Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C([Mg]Br)(C)C.CN(C)[CH:23]=[O:24]>C(OCC)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2ccc(Br)c(I)c2)cc1
Agent: CC(C)[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: -75 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (4.80 g, 0.012 mol) (described in WO 2008/071405) in anhydrous diethyl ether/tetrahydrofuran (120 ml, 1:1 ratio) at −75° C. is added isopropyl magnesium bromide (18.96 ml, 15% solution in tetrahydrofuran) dropwise such as to maintain an internal temperature below −70° C. Once addition is complete the reaction mixture is stirred at −75° C. for 2 hours, then warmed to −45° C. Anhydrous N,N-dimethylformamide (1.71 g, 0.0184 mol) is next added dropwise, maintaining temperature below −40° C., followed by warming to room temperature and quenching with 2M hydrochloric acid (60 ml). The reaction mixture is further diluted with diethyl ether, the two phases separated, and the aqueous phase extracted with additional diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (2% ethyl acetate in hexane eluant) to afford 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.7 g, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](C(C)C)CO4)c3)cc12
Yield: 26.4 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-3-methylbutan-1-ol (111 mg, 1.08 mmol) in PhCl (3 mL) at rt. It was subjected for two interations to microwave irradiation for 1 hr at 200° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (13 mg, 25%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.55 Hz), 4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.14-4.22 (1H, m), 2.98 (3H, s), 1.87-1.97 (1H, m), 1.04 (3H, d, J=7.02 Hz), 0.97 (3H, d, J=6.71 Hz). LC-MS retention time 1.64 min; m/z (MH+): 457. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=10.13 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.58 min, purity=94%.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16](NC)=[O:17])(=[O:14])=[O:13])=[CH:3][Cl:4]>ClC1C=CC=CC=1>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Yield: 98.1 %

Procedure:
9.8 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-methyl urea are solved in 200 ml of chlorobenzene. The solution is dried by azeotropic destilling off of 20 ml of the solvent. 5.3 g of phosgene are introduced into this solution within 45 minutes at a temperature of 120°-130° C. Evaporation of the reaction mixture to dryness yields 8.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-isocyanate in form of a yellowish oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[C:26]1([NH:25][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A solution of 2-chloro-6-trifluoromethyl-nicotinic acid (5 g, 22.2 mmol) in tetrahydrofuran (20 mL) cooled to −78° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 66.5 mL, 66.5 mmol). This solution was stirred at −78° C. for 2 h. At this time, the reaction was treated with a solution of aniline (19.6 g, 19.2 mL, 210 mmol) in tetrahydrofuran (20 mL). The reaction was allowed to gradually warm to 25° C. and was stirred at 25° C. overnight. At this time, the reaction mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×150 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in ether to afford 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.19 g, 96.9%) as a light brown solid.
Reaction SMILES: [CH2:1]([SiH:7]([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC([P]([Pt]([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>[CH2:1]([Si:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pt]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCC[Si](Cl)(Cl)CCc1ccccc1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
3.80 g (20.5 millimol) of n-hexyldichlorosilane, 2.00 g (19.2 millimol) of styrene, and 0.023 g (1.92×10-5 mol) of tetrakis(triphenylphosphine)platinum (O) were introduced into a flask and reacted with stirring by heating in an oil bath at 60° C. for 8 hours and then subjected to distillation under a reduced pressure to produce 5.6 g (17.5 millimol) of n-hexylphenethyldichlorosilane.
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[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.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[S:10][C:9]([CH:31]=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (65) (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 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 poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77%)
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]([CH3:25])=O.C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3][CH:2]([NH:1][CH:23]([C:22]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25])[C:8]1=[O:9])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOC(=O)C(C)=O
Agent: [BH]C#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 2 h
Yield: 50.3 %

Procedure:
1.5 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2.0 g of ethyl pyruvate were dissolved in 15 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 2 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 8 ml of ethanol was slowly added dropwise thereto. After this mixture was allowed to stand overnight, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 3:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.0 g of the desired compound in the form of an oily material.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.1 %

Procedure:
The mixture of 2-chloro-3-nitropyridine (50 g, 0.315 mol, 1.0 eq), TMB (50 mL, 1.1 eq), (PPh3)4Pd (O) (36.4 g, 0.1 eq), K2CO3 (130.6 g, 3.0 eq) and dioxane (1500 mL) was refluxed under argon for 2 days. The mixture was cooled to room temperature and filtered through a celite pad to remove K2CO3 and catalyst. The celite pad was washed with EtOAc. The organic solutions were combined and concentrated to get the crude which was purified by silica gel chromatography (0%˜40% EtOAc/Hex) to obtain the desired product 2-methyl-3-nitropyridine (30.5 g, isolated yield 70%) (Note: isolated yield 42% was obtained when the reaction was refluxed for 24 h).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]OC)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].C(C1[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=C(C(C)(C)C)C=1O)(C)(C)C.C(=O)C(C)C>[OH-].[K+]>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][C:27]([CH3:28])([CH3:26])[CH:29]=[O:30])[CH:8]=[C:7]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:6]=1[OH:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Agent: CC(C)C=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A process comprising reacting 2,6-di-tert.butyl-4-methoxymethylphenol or 2,6-di-tert.butyl-4-hydroxymethylphenol with isobutyraldehyde in the presence of potassium hydroxide as a catalyst to yield 3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropionaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([C:15]3([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with 1-(trifluoromethyl)cyclopropanecarboxylic acid (161 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2Cl2 (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide (229.5 mg, 72% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (br s, 1H), 9.38 (s, 1H), 8.36 (d, 1H), 7.51 (s, 1H), 1.49-1.43 (m, 2H), 1.38-1.33 (m, 2H); LCMS (APCI+) m/z 366, 368 (M+H)+, Retention time=3.32 minutes (Method 3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22].C(O)(C)C>CC(O)CCC>[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COCCOc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC

Procedure:
A suspension of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-5-hydroxy-4-methylaniline (126 mg 0.89 mmol) in 2-pentanol (2.5 ml) was heated at reflux for 7.5 hours. After cooling, isopropanol was added and the solid was filtered off, washed with isopropanol and ether, and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid 196 mg, 64%).
Reaction SMILES: C(N1CCCCC1)C.C(O)=O.CC1(C)[O:20][C:18](=[O:19])[CH2:17][C:15](=O)O1.C(=O)[C:23]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[C:25]([O:26][CH3:27])[CH:24]=1>>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH2:15][CH2:17][C:18]([OH:20])=[O:19])[CH:32]=[CH:31][C:28]=1[O:29][CH3:30]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Agent: CCN1CCCCC1
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 95 °C

Procedure:
After dropwise adding 27.2 g (33.1 ml, 0.24 mol) of 1-ethylpiperidine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the solution which was then heated to 95° C. during 1 hour and reacted at the same temperature for 2 hours. Subsequently the method of Example 1 was followed.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=O)[CH2:3][CH2:2]1.O.Cl>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[CH2:6][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CC1)C(=O)C1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution of N4-cyclopropylmethyl-N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide (220 g, 672 mmol) in tetrahydrofuran (1100 mL) was stirred at an external temperature of 55° C. (hot water bath). A borane-tetrahydrofuran complex (1M solution, 1748 mL) was added dropwise to the reaction mixture, and after heating and stirring for 2 hours, the reaction mixture was cooled in an ice bath and 2N hydrochloric acid (437 mL) was added. The reaction mixture was then stirred for 1 hour at an external temperature of 50° C. (hot water bath). After the reaction terminated, a 5N aqueous sodium hydroxide solution (299 mL) was added dropwise to the reaction mixture to adjust it to pH 8, and the aqueous layer was removed. Toluene (2200 mL) was then added to the organic extract, and after washing the organic extract twice with water, it was concentrated under reduced pressure to afford 209 g of the title compound (99.2% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]#[N:5].[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](OCC2C=CC(OC)=CC=2)=[O:12])[CH2:8]1.O>O1CCOCC1>[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](=[O:12])[CH2:3][C:4]#[N:5])[CH2:8]1
Reactant: COc1ccc(COC(=O)C2CC(F)(F)C2)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(=O)C1CC(F)(F)C1
Reaction time: 0.33 h
Yield: 155.1 %

Procedure:
To a solution of NaH (2.85 g, 71.1 mmol) in dioxane (200 mL) was added MeCN (2.92 g. 71.1 mmol). The mixture was stirred for 20 min, then the solution of 4-methoxybenzyl 3,3-difluorocyclobutanecarboxylate (14.0 g, 54.7 mmol) in dioxane (100 mL) was added dropwise. After the mixture was heated at reflux for 4 h, the reaction mixture was poured into water (400 mL) then extracted with EtOAc (200 mL). The pH of the aqueous layer adjusted to 7 with 3N HCl and extracted with EtOAc. The organic layer was washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to afford 13.5 g crude 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile which was used in the next step without purification.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)=O.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:5]=1[NH2:4])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60° C. The mixture is stirred at 60° C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
An additional trial performed under the same operating conditions but in tert-butanol with another nitrated aromatic aldehyde i.e. 4-nitrobenzaldehyde provided tert-butyl 4-nitro-benzoate in a yield of only 13.5%.
Reaction SMILES: C(O)(=O)C.[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15](=O)[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:23]([NH2:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>O1CCCC1>[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([NH:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 21 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
Acetic acid (22.0 g, 367 mmol) is added dropwise to a solution of 15.0 g (59.2 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and 54.9 g (296 mmol) of dodecylamine in 200 ml of dry tetrahydrofuran containing 5A molecular sieves (25 g). The reaction mixture warms during the addition. The mixture is then diluted with tetrahydrofuran (150 ml) and cooled to 21° C. Sodium cyanoborohydride (4.46 g, 7.1 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 4 hours, then filtered. The filtrate is concentrated and the residue is partitioned between ether (400 ml) and 5% sodium hydroxide (250 ml). The organic layer is dried over magnesium sulfate, filtered, and concentrated. Residual dodecylamine is removed by Kugelrohr distillation (110° C., 0.3 mm). The crude product is purified by chromatography (silica gel) to afford 20.4 g (82% yield) of the title compound, as a nearly colorless oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1cccnc1)c1cccnc1
Reaction time: 1 h

Procedure:
n-BuLi (42 mL, 1.6M, 67 mmol) was added to a solution of 3-bromopyridine (5.9 mL, 9.74 g, 62 mmol) in ether (200 mL) at −78 C. The resulting yellow suspension was stirred for 1 h. A solution of nicotinaldehyde (5.3 mL, 6 g, 56 mmol) in ether (25 mL) was then added. After stirring for 0.5 h, the reaction mixture was allowed to warm gradually to 0 C. The reaction mixture was then quenched by addition of half saturated brine (100 mL). The resulting mixture was extracted once with ethyl acetate and once with chloroform. Drying (1:1 Na2SO4/K2CO3) and concentration gave dipyridin-3-ylmethanol as a very viscous orange oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1F
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 4-benzyloxy-2-fluoro benzaldehyde (Compound 8, 16 g, 69.6 mmol) in methanol (100 mL) and dichloromethane (100 mL) was treated with sodium borohydride (5.26 g, 139 mmol). After 2 h at ambient temperature, the volatiles were evaporated in vacuo, the residue was diluted with water and dilute aqueous hydrochloric acid and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (15 g, 95%).