Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.CO.[SH:4][C:5]1[S:6][C:7]([SH:10])=[N:8][N:9]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>[OH-].[Na+]>[SH:10][C:7]1[S:6][C:5]([S:4][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][N:8]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)CSc1nnc(S)s1
Reaction time: 8 h

Procedure:
In a mixture of 9.66 g of sodium hydroxide, 14.6 ml of water, and 122 of methanol was dissolved 36.3 g of 2,5-dimercapto-1,3,4-thiadiazole. After cooling the mixture, a solution of 24.1 ml of ethyl bromoacetate and 24 ml of methanol was added to the mixture below 10° C. The resultant mixture was stirred for 3 hours at room temperature and cooled below 10° C. 43.5 ml of water and 400 ml of 50% methanol were successively added to the reaction mixture, whereby crystals precipitated, and the mixture was allowed to stand overnight at 4° C. The crystals were collected by filtration, washed successively with water and then 50% methanol, and dried to provide 42.5 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate.
Reaction SMILES: ClCCl.[C:4]([OH:9])(=[O:8])[C:5]([CH3:7])=[CH2:6].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CS(O)(=O)=O.C(N(CC)CC)C>[C:4]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][O:10]1)(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: C1=COCC1
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCO1
Temperature: -40 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, nitrogen inlet and a magnetic stirrer was added 300 mL of dichloromethane, 24.5 g (0.29 mol) of methacrylic acid and 21.4 g (0.305 mol) of 2,3-dihydrofuran. The flask was cooled under Nitrogen to −40° C. and 0.05 g of methanesulfonic acid was added. The mixture was warmed to 0° C. and stirred for 6 hours at which time it was recooled to −40° C. and an excess (1 mL) of triethylamine was added. The solution was then washed with saturated sodium bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Distillation from sodium carbonate at reduced pressure resulted in 26 g (58%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([NH2:7])=[CH:3][N+:4]([O-:6])=[O:5].[CH2:8]([CH:11]1[CH2:16][C:15](=[O:17])[CH2:14][C:13](=O)[CH2:12]1)[CH2:9][CH3:10].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1[OH:28])[CH:23]=O>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:14]3[C:15](=[O:17])[CH2:16][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:12][C:13]=3[NH:7][C:2]([CH3:1])=[C:3]2[N+:4]([O-:6])=[O:5])[CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1[OH:28]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: CC(N)=C[N+](=O)[O-]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C([N+](=O)[O-])C2c1cc(Br)c(O)c(OCC)c1

Procedure:
A mixture of 1-methyl-2-nitro-vinylamine (1 g), 5-propylcyclohexane-1,3-dione (1.61 g) and 3-bromo-5-ethoxy-4-hydroxy-benzaldehyde (2.57 g) in ethanol (50 ml) was stirred at reflux for 17 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane. A precipitate formed, which was collected by filtration. The solid was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 2.8 g. MS-ESI: [M+H]+=465.0/467.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([Cl:31])[CH:23]=1.[CH3:32][PH:33](=[O:35])[CH3:34]>>[Cl:31][C:24]1[CH:23]=[C:22]([P:33]([CH3:34])([CH3:32])=[O:35])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)cc1Cl
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2Cl)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-chlorophenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 487 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution containing 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) and triethylamine (470 μL, 3.36 mmol) in 1-methyl-2-pyrrolidinone (30 mL) was cooled to 0C. Benzoyl chloride (345 μL, 3.05 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was combined with 1% aqueous sodium bicarbonate solution (150 mL) and then stirred overnight. A fine white precipitate was isolated by filtration and washed with hexanes. The material was dissolved in dichloromethane, methanol and toluene. The solution was concentrated under vacuum. The material was purified by column chromatography (60 g silica gel eluting with 7.5% methanol in dichloromethane) and then dried in a vacuum oven at 50° C. for 2 days to provide 0.82 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}benzamide as an off white powder, m.p. 103-125° C. Analysis: Calculated for C25H29N5O2.0.30 H2O: % C, 68.72; % H, 6.83; % N, 16.03. Found: % C, 68.50; % H, 6.55; % N, 16.02.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:21]I.[OH-].[Na+]>CC(N(C)C)=O.C1COCC1>[C:2]([O:5][C:6]([N:8]([CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1)[CH3:21])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (77.7 mmol) of BOC-tranexamic acid in 162 mL of DMA and 320 mL of THF was cooled to 0° C. and treated with 7.46 g (170.99 mmol, 2.2 eq) of NaH (55% in oil) over 30 min. The mixture was warmed to RT, cooled to 0° C. again and treated with 77.42 mL (1243 mmol, 16 eq) of CH3I and warmed to RT overnight. 230 mL (2487.1 mmol, 32 eq) of aqueous 32% NaOH were added at 0° C., the solution was stirred for 1 h at RT and partitioned between Et2O (×3)/H2O. The organic phase was evaporated to remove the DMA. The residue was dissolved in 100 mL of dioxane and treated with 233 mL (233 mmol) of aqueous 1M NaOH at RT, and the solution was stirred overnight. The reaction was partitioned between Et2O (×3)/H2O, the aqueous phase was acidified with aqueous 10% KHSO4 and partitioned between Et2O (×3), washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 19.2 g (87%) of trans-4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexane-carboxylic acid, MS: 270 (M−H−).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:26]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+). N-(3,5-diChlorobenzenesulfonyl)-Proline: To a solution of 39.3 g (0.116 mol) of the above methyl ester in 250 mL methanol was added 115 mL (0.23 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred for three hours, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (˜200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white, foamy solid. This was recrystallized twice from ethyl acetate/hexanes to give 33.8 g (0.104 mol, 90%) of the title compound as colorless, broad, flat needles. M/z=325.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[N:5]=1)(=O)[NH2:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[N:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C(N)=O)CC1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a stirring solution of tert-butyl 4-(3-carbamoyl-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (985 mg, 2.0 mmol) in THF (50 mL) at room temperature under argon was added TEA (405 mg, 4.0 mmol), and was followed by addition of TFAA (840 mg, 4.0 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude product was dissolved in a small amount of DCM (˜5 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 908 mg (91%) of tert-butyl 4-(3-cyano-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.43-1.51 (m, 9H) 1.81-1.95 (m, 2H) 1.95-2.09 (m, 2H) 3.27-3.57 (m, 2H) 3.57-3.88 (m, 2H) 4.38-4.81 (m, 1H) 6.29 (s, 1H) 7.83 (d, J=8.35 Hz, 1H) 8.20 (dd, J=8.57, 2.42 Hz, 1H) 9.04 (d, J=2.64 Hz, 1H). MS (ESI) 419 (M+H-tBu).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 90 °C
Yield: 74 %

Procedure:
A solution of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (172 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77.7 mg, 0.13 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was triturated with methanol and dichloromethane and filtered, washed with ether and dried to give 6-chloro-4-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one (223 mg, 74%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6](S(C(F)(F)F)(=O)=O)=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14].[Li][CH3:26]>[Zn](Br)Br.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6]([CH3:26])=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14]
Reactant: COc1c2occc2c(S(=O)(=O)C(F)(F)F)c2c(=O)cc(C)oc12
Reactant: [Li]C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Br[Zn]Br
Solvent: O
Product: COc1c2occc2c(C)c2c(=O)cc(C)oc12
Yield: 70 %

Procedure:
9-Methoxy-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one (324 mg, 1.0 mmol), ZnBr2.H2O (1.04 g, 4.0 mmol), CuI (28 mg, 0.15 mmol), PdCl2(PPh3)2 (84 mg, 0.12 mmol) and MeLi (2.5 mL of 1.6 M in diethylether, 4.0 mmol) were treated as described under General Procedure D (Step 2) to afford the title compound (Yield 70%). 1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H, Me), 2.94 (s, 3H, Me), 4.21 (s, 3H, OMe), 6.05 (s, 1H), 6.91 (d, J=2.4, 1H), 7.65 (d, J=2.4, 1H). MS (ES) m/z: 244.9 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[S:8]([CH2:18][N+:19]#[C-:20])([C:11]1[CH:17]=[CH:16][C:14](C)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C-:21]#N.[Na+]>>[S:1]1[CH:5]=[CH:4][C:3]([C@@H:6]2[O:7][CH:20]=[N:19][C@@H:18]2[S:8]([C:11]2[C:12]([CH3:21])=[CH:13][CH:14]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccsc1
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@H]1c1ccsc1

Procedure:
In a manner analogous to Preparation 1, 3-thiophene carboxaldehyde (0.35 mL, 3.99 mmol), tosylmethylisocyanide (0.75 g, 3.84 mmol) and NaCN (0.02 g, 0.40 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 614.8 (2M+H+).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:30])[CH:12]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:4]=1>CO>[C:3]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([OH:30])[CH:12]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
Sodium borohydride (1.05 g, 27.7 mmol) was added portion wise to a stirred solution of tert-butyl 5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoate (12.1 g, 25.2 mmol) in methanol (80 mL) at 0° C. under nitrogen. On completion of addition stirring was continued for 1.5 h then the reaction was quenched with saturated aqueous ammonium chloride solution (80 mL). The resulting mixture was extracted with diethyl ether (3×200 mL) then the organic layers were combined, washed with brine (100 mL), dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% to 50% diethyl ether:cyclohexane) to give the title compound (8.47 g, 69%) as a colourless oil which was a mixture of diastereomers. LC/MS: 4.49 min; z/e 485, calcd (M+1) 485. 1H NMR (400 MHz: CDCl3): 7.60 (2H), 7.50 (2H), 7.45 (2H), 3.90 (1H minor), 3.80 (1H minor), 3.70 (1H major), 3.65 (1H major), 3.25 (1H minor), 3.00 (1H major), 2.90 (1H), 2.75 (1H), 2.60 (1H major), 2.55 (1H minor), 1.90 (1H), 1.85 (2H), 1.45 (10H), 0.90 (9H), 0.5 (6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]=2)[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH2:12][CH2:11][C@@:10]4([CH2:16][CH2:15][NH:14][C:13]4=[O:17])[N:9]=3)[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCC[C@@]12CCC(c1cc(Br)ccn1)=N2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=C1NCC[C@@]12CCC(c1cc(-c3ccc(C(F)(F)F)cc3)ccn1)=N2
Temperature: 120 °C
Yield: 74.1 %

Procedure:
To a solution of (5S)-2-(4-bromo-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 19) (200 mg, 0.6800 mmol) in 1,2-dimethoxyethane (3 mL) and water (1 mL) was added [4-(trifluoromethyl)phenyl]-boronic acid (142.05 mg, 0.7500 mmol) and sodium carbonate (216.2 mg, 2.04 mmol). The reaction mixture was degassed with nitrogen and then treated with bis(triphenylphosphine)palladium (II) dichloride (23.86 mg, 0.0300 mmol). The reaction mixture was heated in the microwave at 120° C. for 50 minutes then cooled and diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography eluting with 0-20% methanol in ethyl acetate to give (5S)-2-[4-[4-(trifluoromethyl)-phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D20) as a pale yellow solid (181 mg);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][N:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:32]5[CH2:33][CH2:34][C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Reactant: C1=NCCc2ccccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ccccc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,4-dihydro-isoquinoline following a procedure analogous to that described for Intermediate 42. Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=O)[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=[S:42])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(NC1(C(=O)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: O=C(NC1(C(=S)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a stirred solution of (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-N-(1-(2,2,2-trifluoroethylcarbamoyl)cyclopropyl)-2-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in CH2Cl2 (20 mL) was added P4S10 (34 mg, 0.155 mmol) and hexamethyldisiloxane (HMDO, 0.1 mL, 0.517 mmol) and the reaction mixture was refluxed for 4 h. The reaction mixture was cooled to room temperature and another portion of P4S10 (34 mg, 0.155 mmol) and HMDO (0.1 mL, 0.517 mmol) were added and the reaction mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica (100-200 mesh) eluting with 10% EtOAc in hexane to give the title compounds as yellow gum (37 mg, 18%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](=O)[CH:5]=[CH2:6].O.[NH2:11][NH2:12].[Cl-].[Na+]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]1[CH:5]=[CH:6][NH:12][N:11]=1
Reactant: C=CC(=O)C(OC)OC
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(OC)c1cc[nH]n1
Reaction time: 8 h

Procedure:
A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300 μL) was treated dropwise with hydrazine hydrate (21 mL). After standing at room temperature overnight the reaction mixture was treated with sodium chloride (108 g) and the mixture was then extracted with methyl-t-butylether (200 mL then 100 mL). The combined extracts were dried with magnesium sulfate and then evaporated to give 1H-pyrazol-3-carbaldehyde dimethyl acetal as a light brown oil (18.47 g).