Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:7]([CH3:8])[CH2:6]1)=[O:4].C[Si](C)(C)[Br:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][C:12]=3[Br:24])[N:7]([CH3:8])[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1

Procedure:
Following the process of Example 25, 1 g of lysergic acid methyl ester is reacted with 2.7 ml of trimethylbromosilane and the product is purified by chromatography on a Kieselgel column by using a 7:3 mixture of benzene and acetone as eluant. After recrystallization from benzene, the title compound is obtained in a yield of 0.7 g (0.0019 mole, 55%), m.p.: 177°-178° C., [α]D20 =+41° (c=1, chloroform).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[C:16]([O-:19])([O-])=[O:17].[K+].[K+]>CC(C)=O.O>[C:3]([O:19][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1)=[O:17])([CH3:7])([CH3:4])[CH3:2]
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the 3-piperidin-3-yl-1H-indole obtained in Example 29 in acetone/water (1:1) at 0° C. is treated with di-tert-dicarbonate (4.1 g, 18.7 mmol) and K2CO3 (11.75 g, 85 mmol), stirred for 2 hours while warming to room temperature, and concentrated in vacuo. The resultant aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by column chromatography (silica gel, 1% NH4OH in MeOH:CHCl3, 0:100 to 10:90 as eluent) to afford the title product, 1.25 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:20])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19]
Reactant: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 85 %

Procedure:
To a stirred solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.033 g, 0.10 mmol) in CH2Cl2 (2.0 mL) was added 4-chlorophenyl isocyanate (0.017 g, 0.11 mmol, 1.1 equiv.). The solvent was removed after the completion of the reaction and it was purified by the HPLC. The pure fractions were collected and CH3CN was evaporated under vacuum. The residue was diluted with EtOAc and neutralized with saturated NaHCO3, the EtOAc phase was washed with brine, dried over MgSO4, filtered and evaporated. Compound 69 was obtained in 85% yield. LCMS m/z (%)=492 (M+H79Br35Cl, 28), 494 (M+H81Br35Cl, 100), 496 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.27 (s, 1H), 8.20 (1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.9 Hz, 2H), 7.14 (d, J=9.0 Hz, 1H), 3.98-4.20 (m, 2H), 3.73 (s, 1H), 2.48-2.68 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:26][CH:25]=1>>[O:38]=[C:34]1[CH:33]=[C:32]([O:31][CH2:30][C:27]2[CH:28]=[N:29][C:24]([C:23]([F:40])([F:22])[F:39])=[CH:25][CH:26]=2)[CH:37]=[CH:36][N:35]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)ccn3c2C1
Yield: 38.6 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (175 mg, 0.498 mmol) and 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (134 mg, 0.498 mmol) were reacted according to Example 18 (step g) to provide the title compound (104 mg, 44%) as a yellow solid: ESI MS m/z 542 [M+H]+.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][N:7]([CH3:11])[C:8]([NH2:10])=[O:9]>C(#N)C>[CH3:6][N:7]([C:8]1[O:9][C:2](=[O:3])[S:4][N:10]=1)[CH3:11]
Reactant: O=C(Cl)SCl
Reactant: CN(C)C(N)=O
Solvent: CC#N
Product: CN(C)c1nsc(=O)o1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of chlorocarbonylsulfenyl chloride (11.5 g) in acetonitrile was added to a suspension of N,N-dimethylurea (25.0 g) in acetonitrile (200 ml), over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 23° C., then filtered. Methanol (20 ml) was added to the filtrate to decompose excess chlorocarbonylsulfenyl chloride. The solvents were removed in vacuo. The residue was purified by chromatography on silica using dichloromethane in hexane (3:1) to afford the product as a yellow oil. 1H NMR (250 MHz, CDCl3) d 3.04 (6H, s, (CH3)2); MS (CI+) m/z 164 (M+ +NH4+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH:10]=1)=[O:5])[CH3:2].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:20][C:21]([F:29])([F:30])[C:22]1[CH:23]=[C:24]([NH:25][C:17]([C:15]2[N:16]=[C:12]([CH2:11][N:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[S:13][CH:14]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)Nc3cccc(C(F)(F)F)c3)cs2)c1
Yield: 86.7 %

Procedure:
By a reaction in the same manner as in Reference Example 19 and using the compound (281 mg, 1.00 mmol) obtained in Example 4a and 3-(trifluoromethyl)aniline (0.149 mL, 1.20 mmol), the title compound (368 mg, 86%) was obtained as a colorless oil.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5][N:4]=1.O.[NH2:16][NH2:17]>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:16][NH2:17])[N:8]=1
Reactant: NN
Reactant: CSc1ncnc(-c2ccccn2)n1
Solvent: O
Solvent: CCO
Product: NNc1ncnc(-c2ccccn2)n1

Procedure:
A stirred solution of the product of step 2 (0.763 g, 3.74 mmol) and hydrazine hydrate (0.22 mL, 3.9 mmol) in ethanol (8 mL) was heated at reflux for 30 minutes. The reaction was cooled in an ice bath and the precipitate was filtered off. Vacuum oven drying afforded crude product as light brown solid. This material was used without further purification in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:21]1([N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[N:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(Nc3ccn(-c4ccccc4)n3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Yield: 55.7 %

Procedure:
A suspension of N-(4-benzyloxyphenyl)-1-phenyl-1-H-pyrazol-3-amine (3.17 g) in ethanol (600 ml) was hydrogenated at atmospheric pressure over 10% palladium on carbon until hydrogen uptake ceased. The reaction mixture was filtered and solvent was evaporated. The resulting solid was recrystallised from ether: petroleum ether to give the title compound (1.3 g) mp 147°-148°.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:42](=[O:43])[NH:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A mixture of the compound obtained in Example 5A (1.0 g), phenyl isocyanate (0.27 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 3 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-phenylcarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (1.10 g, 88%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 154 to 155° C. ##STR52##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OC(C)c1ccc(F)cc1
Solvent: C1COCCO1
Product: CCN(CC)CCc1ccc2[nH]c(C)c(C(=O)OC(C)c3ccc(F)cc3)c2c1
Yield: 79.3 %

Procedure:
To a solution of the product of Step A (58 mg, 0.14 mmol) in dioxane (1 mL) was added diethyl amine (0.14 mL, 1.4 mmol) and the resultant solution was heated at 70° C. overnight. The reaction solution was concentrated in vacuo and the crude product purified by flash chromatography (9:1 Ethyl Acetate:Methanol w/0.5% triethylamine) to provide the compound (44 mg, 80%) as a yellow oil. LC/MS (ESL+) 397 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:12][C:7]1[CH:8]=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1]
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Temperature: 155 °C
Yield: 83.4 %

Procedure:
Synthesized according to general procedure 69. A mixture of 2,2,2-trifluoro-N-o-tolylacetamide (6.3 gm, 31 mmol) and chlorosulfonic acid (10.3 mL, 155 mmol) was heated at 155° C. for 15 min. After cooling to RT, the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated and purified via silica gel chromatography using 0-25% EtOAc in hexanes gave 3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (7.8 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.21 (dd, J=8.1, 2.9 Hz, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])([CH3:10])[CH2:6][CH2:7][CH2:8]Cl)[CH3:2].Cl.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4]([C:5]1([CH3:10])[CH2:6][CH2:7][CH2:8][NH:12][CH2:11]1)=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C)(C#N)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(C)CCCNC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
Ethyl-5-chloro-2-cyano-2-methylpentanoate (DE 31 39 301 A1) (10.43 g, 51.2 mmol), PtO2 hydrate (1.16 g) and concentrated HCl (12.5 ml) in absolute EtOH (125 ml) were stirred and heated at 40° C. under hydrogen at normal pressure for 2 h. The cooled solution was filtered. After evaporation of the solvent, the residue was dissolved in absolute EtOH (125 ml). The solution was cooled with an ice-water bath and triethylamine (9.8 g, 96.8 mmol) was added. After the addition the mixture was stirred at RT for 16 h under nitrogen atmosphere. The solvent and triethylamine were evaporated, and the residue was dissolved in DCM (100 ml) and extracted with 1 M HCl (3×100 ml). After separating the layers, ice (150 g) and 5 M NaOH (100 ml) were added to the aqueous layer, which was then extracted with DCM (3×60 ml). The combined extracts were dried, filtered and evaporated to dryness followed by vacuum distillation (bp. 62-65° C./2 mbar) to give 6.0 g of the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N=C=NCCCN(C)C)C.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:18][C:12](=[N:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(N)=NOC(=O)c1ccc(F)cc1
Yield: 88.2 %

Procedure:
To a mixture of 4-fluorobenzoic acid (2.0 g), ethyl 2-amino-2-hydroxyiminoacetate (2.07 g) and 4-dimethylaminopyridine (0.52 g) in methylene chloride (30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.87 ml) at 0° C. under stirring. After stirring at ambient temperature for 1 hour, diethyl ether (10 ml) was added thereto and the resulting precipitate was filtered off, washed with diethyl ether, and dried in vacuo to give ethyl 2-amino-2-(4-fluorobenzoyloxyimino)acetate (3.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:28]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][CH:22]([O:24][CH3:28])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CC(O)CC2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((3-fluorophenyl)ethynyl)-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.2 g, 0.6 mmol, 1 equiv) in THF (15 mL) was added NaH (57.6 mg, 2.4 mmol, 4 equiv) in portions. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified using silica gel chromatography to give the desired product. MS (ESI): 349 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.27-8.24 (d, J=8.46 Hz, 1H), 8.01 (s, 1H), 7.62-7.50 (d, J=8.19 Hz, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.14-7.09 (m, 1H), 4.58-4.57 (m, 1H), 4.02-4.00 (m, 1H), 3.87-3.81 (m, 1H), 3.42 (s, 3H), 3.33-3.20 (m, 2H), 2.26-2.15 (m, 2H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: +.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:19]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[F:20][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:28])=[CH:19][C:6]2[C:7]3[N:8]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: C#CC(C)(O)c1ccccn1
Product: CC(O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)c1ccccn1
Yield: 6.3 %

Procedure:
9-fluoro-10-(3-hydroxy-3-(pyridin-2-yl)but-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-(2-pyridyl)but-3-yn-2-ol to afford 7.5 mg of the titled compound (6.3% yield). M+1=403.1. 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=7.6 Hz, 1H), 8.58 (d, J=4.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.82 (s, 1H), 737 (d, J=7.9 Hz, 1H), 7.57 (br s, 1H), 7.38-7.32 (m, 1H), 7.29 (d, J=10.1 Hz, 1H), 7.11 (br s, 1H), 6.47 (s, 1H), 4.94-4.87 (m, 1H), 3.75-3.67 (m, 1H), 3.14-3.03 (m, 2H), 1.83 (s, 3H), 1.71-1.64 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15](=O)[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[BH3-]C#[N:22].[Na+]>CCO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([NH2:22])[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1ncc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 120 °C
Yield: 100.3 %

Procedure:
1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977 mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) were taken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 262 mg crude yellow oil, which was carried forward without further purification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)CCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[C:21](=[O:23])[O:22][C:4]=2[CH:3]=1.Cl[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][C:8]3[C:5]4[CH:6]=[CH:7][C:2]([O:1][C:25]5[N:29]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:28]=[N:27][N:26]=5)=[CH:3][C:4]=4[O:22][C:21](=[O:23])[C:9]=3[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1oc2cc(O)ccc2c2c1CN(Cc1ccccc1)CC2
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(Oc3nnnn3-c3ccccc3)ccc2c2c1CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-hydroxy-3(phenylmethyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (15 g, 0.049 moles), 5-chloro-1-phenyl-1H-tetrazole (9 g, 0.0498 moles), and potassium carbonate (30 g) in dimethylformamide (250 ml) is heated at 85°-95° C. for 5 hours. The reaction mixture is cooled and poured over ice water. The aqueous mixture is allowed to stand at room temperature overnight. The solid is filtered off and washed with water. Recrystallization from ethyl acetate gave the product (10.14 g), mp 165°-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:19].[C:20]1([CH2:26][C:27](=[NH:31])OCC)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[ClH:19].[CH3:18][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c(COc2cccnc2NC(=N)Cc2ccccc2)c(C)c1
Yield: 24.6 %

Procedure:
A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (4.84 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.95 g), m.p. 173°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:4](=[O:6])[C:3]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
2-Chloro-6-nitro-benzoic acid (1.2 g, 5.97 mmol), 4-amino-1-benzylpiperidine (1.1 mL, 5.97 mmol), 1-hydroxybenzotriazole (0.84 g, 1.05 equiv) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.1 g, 1.05 equiv) were combined in ethyl acetate (20 mL). To this solution was added triethylamine (2.5 mL. 3.0 equiv) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 1.9 g (85%) of the desired product.