Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[CH:16][CH:15]=2)=[O:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12](=[O:13])[C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)N[C@@H](CO)c3ccc(F)cc3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CO)c1ccc(F)cc1)c1ccc([C@H]2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 2-(4-((R)-1-(4-fluorophenyl)-2-hydroxyethylcarbamoyl)phenyl)morpholine-4-carboxylate (44 mg, 0.099 mmol) was dissolved in dichloromethane (0.3 ml) and trifluoracetic acid (447 mg, 0.3 ml, 3.92 mmol) was added. The reaction mixture was stirred at room temperature for 60 min. The solvent and excess of trifluoracetic acid were evaporated. The residue was dissolved in dichloromethane (3 ml) and extracted with odium bicarbonate saturated solution (2 ml). The organic layer was dried over MgSO4 and evaporated. The crude product was directly used for the next step.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:33](C1NC=CN=1)(=[O:35])[CH3:34].CO.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([F:31])[CH:28]=1)[CH2:24][C@H:4]([NH:3][C:33](=[O:35])[CH3:34])[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)c1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CCCCC2)c1
Reactant: CC(=O)c1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 0.25 h

Procedure:
The free base of compound 6 (1.6 g, 3.8 mmol) is dissolved in 20 mL of CH2Cl2 under nitrogen, and 0.87 g (7.9 mmol) of acetyl imidazole is added with stirring. After 15 min., 30 mL of methanol is added, followed by 15 mL of 1 N NaOH to saponify the ester that is formed along with the amide. The CH2Cl2 is removed in vacuo, and the mixture is neutralized with 1N KH2PO4. The product is extracted into ethyl acetate and the organic phase is washed with water, with 1 N NaHCO3, and with brine. The solution is dried over Na2SO4, filtered and concentrated to an oil, which is chromatographed over silica gel, eluting with 5%-7% methanol (containing 1% of NH4OH) in CH2Cl2. Product-containing fractions are pooled, concentrated, dissolved in a small volume of ethanol, and acidified with 0.6 N HCl in dry ether. Concentration from this solvent mixture affords a gel-like material. This can be dissolved in ethanol and ethyl acetate, and concentrated to 1.65 g (3.3 mmol, 87%) an off-white solid. This solid is triturated with ethyl acetate to remove a pale yellow mother liquor, leaving hydrochloride 7 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.29 (m, 1H), 6.70 (m, 2H), 6.62 (m, 1H), 3.94 (m, 1H), 3.87 (m, 1H), 3.0-2.94 (m, 2H), 2.64 (m, 4H), 2.36 (m, 1H), 2.09 (m, 2H), 1.84 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5-1.3 (m, 3 H), 1.27 (d, J=7 Hz, 6H); IR (diffuse reflectance) 3343, 3254, 2958, 2937, 2866, 2497, 2442, 2377, 1660, 1628, 1598, 1553, 1460, 1116, cm −1. MS (EI) m/z (rel intensity) 458 (M+, 7), 415 (20), 230 (35), 202 (18), 201 (99), 200 (26), 159 (35), 157 (32), 133 (41), 129 (28), 117 (17). HRMS (ESI) calcd for C27H36N2O2F2+H1 459.2823, found 459.2837. Anal. Calcd for C27H36F2N2O2.HCl: C, 65.51; H, 7.53; N, 5.66; Cl, 7.16; F, 7.68. Found: C, 65.19; H, 7.70; N, 5.67. Found; Cl, 7.08.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16])([O-:11])=[O:10].C(O)(=O)C>N1C=CC=CC=1.CCOC(C)=O>[N+:9]([C:12]1[CH:13]=[C:14]([C:15]2[O:16][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:18]=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2nc3cccnc3o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
2-Chloropyridin-3-amine (3.20 g, 0.025 mol) was suspended in 15 mL of pyridine and added slowly to a suspension of 3-nitrobenzoyl chloride (4.64 g, 0.025 mol) in 15 mL of pyridine in an ice bath. The reaction mixture was slowly warmed to room temperature and stirred overnight. The next day, the reaction mixture was cooled in an ice bath and 30 mL of glacial acetic acid was added slowly. The resulting mixture was diluted with 200 mL of EtOAc and washed with water (3×20 mL). The organic layer was then dried (Na2SO4) and concentrated. The resulting residue was mixed with 10 mL of PPA and stirred at 160 degree for 6 hours. The reaction mixture was then poured carefully into 150 mL of water. The pH was brought to about 5 with solid NaOH and the solids were collected by filtration and dried. This material was mixed with 50 mL of MeOH and filtered. The filtrate was concentrated to afford 2.1 g of 2-(3-nitrophenyl)oxazolo [5,4-b]pyridine (35% yield) (MS, M++H=242).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)CO1
Yield: 16 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-chloropicolinic acid yielded the title compound (16% yield) as an off-white solid. MS (ISP): m/z=393.0 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=1>CN(C=O)C>[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.025 g of product in 86% yield: LCMS (ESI) m/z 422 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.OC1(C2C=CC(OC)=CC=2)C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 4-Bromo-2-nitroaniline (435 mg, 2 mmol) and benzaldehyde (0.204 ml, 2 mmol,) in 4 ml dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (424 mg, 2 mmol). Then acetic acid (120 μl, 2 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 276 mg (0.9 mmol, 45%) of benzyl-(4-bromo-2-nitrophenyl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1)#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=4)[CH2:38][CH2:37]3)=[O:40])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 562.1 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][N:12]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[O:6][N:5]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1noc(-c2nc[nH]n2)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
3-(3-Ethoxy-4-methylisoxazol-5-yl)-1H-1,2,4-triazole (1.1 g, 5.7 mmol), triethylamine (2.5 mL, 18 mmol) and DMF (20 mL) was added trityl chloride (1.6 g, 5.7 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 5 h and poured onto an ice/water mixture (200 mL). The aqueous phase was extracted with diethyl ether (3×200 mL) and the organic extracts were washed with an aqueous solution of Na2CO3 (10%) (200 mL) and brine (200 mL). The solution was dried (Na2SO4) and concentrated in vacuo to give crude title compound (2.5 g). A small sample was crystallized (EtOAc) to give a single isomer as colourless crystals: mp 181-183° C. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[C:22]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:23][C:24]([CH:30]=O)=[N:25]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[C:22]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:23][C:24](/[CH:30]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[N:25]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of trimethyl phosphonoacetate (0.225 g 1.00 mmol) in THF (20 mL) was added 95% sodium hydride (0.050 g, 2.0 mmol). Upon the completion of addition, the mixture was stirred at 0° C. for 30 min and then 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbaldehyde (Example 212, prepared in a similar manner to the procedure described below, 0.340 g, 1.00 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 14 h. After this time, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated and the resulting residue was subjected to silica gel column chromatography using 5% MeOH in chloroform as the eluent to provide (E)-methyl 3-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)acrylate (0.30 g, 72%) as a brown solid. LCMS Method V: retention time 1.94 min; [M+1]=411.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1)[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCN
Product: CCNC(=O)c1cccc(C(F)(F)F)c1
Yield: 19 %

Procedure:
3-Trifluoromethylbenzoic acid was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method E1 to afford the title compound Purification by recrystallization from hexanes gave 2.24 g of N-ethyl-3-(trifluoromethyl)benzamide as a white needles in 19% yield. m.p. 98°-99° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]([F:36])([C:32]([F:35])([F:34])[F:33])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=O.O>C1COCC1>[F:17][C:18]([F:36])([C:32]([F:33])([F:34])[F:35])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOCc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1cccc(COCOC)c1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (481 mg) in THF (15 mL) was added ethyl diethylphosphonoacetate (2.55 mL) at 0° C., and the mixture was stirred at room temperature for 5 min. To the obtained colorless solution was added 2,2,3,3,3-pentafluoro-1-(3-((methoxymethoxy)methyl)phenyl)propan-1-one (1.28 g) at room temperature, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3].Cl.Cl.[CH3:24][C:25]1[N:29]=[C:28]([C@H:30]([NH2:32])[CH3:31])[O:27][N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:32][C@@H:30]([C:28]3[O:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH3:31])=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1nn(-c2ccsc2)c2cc(C(=O)O)ccc12
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(C(C)(C)O)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
3-(2-Hydroxypropan-2-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (457.8 mg, 1.514 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (374.3 mg, 1.871 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600.2 mg, 3.13 mmol), 1-hydroxy-7-azabenzotriazole (105.3 mg, 0.774 mmol), and N-methylmorpholine (670 μl, 6.09 mmol) were dissolved in N,N-dimethylformamide (15 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 1 mL) and trifluoroacetic acid (ca 1 mL). The reaction mixture was purified directly by preparative HPLC (reverse phase (C-18)), eluting with acetonitrile/water 0.1% trifluoracetic acid, to give the title compound (559.5 mg, 1.360 mmol, 90% yield) as a white solid. FIRMS: [M+1]=412.1452. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H); 8.06 (d, J=8.5 Hz, 1H); 7.54 (dd, J=8.5, 1.4 Hz, 1H); 7.52-7.46 (m, 2H); 6.89 (d, J=7.7 Hz, 1H); 5.65-5.56 (m, 1H); 2.83 (s, 1H); 2.40 (s, 3H); 1.81 (s, 6H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([OH:22])[CH2:15]2.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:9](=[O:10])([O:22][C@@H:16]1[CH:17]2[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]2)[CH2:15]1)[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)Cl
Reactant: O[C@H]1CN2CCC1CC2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)O[C@H]1CN2CCC1CC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
In 100 ml of chloroform and in the presence of 16 g of triethylamine and 0.1 g of 4-dimethylaminopyridine, 12.8 g of ethyl chloroformate was added to 10.0 g of (R)-quinuclidin-3-ol at 10° C. This was heated to 20° C., stirred for 2 hours and mixed with 50 ml of water, the thus obtained organic layer was washed with 50 ml of water, and then the organic layer was concentrated under a reduced pressure and dried in vacuo to obtain 15.49 g of a oily substance. By purifying this oily substance by a silica gel column chromatography, 7.24 g of ethyl (R)-quinuclidin-3-yl carbonate was obtained (1H-NMR (DMSO-d6, tetramethylsilane internal standard): δ 1.21 (3H, t, J=7.2 Hz), 1.26-1.37 (1H, m), 1.42-1.53 (1H, m), 1.55-1.70 (2H, m), 1.91-1.98 (1H, m), 2.48-2.76 (5H, m), 3.06-3.17 (1H, m), 4.11 (2H, q, J=7.2 Hz), 4.56-4.64 (1H, m), mass spectrum: m/z=200 [M+H]+ (FAB)).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]>>[OH:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][OH:38])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:18]([F:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[F:23])[C:11]=1[C:26]([NH2:27])=[O:28]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCCCN(CCO)CCO
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(CCO)CCO)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedure analogous to Example 1. MS (APCl, m/z): 502 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[C:10]3[S:19][CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1>[Ni].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[C:10]3[S:19][CH:20]=[CH:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCS2
Agent: [Ni]
Solvent: CCO
Product: O=c1c2cccnc2n(-c2cccc(Cl)c2)c2ccsc12

Procedure:
Reflux a mixture of 4-(3-chlorophenyl)-2,3-dihydrothieno[3,2-b][1,8]naphthyridin-9(9H)-one (0.11 g), ethanol (100 ml), and commercial aged Raney nickel (from 5 ml of an aqueous suspension) for 10 hours under nitrogen. Filter the resulting mixture, evaporate the solvent, and chromatograph the residue over silica gel. Elute with CHCl3 to give 4-(3-chlorophenyl)-thieno[3,2-b][1,8]naphthyridin-9(4H)-one, m.p. 264°-267° C. from CHCl3 hexane.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][NH:17][N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].[OH-].[K+].CCOC(C)=O.CCCCCC>CS(C)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:21]=[CH:20]\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Reactant: C#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3ccccc3)n2)cc(C(F)(F)F)c1

Procedure:
In a 10 mL microwave seal tube 3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.5 g, 1.0 eq.) and ethynylbenzene (0.25 mL, 1.2 eq.) were dissolved in DMSO (5 mL). KOH (0.29 g, 2.5 eq.) was added and the reaction mixture was irradiated at 120° C. for 45 min in CEM Microwave. The completion of the reaction was confirmed by TLC using 30% EtOAc-hexane as mobile phase. Reaction mixture was quenched into ice water slurry. Compound was extracted by ethyl acetate. Organic layer was washed with brine, dried over Na2SO4, filtered and concentrated by rotary evaporation (40° C., 20 mmHg) to afford 0.373 g of brown oil. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection from 5% to 10% ethyl acetate in hexane. Compound started eluting with 14% ethyl acetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (30 mg); LCMS (%): Retention time for cis 4.7970 min (100.0%); For trans 3.975 min (98.06%).