoyl chloride (29 μl, 0.24 mmol) followed by addition of DIEA (105 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (180 μl) at r.t. for 40 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 24.1 mg N-[5-(5-methylbenzoxazol-6-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (45) as off-white solid. (yield: 57.8%, purity>95%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc2c(-c3ccc(Br)cc3)ccnc12
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(-c3ccc(Br)cc3)ccnc12
Temperature: 25 °C

Procedure:
A solution of tin (II) chloride dihydrate (9.50 g) and 4-(4-bromophenyl)-8-nitroquinoline (4.60 g) in 50 mL absolute ethanol was refluxed for 6 hours. The reaction mixture was cooled to room temperature and then made alkaline with 30% KOH solution. The precipitated solid was filtered off, and dissolved in chloroform. The filtrate was extracted with ether. The ether extract and chloroform solution were combined and dried over MgSO4. Evaporation gave a solid with 1H-NMR spectral signals consistent with 8-amino-4-(4-bromophenyl)quinoline.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reaction time: 7 h
Yield: 66 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.45 gm (61 mmol) of 60% sodium hydride, 10 gm (51 mmol) of methyl 3,4-dimethoxybenzoate, and 100 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 6.1 gm (61 mmol) of pinacolone was added dropwise. The refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 8.9 gm of the target compound as colorless needles (yield: 65%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@:8]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:27](=N)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@:8]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:18][C:13]=2[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC(=N)OCC
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c(N)c1
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1nc2cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc2o1

Procedure:
A solution of [(R)-3-(3-Amino-4-hydroxy-phenyl)-1-hydroxymethyl-1-methyl-propyl]-carbamic acid tert-butyl ester (500 mg, 1.61 mmol) and hexanimidic acid ethyl ester hydrochloride (318 mg, 1.77 mmol) in DCM (6 ml) was stirred for 16 hours at RT. Evaporation of the solvent in vacuum was followed by silica gel chromatography (eluent: DCM/methanol 40/1). Product containing fractions were pooled and evaporated in vacuum. Crystallization from pentane provided the title compound as a colorless solid. mp: 92.7/92.6
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[N:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH:16]1(N)CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]1[C@@H:15]([NH2:14])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: O=C1CCC(CO)(c2cnccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyrazin-2-yl)cyclohexanone (360 mg, 2.0 mmol, 1.0 equiv) in acetonitrile (4 mL) was treated with cyclopropylamine (280 μL, 4.0 mmol, 2.0 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 4.0 mmol, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, EtOAc containing 2.5% NH4OH then EtOAc/5% MeOH containing 2.5% NH4OH, the second spot was collected) to provide 180 mg of trans amine as a white solid (0.70 mmol, 42%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[C:12](Cl)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>CCO.[Pd]>[CH2:1]([C:8]1[CH:9]=[C:10]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:26]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[CH:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)nc(Cl)c4o3)c(F)c2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ncc4o3)c(F)c2)C1
Temperature: 85 °C

Procedure:
A mixture of methyl 1-(4-(5-benzyl-7-chlorofuro[2,3-c]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate (0.320 g, 0.69 mmol), cyclohexene (1.00 mL, 9.9 mmol), palladium (10 wt. % on activated carbon, 0.320 g, 3.0 mmol) in EtOH (6.0 mL) was prepared in a sealed tube and heated under N2 to 85° C. for 4 h. The mixture was filtered through Celite, and the filtrate evaporated purified by flash chromatography using EtOAc/hexanes to give title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.82 (s, 1H), 7.96 (t, J=7.7 Hz, 1H), 6.99-7.38 (m, 9H), 4.25 (s, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 3.48-3.59 (m, 2H), 3.33-3.39 (m, 3H). MS (ESI) m/z: Calculated; 430.2 Observed: 431.2 (M++1).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-p-tolylacetate dihydrochloride (I109) (116 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (139 μl, 1.00 mmol) and benzoyl chloride (46.5 μl, 0.40 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-p-tolylacetate (70.0 mg; 55% yield). The product was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:17]=[C:16]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of 3,4-diaminobenzonitrile (350 mg) in toluene (5.5 ml) was added CDI (554 mg), followed by stirring at 125° C. for 2 hours. To the reaction mixture was added a 1M aqueous NaOH solution (0.117 ml), followed by extraction with EtOAc. The organic layer was dried over anhydrous MgsO4, and then filtered, and the filtrate was concentrated. It was powdered/washed with IPE/IPA to obtain 2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (423 mg) as colorless powders.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])[CH3:28].C(N(CC)CC)C>O1CCCC1.[Pd](Cl)Cl.[Cu]I>[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](=[O:33])[C:2]#[C:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:23])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH3:28]
Reactant: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: CCOc1ccccc1C(=O)Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1C(=O)C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
At room temperature and under an atmosphere of argon, palladium(II) chloride (5.8 mg) and copper(I) iodide were added to a solution of 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (250 mg) and 2-ethoxybenzoyl chloride in tetrahydrofuran. The mixture was stirred at room temperature for 1 minute, and triethylamine (83 mg) was then added. The reaction mixture was stirred at room temperature overnight. 5 g of silica gel were then added, and the solvent was removed under reduced pressure. The residue was purified chromatographically. This gave 1-(2-ethoxyphenyl)-3-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-yn-1-one (244 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[OH2:17]>>[OH:17][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O
Reactant: O=c1c(CCl)c[nH]c2c([N+](=O)[O-])cccc12
Product: O=c1c(CO)c[nH]c2c([N+](=O)[O-])cccc12

Procedure:
A suspension of 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (2.0 g) in water (30 ml) was refluxed for 15 minutes and allowed to stand to ambient temperature. The resulting precipitates were collected by filtration and washed with water to give 1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline (1.82 g). mpD 182-184° C. NMR (DMSO-d6, δ): 4.41 (2H, s), 5.14 (1H, br), 7.49 (1H, t, J=7 Hz), 8.00 (1H, s), 8.59 (1H, d, J=7 Hz), 8.66 (1H, d, J=7 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccccc1C1CCCN1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccccc1F

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=340.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.