Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27](O)=[O:28].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:28]
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.302 g (1.2 mmol) of anthraquinone-2-carboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=2/1); the resulting solid was washed with ethyl acetate to yield the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.0 g), 4-(benzyloxy)aniline hydrochloride (3.6 g), and cesium carbonate (12.3 g) in NMP (50 mL) was heated at 100° C. for 5 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/1) to give N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (3.04 g) as a brown solid.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O-].[Na+].[Na].CI>CO>[CH3:11][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[O-]
Reactant: Sc1nc2ccccc2o1
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CO
Product: CSc1nc2ccccc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2-Mercaptobenzoxazole (6.0 g, 0.04 mole) was slowly added, with stirring, to a solution of sodium methoxide prepared by the addition of sodium (1.0 g) to anhydrous methanol (150 ml). Methyl iodide (5 ml) was added and the mixture was stirred at a temperature of 50° C. for a period of 3 hours and allowed to stand overnight at room temperature. The methanol was removed by distillation under reduced pressure and the solid residue was triturated with ice water and the insoluble material was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous magnesium sulfate and the solvent removed to give 2-(methylthio)benoxazole (5.8 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O.CO>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CN1CCCNCC1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
1-methyl-1,4-diazepane (0.20 ml, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (296 mg, 79%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:20]4[S:19][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5s4)cc3CC[C@@H]12
Yield: 80.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-benzothiopheneboronic acid (140 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 17 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (70% ethyl acetate/hexanes eluent), to give 190 mg (81%) of the title compound as a white solid. mp 247°-250°. FDMS: m/e=361. α[D]589 =+93.33 (c=0.36, chloroform).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:5]([O:8][CH:9]1[CH2:13][CH:12]2[CH:11]([CH:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)C1C2CC(O[Si](C)(C)C(C)(C)C)CC21
Reaction time: 8 h
Yield: 73 %

Procedure:
To a flask was added tert-butyl(cyclopent-3-en-1-yloxy)dimethylsilane (0.5 g, 2.52 mmol) and rhodium(II) acetate dimer (22 mg, 0.05 mmol). The flask was evacuated and purged 5 times with argon. Dichloromethane (8.4 mL) was added and the flask was evacuated and purged 5 times with argon. In a separate flask, ethyl diazoacetate (0.37 mL, 3.02 mmol) was added. The flask was evacuated and purged with argon five times. Dichloromethane (8.4 mL) was added and the solution was added to the first flask via syringe pump over a six hour time period and then allowed to stir overnight. The mixture was filtered over a pad of celite and then concentrated. Flash chromatography was used for purification to yield ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}bicyclo[3.1.0]hexane-6-carboxylate (524 mg, 1.84 mmol, 73% yield). 1H NMR (500 MHz, CDCl3) δ 4.13-4.03 (m, 2H), 2.37-2.20 (m, 1H), 2.20-2.12 (m, 1H), 2.11-1.96 (m, 1H), 1.94-1.70 (m, 4H), 1.35-1.14 (m, 4H), 0.89-0.79 (m, 9H), 0.05-−0.11 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH:18]([NH2:23])[C:17]=2[CH:16]=[CH:15][CH:14]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:23][CH:18]1[CH2:19][CH2:20][CH2:21][C:22]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)=[S:12]
Reactant: Fc1ccc(N=C=S)c(Cl)c1Cl
Reactant: NC1CCCc2ncccc21
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: Fc1ccc(NC(=S)NC2CCCc3ncccc32)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichloro-4-fluorophenylisothiocyanate and 5,6,7,8-tetrahydroquinolin-5-ylamine using General Procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.77-1.93 (m, 2H), 1.93-2.12 (m, 2H), 2.81-2.97 (m, 2H), 5.70-5.83 (m, 1H), 7.28 (dd, 1H, J=4.7 Hz, J=7.8 Hz), 7.51 (t, 1H, J=8.9 Hz), 7.62-7.78 (m, 2H), 8.37 (d, 1H, J=8.5 Hz), 8.43 (dd, 1H, J=1.4 Hz, J=4.5 Hz), 9.39 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile—0.1M ammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt min. (98.9%); MS: M+H+ 370.
Reaction SMILES: [CH:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:9]1[CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:6][CH2:7][C:8]1=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OC1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)OC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a suspension of 2.5 g of 5-isopropoxy-pyrrolidin-2-one, 1.23 g of potassium hydroxide hydrated to 85%, and 0.25 g of n-tetra-butylammonium bromide in 50 cm3 of tetrahydrofuran, there is added a solution of 2.99 g of benzyl bromide, without exceeding 30° C. After agitating for 1 hour at ambient temperature, the insoluble matter is filtered off and the solvent is evaporated. The residue (4 g) is distilled at 200° C. under 0.05 mbar. The distillate is chromatographed on silica (eluent: ethyl acetate--n-hexane, 1--1). 2.9 g of the expected product is obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1
Reactant: Brc1ccc(C2OCCO2)s1
Reactant: Clc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc(Cc2ccc(C3OCCO3)s2)c1
Reaction time: 0.33 h
Yield: 19 %

Procedure:
n-Butyl lithium (2.6N hexane solution, 15.6 mL, 39 mmol) was added dropwise to a solution of 2-(5bromo-thiophen-2-yl)-[1,3]dioxolane (7.0 g, 30 mmol) in tetrahydrofuran (40 mL) at from −75° to −68° C., and the solution was stirred for 20 minutes. 3-Chlorobenzyl bromide (4.3 mL, 33 mmol) was added dropwise to this reaction solution at from −75° C. to −68° C., and the solution was stirred for 20 minutes. The cold bath was removed, and the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (1.6 g, 5.7 mmol, 19.0%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[CH:5][C:4]=1[OH:13])[CH3:2].[ClH:14]>>[ClH:14].[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([OH:13])[CH:5]=1
Reactant: CCc1ccc(NC(C)=O)cc1O
Agent: Cl
Product: CCc1ccc(N)cc1O
Temperature: 100 °C
Yield: 79 %

Procedure:
N-(4-Ethyl-3-hydroxyphenyl)acetamide (3.5 g, 19.5 mmol) was suspended in 5N hydrochloric acid, and the suspension was stirred with heating at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, and the yielded crystals were collected by filtration, and air-dried to give the title compound (2.66 g, 79%) as pale-gray crystals.
Reaction SMILES: CC([N:5]([C@@H:9]([C:11]1([OH:34])[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:16])[CH2:12]1)[CH3:10])C(=O)[O-])(C)C.[ClH:35]>CO>[ClH:35].[NH2:5][C@@H:9]([C:11]1([OH:34])[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:16])[CH2:12]1)[CH3:10]
Reactant: C[C@@H](N(C(=O)[O-])C(C)(C)C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 96.4 %

Procedure:
A solution of 1,1-dimethylethyl{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (333 mg, 0.56 mmol) in methanol (10 mL) was treated with hydrochloric acid (4 N in dioxane, 1.4 mL, 5.6 mmol) at 60° C. for 30 min. After cooling, the volatile materials were removed in vacuo to provide 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride as a white solid (285 mg, 0.54 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.83 (br s, 3H), 7.59 (dd, 1H), 7.39 (d, 1H), 7.34 (m, 1H), 7.21 (q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25 (dd, 1H), 4.10 (dd, 1H), 3.98 (dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11 (dd, 3H); MS (EI) for C18H17F3IN3O2: 492 (MH+)
Reaction SMILES: [OH:1][C@@H:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4].O[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O>>[O:1]=[CH:2][C@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@@H]1O[C@@H](O)[C@@H](O)[C@H]1O
Agent: OC[C@@H]1O[C@H](O)[C@@H](O)[C@H]1O
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
α-L-ribofuranose; β-L-ribofuranose
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.B.CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C#N)c1nc(-c2ccc(F)cc2)cs1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(CN)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (140 mg, 0.6 mmol) in THF (3 mL) at room temperature was added borane (1M in THF; 3.01 mL, 3.01 mmol) and the reaction mixture was stirred at room temperature for 1 h and then heated at 40° C. for 1 h. The reaction mixture was then cooled to 0° C. and quenched with MeOH (˜5 eq, ˜0.2 mL), and allowed to warm to room temperature where 2N HCl solution was added until the pH ˜2. The reaction mixture was refluxed at 65° C. for 15 min and then cooled to room temperature and concentrated under reduced pressure. The solid obtained was triturated with ether twice and dichloromethane another two times. The remaining solid was dissolved in water (˜50 mL) and basified to pH ˜11 with NaOH pellets. The aqueous mixture was then extracted with ether and dried over sodium sulfate and concentrated under reduced pressure to give 2-(4-(4-fluorophenyl)thiazol-2-yl)propan-1-amine (75 mg, yield 52%), which was carried through without further purification; MS (ESI) m/z: Calculated for C12H13FN2S: 236.08. found: 237.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].P([O-])(O)(O)=[O:12].[Na+].Cl([O-])=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O.OO>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:12])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: O=P([O-])(O)O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 339.1 %

Procedure:
5-Nitro-2-thiophenecarbaldehyde (7.86 g) was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.6 g) in water (20 ml) and 30% aqueous hydrogen peroxide (5.9 ml) were added. Furtherl sodium chlorite (8.0 g) in water (70 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, and then sodium thiosulfate was added to remove an excess amount of hydrogen peroxide. The mixture was alkalified with 1N sodium hydroxide and extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-nitro-2-thiophenecarboxylic acid (7.83 g) as crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 40 °C
Yield: 109.3 %

Procedure:
1-Fluoro-4-nitrobenzene (10.0 g, 70.9 mmol) was melted into 4-hydroxy-1-Boc-piperidine (12.97 g, 64.4 mmol). The mixture obtained was treated with a 25 wt % potassium hydroxide solution (60 mL) and tetrabutylammonium bromide (1.60 g, 4.96 mmol) and heated at 40° C. for 70 hours. The precipitate was collected by filtration, washed with water and air-dried to leave the title compound (22.7 g, quantitative yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 6.95 (m, 2H), 4.60 (m, 1H), 3.70 (m, 2H), 3.38 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)=[CH:26][C:16]=3[N:15]=2)=[C:10]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:9]=1)C.[OH-].[Na+]>O1CCOCC1.O>[NH2:33][C:30]1[N:29]=[CH:28][C:27]([C:25]2[CH:24]=[CH:23][C:17]3[N:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([CH3:39])([CH3:40])[C:4]([OH:41])=[O:3])=[CH:9][C:10]=4[N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)=[N:15][C:16]=3[CH:26]=2)=[CH:32][N:31]=1
Reactant: CCOC(=O)C(C)(C)COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1)C(=O)O
Temperature: 65 °C
Reaction time: 144 h
Yield: 70.4 %

Procedure:
To a solution of 3-{4-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-3-[1,2,4]triazol-1-yl-phenoxy}-2,2-dimethyl-propionic acid ethyl ester (example 66) (95 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) is added 3 M NaOH solution (0.17 mL, 0.52 mmol) at room temperature. The solution is stirred at 65° C. for 6 days. The solution is concentrated and the residue is re-dissolved in H2O (5 mL). The pH of the solution is adjusted to 5 with 12N HCl solution. The milky solution is extracted with EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (63 mg, 70%). LCMS (ESMS): m/z: 527.40 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH2:5][CH3:6].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:1][CH2:2][CH2:3][N:4]([C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=1)[CH2:5][CH3:6])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCO)c1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 193.2 g (1 mole) of 4-(N-2-hydroxyethyl-N-ethylamino)benzaldehyde in dichloromethane are added 153.1 g (1.5 moles) of acetic anhydride, 151.8 g (1.5 moles) of triethylamine, and 8.5 g (7 mole %) of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 16 hours. The product solution then is washed with cold 2N HCl followed by saturated sodium bicarbonate, and the organic layer is filtered through cotton, and evaporated to dryness.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([C:9](=[O:33])[CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])=[C:19]3[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]3=[O:29])=[CH:13]2)[S:7][CH:8]=1>CO>[Cl:3][C:4]1[N:5]=[C:6]([CH:9]([OH:33])[CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])=[C:19]3[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]3=[O:29])=[CH:13]2)[S:7][CH:8]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Reaction time: 0.42 h

Procedure:
Sodium borohydride (408 mg, 10.80 mmol) was added to a solution of 3-(6-(3-(4-chlorothiazol-2-yl)-3-oxopropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (490 mg, 1.080 mmol) in methanol (20 mL). The mixture was stirred at room temp. for 25 mins, then quenched with saturated NaHCO3(aq) and extracted with chloroform (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[OH:13].[CH3:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][CH2:21]OS(C)(=O)=O.CN1CCCC1CCO.CS(Cl)(=O)=O>C(Cl)Cl.C(N(CC)CC)C.CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[O:13][CH2:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH3:14]
Reactant: N#CCc1ccc(Br)c(O)c1
Reactant: CN1CCCC1CCOS(C)(=O)=O
Agent: CN1CCCC1CCO
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN1CCCC1CCOc1cc(CC#N)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MEOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.