Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17]CC)=O)[CH2:10]1)=[O:8].[BH4-].[Na+].[CH2:22](O)[CH3:23]>ClCCl>[CH2:22]([C@H:10]1[CH:11]([CH2:15][OH:17])[CH2:12][CH2:13][CH2:14][N:9]1[C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCO
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)Cc2cccs2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1C(CO)CCCN1C(=O)Cc1cccs1
Temperature: 25 °C

Procedure:
(S)-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (1.053 g; 3.75 mmol) was dissolved in absolute ethanol (40 ml). Sodium borohydride (2 g; 52.9 mmol) was added and this mixture was heated to reflux. The mixture was allowed to reflux for 1 hour and was then cooled to ambient temperature, diluted with dichloromethane and carefully quenched and washed with 1 N HCl. The dichloromethane was separated, washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 100% ethyl acetate, giving (S)-ethyl 1-(2-thiopheneacetyl)-3-hydroxymethylpiperidine (715.5 mg) as a thick colorless oil. MS m/z (positive ion) 501 (dimer+Na+; 50), 488 (30), 262 (M+Na+; 75), 249 (50), 240 (MH+; 80), 102 (Et3NH+; 100).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)O)#N.[CH:18]([CH:20]1[CH:22](C(O)=O)[C:21]1([CH3:27])C)=[O:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39]1([N:45]=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:39]([C:1]1([CH2:3][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:6]=2)[CH:20]([CH:18]=[O:19])[C:21]1([CH3:27])[CH3:22])#[N:45]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC1(C)C(C=O)C1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC1(C)C(C=O)C1(C#N)Cc1cccc(Oc2ccccc2)n1

Procedure:
To a 250 ml round bottom flask was added 6.0 g (26.7 mmol) of cyano(6-phenoxy-2-pyridinyl)methanol, 3.8 g (26.7 mmol) of 3-formyl-2,2-dimethylcyclopropane carboxylic acid and 60 ml of pyridine. The mixture was stirred to assure homogeneity and 0.28 g (1.45 mmol) of p-toluene sulfonic acid was added. Stirring was maintained for 15 minutes and then 6.30 g (30.4 mmol) of dicyclohexyl carbodiimide, dissolved in a minimum amount of pyridine, was added. The reaction mixture was stirred at room temperature for 24 hours. At the completion of this time, the reaction mixture was filtered and then the solvent was removed by evaporation under reduced pressure. The residue was taken up in diethyl ether and extracted three times with equal volumes of 2 normal hydrochloric acid and water, respectively. The mixture was dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure. The desired cyano((6-phenoxy-2-pyridinyl)methyl)-2,2-dimethyl-3-cyclopropane carboxaldehyde product was recovered by distillation at 140° C. and 0.1 torr in a yield of 3.0 grams.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:11])[C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cnc2[nH]cnc(Cl)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-dichloro-1H-pyrrolo[2,3-d]pyrimidine D39 (1 g) in DMF (20 ml) at 0° C. was added sodium hydride (60% w/w in mineral oil, 255 mg, 6.4 mmol) and the mixture stirred for 20 mins. Phenylsulfonyl chloride (1.31 g, 7.4 mmol) was the added dropwise and the reaction mixture was kept in a cool bath for 15 hours. The mixture was poured into water (40 ml), and the precipitate was filtered, washed with water and Et2O, dried in a vacuum to give the desired product D40 in 1.62 g as an ashen solid. LCMS [MH+] 329.9@1.77 min (5 min run)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[OH:40])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[OH:40])[C:33]([O:35][CH3:36])=[O:34])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.40 g, 17.9 mmol) and triethylamine (2.50 mL, 17.9 mmol) in THF (20 mL) was added 2-methylpropyl chlorocarbonate (2.33 mL, 17.9 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this solution was added dropwise a solution of methyl 3-amino-4-hydroxybenzoate (3.00 g, 17.9 mmol) in THF (10 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was triturated with hexane-chloroform (1:1) to give the title compound (2.57 g, yield 42%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]([CH3:14])([CH3:13])[C:10]([O-:12])=[O:11].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:32][CH2:31]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)([CH3:14])[C:10]([O:12][CH2:31][CH3:32])=[O:11]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(Sc1ccccc1Br)C(=O)[O-]
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccncc1
Temperature: 80 °C

Procedure:
A mixture of 2-(2-bromophenylthio)-2-methylpropanoate (1 eq), pyridin-4-ylboronic acid (leq), aqueous sodium carbonate solution (2 M, 4 eq), and Pd(PPh3)4 (0.05 eq) in dioxane is degassed. The mixture is sealed, heated at 80° C., washed with water, extracted with ethyl acetate, dried (MgSO4), concentrated and purified by chromatography.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C)C=O>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: NCCCCCCO
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCCO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A mixture of 10.0 g (41 mmoles) biotin (1) and 800 ml N,N-dimethylformamide was stirred until all of the biotin had dissolved. Then 12.8 ml (53.8 mmoles) of tributylamine was added and the solution stirred for 10 minutes. To this solution was added 6.4 ml (49.4 mmoles) of isobutyl chloroformate followed by stirring for 30 minutes. This solution was then slowly added to a cold (-5° C.) solution of 5.80 g (49.4 mmoles) 6-amino-1-hexanol in 800 ml N,N-dimethylformamide. Addition took place over a 30-minute period, and the temperature of the reaction mixture was maintained at 0° C. during the addition. After addition was complete, the reaction mixture was stirred at 0° C. for 3 hours, then allowed to warm to 20° C. The solution was evaporated under high vacuum (2 Torr) and the residue was dissolved in 400 ml of anhydrous ethanol with heating. The solution was stored at -20° C. overnight, filtered, and the white crystalline precipitate washed with anhydrous ethanol. The washed precipitate was allowed to air dry to yield 13.4 g of white crystals, with an Mp of 170°-176° C. Recrystallization from anhydrous ethanol yielded material of MP 179°-181° C.
Reaction SMILES: [NH3:1].[CH:2]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:16][CH:15]=3)[CH:10]=[C:9]([CH2:25][CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH2:1])=[O:23])=[CH:18][CH:19]=3)[CH:10]=[C:9]([CH2:25][CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(C2CCCC2)n1
Reactant: N
Product: CCc1cc(Cc2ccc(CC(N)=O)cc2)nc(C2CCCC2)n1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of ammonia (7.0 N in methanol, 4 mL) and methyl 2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (0.067 g, 0.20 mmol) and heated at 100° C. for 48 h. After this time, the mixture was cooled and filtered through celite with ethyl acetate washings. The filtrate was washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.039 g, 59%) as a white solid. MW=323.43. 1H NMR (DMSO-d6, 500 MHz) δ 7.44 (s, 1H), 7.27-7.11 (m, 4H), 7.01 (s, 1H), 6.86 (s, 1H), 3.95 (s, 2H) 3.31 (s, 2H), 3.29-3.14 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 2.06-1.91 (m, 2H), 1.90-1.67 (m, 4H), 1.66-1.53 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); APCI MS m/z 324 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]4=[N:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:39][CH:38]7[O:40][CH:35]([CH2:36][CH2:37]7)[CH2:34]6)[CH:28]=5)=[CH:25][CH:26]=[C:21]4[N:20]=[C:19]3[C:41]3[C:42]([NH2:47])=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:49].O1CCOCC1>C(Cl)Cl.CO>[ClH:49].[ClH:49].[ClH:49].[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]4=[N:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:34][CH:35]7[O:40][CH:38]([CH2:37][CH2:36]7)[CH2:39]6)[CH:28]=5)=[CH:25][CH:26]=[C:21]4[N:20]=[C:19]3[C:41]3[C:42]([NH2:47])=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CC7CCC(C6)O7)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CC5CCC(C4)O5)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 87 %

Procedure:
tert-Butyl[1-(4-{2-(2-aminopyridin-3-yl)-5-[3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)cyclobutyl]carbamate (62.1 mg, 0.0965 mmol) was dissolved in DCM (1 mL)-MeOH (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 1.25 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (54.8 mg, 87.0%) as yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)O)C(=O)CF
Yield: 72.2 %

Procedure:
A solution of N-[(1-methylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (19 mg, 0.041 mmol) and anisole (0.1 mL) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature. After 30 min the reaction mixture was concentrated and chased with methylene chloride. The crude residue was triturated with diethyl ether and the solid filtered to afford the title compound as a light brown solid (12 mg, 72% yield).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[C:19](Cl)(=O)[C:20](Cl)=O.C(O)C>C1C=CC=CC=1>[CH2:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])[CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(C(=O)O)c2ccc(C(C)C)ccc1-2
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(CC)c2ccc(C(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above-mentioned azulene carboxylic acid (3) (4.84 g, 0.002 mole) is suspended in benzene (100 ml), and oxalyl chloride (2.8 g, 0.02 mole) is added dropwise thereto under cooling with ice. The mixture is stirred for 3 hours at room temperature and cooled with ice again. Ethyl alcohol (100 ml) is added dropwise thereto and stirred for 2 hours at room temperature. The mixture is poured into ice-water (300 ml) and extracted with benzene (100 ml). The benzene layer is separated, and then washed with water. The benzene solution is concentrated under reduced pressure, and n-hexane is added thereto to obtain the ethyl ester derivative (2) at a yield of 4.5 g, 83.3%, having a melting point of 48° to 49° C.
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([O:16]C)=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:26])[F:25].[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:25])[F:26]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 45 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of methyl 1-(2,3-dichlorobenzyl)-2-(difluoromethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate (1350 mg, 2.88 mmol) and 2 N LiOH (10 mL) in THF (2 0 mL) was stirred at 45° C. for 4 h. It was filtered, the filter cake was dissolved in water (10 mL) and formic acid was added to adjust pH=3-4. Then a filtration was performed and the filter cake was dried under vacuum to give the desired product (600 mg, 46%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 3.15 (s, 4H), 3.73 (s, 4H), 5.76 (s, 2H), 6.22 (d, 1H, J=7.5 Hz), 7.20-7.60 (m, 5H), 12.98 (br s, 1H); LC-MS: m/e=456 [M+1]+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=[CH:10]1.O>CN(C)C=O>[Br:1][C:10]1[S:9][C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=1
Reactant: c1cc2c(cn1)-c1sccc1CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c(s1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
N-Bromosuccinimide (0.237 g, 1.33 mmol) in dimethylformamide (4 mL) was added dropwise to a solution of 4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.250 g, 1.23 mmol) in dimethylformamide (4 mL, 100 mmol) at 0° C. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was mixed with 40 ml of water and extracted with 20 ml of ethylacetate twice. Combined organic extracts were washed with water and brine, and dried over MgSO4. The solvent was evaporated affording 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.227 g, 63%). 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.26 (d, J=5.4, 1H), 6.90 (d, J=5.5, 1H), 6.88 (s, 1H), 4.36 (t, J=4.7, 2H), 3.19 (t, J=4.8, 2H). MS (ESI+) 282.0
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccc3)c2c1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of (R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (298 mg, 0.83 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (200 mg, 0.83 mmol) and DIPEA (700 μL, 4.2 mmol) in n-butanol (5 mL) was heated at 90° C. in a sealed vial for 48 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a colourless oil (256 mg, 64%). LCMS (Method B): RT 3.26 min [M+H]+ 480.2.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:11]([OH:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
(3S)-3-Benzoylamino-1-chloro-4-phenyl-2-butanone (301.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to afford a desired compound, (2R, 3S)-3-benzoylamino-1-chloro-2-hydroxy-4-phenylbutane (300.1 mg; yield: 98.8%). The production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 27.3:1. The results of elementary analysis were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:17]2[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: O=C1CN2CCC1CC2
Reactant: COC(Cc1cc(Br)ccc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(Cc1cc(Br)ccc1NC1CN2CCC1CC2)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
Compound 67 (160 mg, 0.615 mmol) and quinuclidin-3-one (115.5 mg, 0923 mmol) were stirred in acetic acid (5 mL) under argon in the presence of anhydrous sodium sulfate (874 mg, 6.150 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (391 mg, 1.845 mmol) was then added and the mixture stirred for 24 hours at room temperature. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows incomplete consumption of 67, thus a second portion of quinuclidin-3-one (38.4 mg, 0.307 mmol) is added and the mixture stirred for a further 20 hours. After dilution with a mixture of 8:1 ethyl acetate:hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5 to 5:95) to yield a colorless residue, 68 (137 mg, 60.3%). 1H NMR (DMSO-d6) δ 1.25-1.39 (m, 1H), 1.53-1.80 (2×m, 3H), 1.86-1.94 (m, 1H), 2.64-2.77 (m, 4H), 2.80 (d, 2H, J=5.2 Hz), 3.14-3.24 (m, 1H), 3.27 and 3.29 (2×s, 6H), 3.34-3.40 (m, 1H), 4.54 (t, 1H, J=5.2 Hz), 5.04 (d, 1H, J=5.8 Hz), 6.43 (d, 1H, J=8.3 Hz), 7.13-7.15 (m, 1H), 7.17 (s, 1H); ESI-MS (m/z, %): 369/371 (MH+, 100%).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([NH2:5])=O.[CH3:7]OC(OC)N(C)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:22]=[C:23]([NH:25][NH2:26])[CH:24]=1)=[O:18]>COCCOC.CC(O)=O>[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:22]=[C:23]([N:25]2[C:3]([CH:2]([OH:1])[CH3:6])=[N:5][CH:7]=[N:26]2)[CH:24]=1)=[O:18]
Reactant: COC(=O)c1cc(NN)cc(-c2ccc(C)cc2)c1
Reactant: COC(OC)N(C)C
Reactant: CC(O)C(N)=O
Solvent: CC(=O)O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ncnc2C(C)O)c1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
A mixture of 2-hydroxy-propionamide (1.0 g, 11.2 mmol) and N,N-dimethylformamide dimethyl acetal (1.06 g, 8.96 mmol) in dimethyl glycol (6 mL) was heated to 80° C. for two hours, then cooled to room temperature. T mixture was added to a solution of 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.2 g, 4.1 mmol) in HOAc (5 mL), and the mixture was heated to 80° C. for another two hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 5-[5-(1-hydroxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a white solid (410 mg, 29.76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]=1[C:25]([O-:27])=[O:26]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]=1[C:25]([OH:27])=[O:26]
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(-c2ccc(Cl)cc2Cl)c1C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(-c3ccccc3)nn2c(-c2ccc(Cl)cc2Cl)c1C(=O)O
Reaction time: 5 h

Procedure:
To a stirred solution of 7-(2,4-dichlorophenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate (27.5 mg, 0.07 mmol) in THF (2 mL) and H2O (0.5 mL) was added LiOHH2O (4.2 mg, 0.1 mmol). After 5 h at 50° C., the reaction was concentrated under reduced pressure and diluted with EtOAc (10 mL). The organic layer was extracted with 1N HCl (6 mL), saturated NH4Cl (10 mL) and brine, dried (MgSO4), filtered and concentrated. The crude reaction product, 7-(2,4-dichlorophenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid, was moved onto next step without further purification (purity ˜90%).