Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C.C(OCC)(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Yield: 96.4 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1.00 g, 4.638 mmol) in anhydrous ethanol (40 mL) was treated with 4-aminothiophenol (0.813 g, 6.494 mmol) and anhydrous sodium acetate (1.90 g, 23.19 mmol) at room temperature under a nitrogen atmosphere, at reflux for 2 hours. The reaction was cooled, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The resulting orange solid was triturated with ethyl ether/hexanes (1:1 v/v, 3×30 mL), and dried in vacuo to afford the title compound (1.36 g, 4.469 mmol, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.87 (s, 3 H) 5.80 (s, 2 H) 6.70 (d, J=8.46 Hz, 2 H) 7.00 (d, J=8.46 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 8.05 (dd, J=8.46, 1.84 Hz, 1 H) 8.64 (d, J=1.84 Hz, 1 H). MS (ESI+) m/z 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1>ClC1C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Clc1ccccc1
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole (0.182 g, 1.00 mmol) and manganese (IV) oxide (0.870 g, 10.0 mmol) (Carus black) in chlorobenzene (2 mL) was heated at 80° C. for 24 hours. The mixture was allowed to cool to room temperature, filtered through Celite®, and the wetcake was rinsed with chlorobenzene (2 mL). The lightly tinted solution was acidified with hydrochloric acid (4 M in 1,4-dioxane) to ˜pH 1.5 to give a thick, white mixture. After stirring in an ice-bath for 30 minutes, the mixture was filtered through a sintered glass funnel and rinsed with cold chlorobenzene (2 mL). The solids (0.380 g) were allowed to air-dry in a hood overnight to give the title compound as an off-white solid (0.140 g, 64%, LC internal standard analysis indicated a purity of 98.7 wt %): mp 229-237° C.; 1H NMR (DMSO-d6) δ 11.11 (bs, 1H), 9.27 (d, J=2.4 Hz, 1H), 8.82 (d, J=2.7 Hz, 1H), 8.71 (dd, J=5.1, 1.2 Hz, 1H), 8.61 (ddd, J=8.5, 2.5, 1.2 Hz, 1H), 7.89 (dd, J=8.5, 5.1 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:4][CH2:3][CH2:2]2.C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24][CH:25]=O)=[O:21].C(O)(=O)C>C(OCC)C.O>[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24]/[CH:25]=[C:7]1/[C:6](=[O:9])[CH:5]2[CH:1]([CH2:8]/1)[CH2:2][CH2:3][CH2:4]2)=[O:21]
Reactant: COC(=O)CCCC=O
Reactant: O=C1CCC2CCCC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]bicyclo[3,3,0]-octan-6-one (0.22 g; prepared as described in Reference Example 33 and predominantly in the 2β-configuration) in dry diethyl ether (3 ml) at -78° C. in an atmosphere of argon was treated with a solution of lithium diisopropylamide in diethyl ether (0.5 ml; 1.38M). The solution was stirred for 10 minutes at -78° C. and then treated with 4-methoxycarbonylbutanal (112 mg) at -78° C. After stirring for 10 minutes at -78° C. the reaction mixture was treated with a solution of glacial acetic acid (200 mg) in diethyl ether (400 mg) and the resulting white suspension was allowed to warm to room temperature. The mixture was then diluted with diethyl ether (20 ml) and poured into water (10 ml). The organic phase was separated and washed with aqueous sodium bicarbonate solution (5 ml; 10% w/v) and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The resulting oil (0.4 g) was dissolved in benzene (0.2 ml) at 20° C. and treated with methanesulphonyl chloride (83 mg). The stirred mixture was then treated dropwise with triethylamine (0.095 ml) and stirred for a further period of 40 minutes in an argon atmosphere. The mixture was then treated with 1,8-diazabicyclo[ 5,4,0]undec-7-ene (0.51 g) and it was stirred for a further period of 2 hours. The mixture was then treated with diethyl ether (20 ml). glacial acetic acid (2 ml) and water (20 ml). The organic phase was separated and the aqueous layer was extracted with diethyl ether (2×10 ml). The combined organic solutions were washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulphate. Concentration in vacuo, followed by chromatography on a silica gel column, using a mixture of ethyl acetate and hexane (1:9 v/v) as eluant, gave 6-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (54 g), predominantly in the 6β-configuration, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>ClCCl>[Si:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
A solution of 4-hydroxyindole (13.31 g, 75 mmol) in dry dichloromethane (400 mL) was treated with imidazole (8.17 g, 120 mmol) and t-butyldimethylsilyl chloride (18.09 g, 120 mmol) and the mixture was stirred at room temperature under nitrogen overnight. The precipitated white solid was filtered off and washed with dichloromethane and the combined filtrates were washed successively with 0.5 M aq. hydrochloric acid, 0.5 M aq. sodium hydroxide and brine, dried and evaporated to give 9 as white crystals (21.03 g, 85%), mp 80-81° C. (from hexanes); 1H NMR (500 MHz) δ 8.06 (br s, 1H), 7.08 (dd, J=3.1, 2.4 Hz, 1H), 6.99-7.05 (m, 2H), 6.58-6.59 (m, 1H), 6.52 (dd, J=7, 1.5 Hz, 1H, 1.06 (s, 9H), 0.23 (s, 6H). Anal. Calcd. for C14H21NOSi: C, 67.97; H, 8.56; N, 5.66. Found: C, 67.60; H, 8.80; N, 5.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:20]([OH:23])[C:21]#[CH:22].Cl>O1CCCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][CH2:20][OH:23])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1-chloro-4-iodobenzene (23.9 g, 100.0 mmol) in dry tetrahydrofuran (100 mL) was degassed and copper(I)iodide (570 mg, 3.0 mmol), tetrakis(triphenylphosphine)-palladium (3.4 g, 3.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (18.2 g, 120.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (6.7 g, 120.0 mmol) was added under inert atmosphere at ambient temperature. The reaction mixture was stirred (initially under cooling with ice water) for 24 h, then treated with water (20 mL) and acidified with 2 M hydrochloric acid (20 mL). The organic phase was separated and the aqueous phase was extracted with ether (4×30 mL). The combined organic phases were dried with anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) yielding 3-(4-chlorophenyl)prop-2-yn-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CN(C1C=CC=CN=1)C>O.C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To 13 ml of methylene chloride, were dissolved 1.25 g of 4'-hydroxybiphenyl-4-carboxylic acid and 0.52 g of triethyl amine. To the solution was added 10 ml of methylene chloride solution of 1.2 g of nonanoyl chloride dropwise with stirring at an ambient temperature. Further, 0.2 g of dimethylamino pyridine was added and the solution was stirred for a whole day and night at an ambient temperature. After the termination of the reaction, the solution was concentrated under a reduced pressure, the reaction liquid was poured into water and neutralized, and the precipitate thus formed was separated by filtration, and washed with hexane, and dried under a reduced pressure to obtain 1.72 g of the desired compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CC(C)=O>[CH2:17]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCOc1ccc(C=O)cc1

Procedure:
Anhydrous potassium carbonate (55.5 g, 0.4 mol) was added to a stirred solution of 4-hydroxybenzaldehyde (24.5 g, 0.2 mol) in acetone (300 cm3), over a period of 30 min at room temperature. 1-Bromoheptane (40.3 g, 0.225 mol) was added dropwise and the resulting mixture heated under reflux (12 h). The solution was poured into water (1000 cm3), the product extracted into diethyl ether (2×300 cm3), and the combined ethereal extracts dried (MgSO4). The solvent was removed in vacuo and the product isolated as a colourless oil by distillation under reduced pressure.
Reaction SMILES: CS(C)=O.CN(C)CCCN=C=NCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[C@@H:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C@@H:24]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Alternatively, dimethyl sulfoxide (20.80 mL, 22.90 g, 29.3 mmol) in dichloromethane (75 mL) is added dropwise to a cooled (0° C.) solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (160 mmol) in dichloromethane (350 mL). The mixture is stirred at 0° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (36.91 g. 133 mmol) in dichloromethane (150 mL) is added dropwise. The mixture was stirred at 0° C. for 20 min and pyridine (400 mmol) is added slowly followed by trifluroacetic acid (400 mmol). The mixture is allowed to warm to 0° C. and diluted with ice-cooled dichloromethane (250 mL). The mixture is washed with ice cold aqueous citric acid solution (5%, 2×300 mL) and water (300 mL), dried (MgSO4), and the solvent is evaporated under reduced pressure to give (2S)-1-tert-butoxycarbonyl-2-phenylpiperidi n-3-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)=[O:1]
Reactant: OCc1ccc(CO)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CO)cn1
Reaction time: 0.5 h

Procedure:
2,5-Di(hydroxymethyl)pyridine (10 g.) in 300 ml. of hot chloroform is treated with 100 g. of manganese dioxide. After 1/2 hour of stirring, the mixture is filtered and the filtrate is evaporated to dryness to give 2-formyl-5-hydroxymethylpyridine.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]=[N+:10]=[N-:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.C(O)(C)(C)C.[CH2:18]([O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[N:26][CH:27]=1)[C:19]#[CH:20].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:7][CH2:8][N:9]1[CH:20]=[C:19]([CH2:18][O:21][C:22]2[CH:27]=[N:26][C:25]([N:28]3[CH:32]=[N:31][N:30]=[N:29]3)=[CH:24][CH:23]=2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#CCOc1ccc(-n2cnnn2)nc1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)C(=O)OCn1cc(COc2ccc(-n3cnnn3)nc2)nn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of azidomethyl pivalate (4.26 g, 27.1 mmol) in 1:1 tert-butanol water (90 mL total) was added 5-(prop-2-ynyloxy)-2-(1H-tetrazol-1-yl)pyridine (5.45 g, 27.1 mmol), sodium ascorbate (1.4 mL of a 1M solution in water) and copper sulfate (1.4 mL of a 1M solution in water). The solution was stirred at room temperature for 72 hours. Water was added and the suspension was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the expected product which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.43-8.41 (2H, m), 8.00 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=3.2, 8.8 Hz), 6.32 (2H, s), 5.38 (2H, s), 1.08 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Also, to a suspension of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine (1.75 g, 6.85 mmol) in dry THF at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 uL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.5 g, 77% yield) MS (Q1) 284 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][Cl:12])[N:7]=1
Reactant: OCc1cccc(Cl)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a mixture of (6-chloro-pyridine-2-yl)-methanol (200 mg, 1.39 mmol) described in Manufacturing Example 52-1-1 and toluene (3 mL) was added thionyl chloride (152 μL, 2.09 mmol) on an ice bath, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (163.2 mg, 73%).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C1COCC1.[BH4-].[Li+].[Cl-].[NH4+]>CCOC(C)=O.CCCCCC.O.CCOC(C)=O>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]1[CH2:5][C@@H:2]([OH:1])[CH2:3]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Temperature: -73 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3-oxocyclobutyl)carbamate (43.2 g, 233 mmol) was charged into a 2 L 3-necked flask equipped with a thermometer and an addition funnel. THF (0.7 L) was added and the mixture was cooled to −73° C. internal temperature. Lithium borohydride, 2M in THF (140 mL, 280 mmol) was added over 30 minutes via the addition funnel, during which time the temperature did not exceed −72° C. After stirring for an additional 1 h at that temperature, TLC analysis indicated reaction was complete. Saturated aqueous ammonium chloride (0.3 L) was added and the mixture was warmed to 0° C. After gas evolution ceased, EtOAc (0.3 L) and water (0.3 L) were added and the mixture was stirred vigorously for 1 h. The layers were then separated and the aqueous layer was extracted with EtOAc (1×). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a yellow solid. This solid was suspended in 3:1 EtOAc/hexane and heated to boiling. The remaining solid was filtered off and additional hexane (100 mL) was added to the filtrate. The filtrate was then cooled in the freezer overnight. The resulting solid was collected by filtration and washed with cold 1:1 EtOAc/hexane solution, then dried to give tert-butyl(cis-3-hydroxycyclobutyl)carbamate (25.8 g, 59.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9 H) 1.68 (qd, J=8.54, 2.93 Hz, 2 H) 2.33-2.45 (m, 2 H) 3.34-3.44 (m, 1 H) 3.65-3.76 (m, 1 H) 4.98 (d, J=5.67 Hz, 1 H) 7.03 (d, J=7.82 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>O1CCCC1.N1C=CC=CC=1.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1F
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-fluoroaniline (20.00 g, 180.0 mmol) in tetrahydrofurane (100 mL) and pyridine (22 mL) was stirred for 15 min, and then 3-chloropropionyl chloride (25.14 g, 198 mmol) in tetrahydrofurane (50 ml) was added at 0° C. The mixture was stirred for 18 h at room temperature under inert atmosphere. After completion of the reaction, the mixture was diluted with water. The aqueous layer was separated and extracted with diethylether. The collected organic parts were washed with water and brine, then dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (white solid). This intermediate was used directly in the next step without further purification and characterization.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=[CH:16][C:13]=1[C:14]#N.C[OH:38]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:38]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of the 2-fluoro-4-(hexadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added during 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes, diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 2-fluoro-4-(hexadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1.[C:18]([C:20]1([NH:23][C:24]([C@H:26]2[N:30]([C:31]([C:33]3([CH3:36])[CH2:35][CH2:34]3)=[O:32])[CH2:29][C@@H:28](OS(C3C=CC=CC=3)(=O)=O)[CH2:27]2)=[O:25])[CH2:22][CH2:21]1)#[N:19].CC(C)([O-])C.[Li+].O>C1COCC1.C1(C)C=CC=CC=1>[C:18]([C:20]1([NH:23][C:24]([C@@H:26]2[CH2:27][C@@H:28]([S:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:6][C:7]=3[C:12]([F:13])([F:14])[F:15])[CH2:29][N:30]2[C:31]([C:33]2([CH3:36])[CH2:35][CH2:34]2)=[O:32])=[O:25])[CH2:21][CH2:22]1)#[N:19]
Reactant: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Reactant: FC(F)(F)COc1ccc(S)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C(=O)N2C[C@H](Sc3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a stirred suspension of 4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenethiol (30.4 g, 110 mmol) and benzenesulfonate (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (41.7 g, 100 mmol) in THF (50 mL) was added at room temperature 20% lithium tert-butoxide in THF (44.0 g≅49.5 mL, 110 mmol) over 40 min. After stirring at room temperature for 18 h, the reaction mixture was hydrolyzed with deionized water (400 mL) and extracted twice with ethyl acetate (400 mL & 200 mL). Both organic layers were washed with 10% brine (200 mL), combined, dried over Na2SO4, and filtered. Evaporation of the solvent and careful drying (45° C./≧10 mbar) gave 56.3 g crude product as voluminous, off-white foam, which was dissolved in 250 mL toluene at 50° C. The crystallization, which started during cooling, was completed after stirring at room temperature for 1 h by the dropwise addition of 200 mL heptane (note 11), followed by stirring at room temperature for 20 h. Filtration and drying (50° C./10 mbar/3 days for removal of toluene to ˜1%) yielded 51.2 g (95.7%) title product as an off-white crystalline powder, mp. 66-76° C. [α]D20=−67.5 (c 1.0; CHCl3). 1H NMR (CDCl3, 400 MHz) δ0.55-0.70 (m, 2H), 0.87-0.95 (m, 1H), 1.02-1.10 (m, 1H), 1.13-1.23 (m, 2H), 1.31 (s, 3H), 1.42-1.55 (m, 2H), 1.85-1.97 (m, 1H), 2.74-2.85 (m, 1H), 3.80-4.00 (m, 3H), 4.40 (q, J=7.8 Hz, 2H), 4.60 (dd, J1=8.1 Hz, J2=4.6 Hz, 1H), 7.11 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 8.05 (s, 1H).