Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([C@@H:7]1[CH2:8][C@H:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:10][CH2:11][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(Cl)cc12

Procedure:
Example 2ah, Step 1: A sample of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide was combined with 4,6-dichloroquinazoline (1.2 equivalents) and triethylamine (1.2 equivalents) in ethanol. The resultant solution was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)-2-(6-chloroquinazolin-4-ylamino)acetamide. MS found: (M+H)+=446.44; 1H NMR (400 MHz, CDCl3) δ(TMS): 0.52-1.77 (m, 25H), 2.36-2.48 (m, 1H), 3.92-4.06 (m, 3H), 6.52-6.63 (M, 1H), 7.37-7.55 (m, 3H), 7.70-7.73 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.C([Li])CCC.[B:43]([O:48]C)(OC)[O:44]C.Cl>C1(C)C=CC=CC=1.CCOCC>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:43]([OH:48])[OH:44])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:17][CH:18]=1
Reactant: COB(OC)OC
Reactant: Brc1c2ccccc2c(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB(O)c1c2ccccc2c(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
9-Bromo-10-(4-naphthalene-2-yl-phenyl)anthracene 13.8 g was dispersed in dehydrated toluene 80 ml and dehydrated ether 80 ml, and the mixture was cooled down to −30° C. A 1.58M n-butyllithium hexane solution 21. 0 ml was dropwise added thereto, and after the solution was stirred at −40° C. for 30 minutes, the temperature was elevated up to −10° C. The solution was cooled again down to −70° C., and a dehydrated ether solution of trimethyl borate 10.0 ml was gradually added thereto. The solution was stirred at −70° C. for 2 hours and then gradually heated up to room temperature. After left standing for a night, a 10% hydrochloric acid aqueous solution 100 ml was added thereto and stirred, and then it was extracted twice with toluene. The organic layer was washed with saturated brine and dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from toluene/hexane, filtered and dried, whereby targeted 10-(4-naphthalene-2-yl-phenyl)anthracene-9-boronic acid 8.48 g was obtained in the form of yellow crystal (yield: 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH2:12]([NH2:14])[CH3:13].O.[OH-].[Na+]>O1CCCC1>[CH2:12]([NH:14][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Nitrobenzylbromide (0.23 mol) in tetrahydrofuran (500 ml) was added to a stirred mixture (4.35M) of 70% aqueous ethylamine (350 ml) and water (350 ml) over a 20 minutes. The reaction stood at ambient temperature for 1 hour, was reduced to low volume, treated with ice/water to 800 ml and basified with an aqueous solution of sodium hydroxide (ION, 23 ml). It was extracted with ether (2×) and the combined extracts dried (MgSO4) and evaporated to give N-ethyl-2-nitrobenzylamine as a yellow oil (44 g, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:14][S:15][CH2:16]Cl>CN(C)C=O>[CH3:14][S:15][CH2:16][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1c(CO)nc2ccccc21

Procedure:
Using the procedure of Preparation C1, 14.8 g of 2-hydroxymethylbenzimidazole, 4.8 g of 50% sodium hydride in oil and 8.36 ml of chloromethyl methyl sulfide in 50 ml of dimethylformamide gave 8.3 g of product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]2[NH:9][C:8](=O)[CH:7]=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:4](=[O:13])[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Product: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Yield: 60 %

Procedure:
In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92) 7,7-dimethyl-7,8-dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give the title compound as a gray solid in 60% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(COC)OC>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:14]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:3]2[CH2:2][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)=[O:23]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: c1c[nH]cn1
Solvent: COCCOC
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cn1ccnc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (150 mg) and imidazole (106 mg) in dimethoxyethane was stirred for 1 hour at 70° C. The mixture was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-(imidazol-1-ylmethyl)quinoline (110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=O.C[Si]([C:26]#[N:27])(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:26]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:27]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture was heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a colorless oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109°-110° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24]([CH2:27][N+:28]([O-])=O)([OH:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[NH4+].[Cl-]>CO.O.[Zn]>[NH2:28][CH2:27][C:24]1([OH:26])[CH2:23][N:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N:15]3[C:9]4[CH:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[N:12]=[CH:11][C:10]=4[CH:13]=[N:14]3)[N:21]=2)[CH2:25]1
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(O)(C[N+](=O)[O-])C3)n2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(O)(CN)C3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol (100 mg, 0.25 mmol) in MeOH (5 mL) and H2O (0.5 mL) was added Zn powder (129 mg, 2 mmol) and NH4Cl (132 mg, 2.5 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 270 as red solid (60 mg, 64.8%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.13 (s, 1H), 8.75 (s, 1H), 8.53 (s, 1H), 8.34-8.40 (m, 2H), 7.98 (s, 1H), 7.72-7.75 (m, 1H), 7.24-7.25 (m, 1H), 6.34-6.36 (d, J=8.5 Hz, 1H), 4.23-4.25 (d, J=8.5 Hz, 2H), 3.89-3.97 (m, 5H), 3.06-3.10 (m, 2H); MS (ESI) m/z: 377 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](NC(C)C)(C)[CH3:13].[Li]CCCC.BrCCBr>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C1Nc2cc(Br)ccc2C12CC2
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 6-bromoindolin-2-one (2 g, 9.43 mmol) and diisopropylamine (2.00 g, 2.82 ml, 19.8 mmol) in tetrahydrofuran (16 ml) was cooled to −25° C. and a solution of nBuLi (1.6 M in hexane, 23.6 ml, 37.7 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and a solution of 1,2-dibromoethane (5.32 g, 2.44 ml, 28.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 hours and carefully quenched with brine (2 ml) and conc. HCl (2 ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as red crystals (1.11 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2](/[CH:37]=[CH:36]/[CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)nc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C/C=C/c1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:32]=[CH:33][C:34]4[S:38][CH:37]=[N:36][C:35]=4[CH:39]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[S:38]1[C:34]2[CH:33]=[CH:32][C:31]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[CH:39][C:35]=2[N:36]=[CH:37]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4scnc4c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3scnc3c2)c1
Yield: 8.9 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-{6-(3-benzothiazol-5-yl-5-ethoxy-phenoxy)-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (61 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (1.0 mL) to afford 4-[3-{6-[3-benzothiazol-5-yl-5-ethoxy-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (9.2 mg, 17%) as a light brown solid: ES(+)-HRMS m/e calcd for C34H39NO7S (M+H)+ 606.2520. found 606.2523.
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]([C:7]1[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH:19]=[O:20])[CH:8]=1)=[O:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:3][O:4][C:5]([C:7]1[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C=O)no1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Lithium borohydride (762.5 mg, 19.4 mmol) was added to a solution of 3-[3-(4-fluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (2.9 g, 8.4 mmol) in methanol (168 mL) and the resulting mixture stirred for 1 h at room temperature. Citric acid (10%, 100 mL) was then added and the resulting mixture extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (1.63 g, 48%) as a white solid. MS: m/e=407.2 [M+AcO]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Using general procedure A, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.800 g, 4.30 mmol), thiophene-3-carbaldehyde (0.480 g, 4.30 mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride (1.27 g, 6.02 mmol) were combined in 1,2-dichloroethane (40 ml) and the resulting mixture was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) gave 4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (0.886 g, 73%). 1H-NMR (CDCl3) δ 1.27 (m, 3H), 1.45 (s+m, 1H), 1.84 (d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.80 (t, 2H, J=12.0 Hz), 3.85 (s, 2H), 4.01 (br d, 2H), 7.03 (d, 1H, J=6.0 Hz), 7.12 (s, 1H), 7.29 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8].F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:8][C:20]1[CH:21]=[N:22][CH:23]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc(OC(F)(F)F)c1
Yield: 4 %

Procedure:
The title compound was prepared in 4% yield from 3-trifluoromethoxy-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.11 (br s, 1H), 7.84 (br s, 1H), 7.59 (s, 1H), 7.24-7.51 (m, 4H), 4.64 (s, 2H). [M+H] calc'd for C14H11F3N2O3, 313. found 313.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[S:1]1[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: c1csc(-c2cccs2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cccs2)s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a suspension of 2,2′-bithiophene (1.0 g) in tetrahydrofuran (10 ml) was added a solution of n-butyl lithium in n-hexane (1.54 M, 4.3 ml) at −25° C. under nitrogen atmosphere. The mixture was stirred at −60° C. for 30 minutes. To the solution dry-ice (1.0 g) was added and the mixture was stirred at ambient temperature for 30 minutes. To the resultant suspension hydrochloric acid (1N, 10 ml) and ethyl acetate were added. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether. The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried to give [2,2′]bithiophenyl-5-carboxylic acid (952 mg, 75.6%).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][N:16]([CH3:19])[CH:17]=O>C(N(CC)CC)C.[OH-].[Na+].[Cu]I>[CH3:10][O:9][CH2:8][CH2:7][O:6][C:5]1[C:11]([CH3:13])=[CH:12][C:2]([C:3]#[C:4][C:5]2([OH:6])[CH:11]3[CH2:13][CH2:19][N:16]([CH2:17][CH2:12]3)[CH2:15]2)=[CH:3][C:4]=1[CH3:14]
Reactant: CN(C)C=O
Reactant: COCCOc1c(C)cc(Br)cc1C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COCCOc1c(C)cc(C#CC2(O)CN3CCC2CC3)cc1C
Temperature: 65 °C

Procedure:
1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (704 mg) and copper (I) iodide (48 mg) in dimethylformamide (DMF) (5.5 ml) and triethylamine (2.7 ml) at ambient temperature and under an atmosphere of argon. The mixture was heated at 65° C. for 14 hours, cooled to ambient temperature, diluted with 2M aqueous sodium hydroxide (20 ml) and extracted with diethyl ether (5×100 ml). The ethereal extracts were combined, washed with water (100 ml) and saturated brine (100 ml), dried (K2CO3) and evaporated. The residue was crystallised from acetonitrile to give 3-[2-(4-{2-methoxyethoxy}-3,5-dimethylphenyl)ethynyl]quinuclidin-3-ol (130 mg) as a solid, m.p. 120° C.; microanaylsis, found: C, 72.4; H, 8.2; N, 4.1%; C2OH27NO3 requires: C, 72.9; H, 8.3; N, 4.2%; NMR([CD3)2SO): 1.3(1H,m), 1.57(1H,m), 1.9(3H,m), 2.21(6H,s), 2.65(4H,m), 2.8(1H,d), 3.02(1H,d), 3.31(3H,s), 3.61(2H,m), 3.87(2H,m), 5.5(1H,br) and 7.07(2H,s); m/z 330 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@H]1C
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@H]1C

Procedure:
The procedure of Reference Example 2 was repeated by using the thus synthesized methyl(3R*,4S*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate crude product (12.28 g) and benzyl chloroformate (21.3 mL, 149.3 mmol) to obtain 4.23 g (14.52 mmol, 2 steps, 15%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C(#N)C>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: O=c1[nH]c2c(cc1[N+](=O)[O-])CCCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1cc2c(nc1Cl)CCCC2
Yield: 98 %

Procedure:
A solution of intermediate (8) (0.072 mol) and BTEAC (0.0362 mol) in ACN (150 ml) was stirred at room temperature. Phosphoric trichloride (0.222 mol) was added dropwise. The mixture was stirred and refluxed for 8 hours. The solvent was evaporated till dryness. The residue was poured out into water and NH4OH. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 15 g of 2-chloro-5,6,7,8-tetrahydro-3-nitroquinoline (intermediate 9).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([N:22]([CH3:24])[CH3:23])[C:20]#[CH:21]>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:21]#[C:20][CH2:19][N:22]([CH3:24])[CH3:23])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C#CCN(C)C
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 27.1 %

Procedure:
To a solution of 5-bromo-2-methoxy-3-nitropyridine (1.50 g, 6.44 mmol) in DMF (30 mL) were added bis(acetonitrile)palladium(II)chloride (83.5 mg, 0.322 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1-1′-biphenyl (399 mg, 0.837 mmol), cesium carbonate (4.19 g, 12.9 mmol) and propargyl(dimethylamine) (0.832 mL, 7.72 mmol). The reaction mixture was flushed with nitrogen gas and allowed to stir for 4 h at 50° C. The reaction mixture was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(6-methoxy-5-nitropyridin-3-yl)-N,N-dimethylprop-2-yn-1-amine (0.41 g, 27%) as a white solid. LCMS (FA): Rt=0.85 min, m/z=236.2 (M+H).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (0.198 g) with 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride (0.404 g) in dichloromethane in the presence of N,N-diisopropylethylamine (0.155 g) gives the product as a solid.