Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:24])[CH3:23])=[O:8].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH:19]([OH:20])[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:23])[CH3:24])=[O:8]
Reactant: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A suspension of 25 g (64 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanone and 1.24 g (32 mmol) of powdered sodium borohydride in 100 ml of ethanol was stirred at 50° C. for 3 hours, during which the solid dissolved. After cooling, the solution was then poured into ice-water acidified with hydrochloric acid, and extracted with methylene chloride. The organic solution was washed with water, dried and evaporated. The resulting 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanol (diastereomer mixture) melted from 165° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[NH:9][N:8]=2)=[N:3][CH:2]=1.[H-].[Na+].[CH3:20]I>O1CCCC1>[CH3:20][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:9]1
Reactant: c1cc(-c2n[nH]c(-c3ccncn3)n2)ncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccncn2)nc1-c1ccncn1

Procedure:
To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (2.3 g.) in dry tetrahydrofuran (125 ml.) is added 57% sodium hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyl iodide (1.4 g.) is added and the mixture is heated at reflux an additional three hours. The reaction mixture is cooled, filtered and concentrated to a solid which after recrystallization yields substantially pure 1-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>C1COCC1.O>[F:25][C:24]1[C:23]([F:26])=[CH:22][CH:21]=[C:20]([N+:27]([O-:29])=[O:28])[C:19]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of aniline (1.6 g, 16.9 mmol) in THF (40 mL) at −78° C. was added LiHMDS (34 mL, 1M, 33.9 mmol) and the reaction mixture stirred at −78° C. for 10 min. This solution was added via cannula to a solution of 2,3,4-trifluoronitrobenzene (3 g, 16.9 mmol) in THF (10 mL) at −78° C. and the dark purple reaction mixture stirred at −78° C. for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo to give the title compound as a dark orange solid (4.2 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.95 (1H, br s), 8.00 (1H, ddd, J=9.7, 5.4, 2.3 Hz), 7.31-7.25 (2H, m), 7.13-7.08 (1H, m), 7.04-6.99 (2H, m), 6.75-6.67 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>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.C(OCC)C>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: Fc1cc(F)cc(CBr)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Temperature: 100 °C
Yield: 129.8 %

Procedure:
3-Cyano-4-fluorophenylboronic acid (1.649 g, 10 mmol), powdered potassium phosphate (4.254 g, 20 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were charged in an oven-dried flask under argon atmosphere. The flask was evacuated and back-filled with argon thrice and then toluene (30 mL) and 3,5-difluorobenzyl bromide (1.295 mL, 10 mmol) were added by means of a syringe through a lattice stopper, under good stirring. The reaction mixture was heated to 100° C. in half an hour and maintained at that temperature for 1.5 hours. The black mixture was taken up with diethylether (200 mL), washed with saturated aqueous ammonium chloride (2×20 mL), brine (3×30 mL), dried over sodium sulphate and evaporated to dryness to afford 3.21 g of yellow oil. The crude was purified by flash chromatography on silica gel eluting with n-hexane/ethyl acetate 95:5 to yield 1.89 g (yield 76.4%) of whitish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][C@@H:28]([OH:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNC[C@@H](O)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C[C@@H](O)c1ccccn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (113 mg, 0.30 mmol), (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparation 28) (100 mg, 0.44 mmol) and diisopropylethylamine (230 μL, 1.32 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (12 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 1 mL of water, left overnight) gave the title compound (98 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:20]=[C:19]4B3OC(C)(C)C(C)(C)O3)=[N:14][N:15]=2)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:79]1[CH:84]=[N:83][CH:82]=[C:81]([CH:85]2[CH2:87][CH2:86]2)[N:80]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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]>[CH:85]1([C:81]2[N:80]=[C:79]([C:19]3[C:18]4[C:22](=[CH:23][CH:24]=[C:16]([C:13]5[O:12][C:11]([NH:10][C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)([CH3:8])[CH3:9])=[N:15][N:14]=5)[CH:17]=4)[N:21]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:27])=[O:26])[CH:20]=3)[CH:84]=[N:83][CH:82]=2)[CH2:87][CH2:86]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 120 °C
Yield: 28.5 %

Procedure:
To a 20 mL microwave vial was added N-(2-phenylpropan-2-yl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (86 mg, 0.167 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (4.8 mg, 9.99 μmol), Pd2(dba)3 (4.6 mg, 5.00 μmol), 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalyst Inc., 36.5 mg, 0.183 mmol) and potassium phosphate (106 mg, 0.500 mmol) followed by purging with argon. The solids were treated with dioxane (3.0 mL) and water (0.3 mL) and heated in the microwave at 120° C. for 20 min. The mixture was treated with water and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification (10-100% EtOAc in Hex) afforded 5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-amine (28.1 mg, 29%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 591.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.64-8.71 (2H, m), 8.39 (1H, s), 8.13 (1H, s), 8.03 (1H, d, J=8.8 Hz), 7.81 (2H, d, J=8.4 Hz), 7.78 (1H, dd, J=8.7, 1.5 Hz), 7.54 (2H, d, J=7.6 Hz), 7.35 (2H, t, J=7.7 Hz), 7.22-7.29 (3H, m), 6.01 (1H, s), 2.35 (3H, s), 2.09-2.16 (1H, m), 1.86 (6H, s), 1.20-1.24 (2H, m), 1.08-1.14 (2H, m).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([O:44][CH3:45])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([O:44][CH3:45])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and isobutylaldehyde (0.23 ml) were dissolved in 1,2-dichloroethane (30 ml), and to the solution, triacetoxy sodium borohydride (0.85 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 10) (0.38 g) as yellow crystals.
Reaction SMILES: O1CCCCC1ON[C:9]([C:11]1[S:25][C:14]2[NH:15][C:16](=[O:24])/[C:17](=[CH:18]\[C:19]3[NH:20][CH:21]=[CH:22][CH:23]=3)/[C:13]=2[CH:12]=1)=[O:10].C1(C)C=CC(S(O)(=O)=[O:33])=CC=1>CO>[O:24]=[C:16]1[NH:15][C:14]2[S:25][C:11]([C:9]([OH:10])=[O:33])=[CH:12][C:13]=2/[C:17]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1Nc2sc(C(=O)NOC3CCCCO3)cc2/C1=C/c1ccc[nH]1
Solvent: CO
Product: O=C1Nc2sc(C(=O)O)cc2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
(Z)-5-Oxo-4-[1H-pyrrol-2-ylmethylene]-5,6-dihydro-4H-thieno[2,3-b]pyrrole-2-carboxylic acid (tetrahydro-pyran-2-yloxy)-amide (65 mg, 0.18 mmol) was dissolved in methanol (2 ml). 4-Toluene sulfonic acid (0.09 mmol, 15 mg) was added in one portion and the solution stirred at room temperature for 2 hours. The solvent was evaporated and the residue triturated with diethyl ether to give 10 mg of (Z)-5-Oxo-4-[1H-pyrrol-2-ylmethylene]-5,6-dihydro-4H-thieno[2,3-b]pyrrole-2-carboxylic acid hydroxamide as a brown solid. MS(ES): m/e 276 [M+H].
Reaction SMILES: CO.C1COCC1.O.[NH2:9][NH2:10].[CH3:11][C:12]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:27][O:28][CH3:29])[C:23](OC)=[O:24]>O>[CH3:11][C:12]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:27][O:28][CH3:29])[C:23]([NH:9][NH2:10])=[O:24]
Reactant: NN
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NN)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
Methanol (10 ml), THF (10 ml) and hydrazine monohydrate (1.68 g, 0.03 mol) were added to methyl 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetate (3.27 g, 0.01 mol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetohydrazide (2.93 g, 89.6%) as colorless cristals.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1ccccc1
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2)c1O
Yield: 40.6 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and phenylisocyanate (32 mg, 0.27 mmol) were coupled to form the desired urea (25 mg, 41%). EI-MS (m/z) 340.3, 342.3 (M−).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8](OC)=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[C:13](OC)(=[O:19])[CH2:14][C:15](OC)=[O:16]>CS(C)=O>[C:3]1([C:4]2[N:5]=[C:15]([OH:16])[CH:14]=[C:13]([OH:19])[N:6]=2)[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c(C(=N)N)c1
Reactant: COC(=O)CC(=O)OC
Solvent: CS(C)=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-Fluoro-5-methoxybenzamidine (10.3 g) and dimethyl malonate (8.09 g) in dry dimethyl sulfoxide (7 mL) was allowed to stand at room temperature for 24 h.. The precipitated product was collected and washed with water and ether to afford 2-Phenyl-4,6-dihydroxy-pyrimidine as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1N)([CH3:4])([CH3:3])[CH3:2].Cl.N([O-])=O.[Na+].[H+].[F:21][P-](F)(F)(F)(F)F>O>[C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a stirred solution of 2-tert-butyl-5-nitroaniline (5.0 g, 25.8 mmol) in H2O (20 mL) was added conc. HCl (10 mL). After a solution was observed, the mixture was cooled to 0° C. followed by the slow addition of NaNO2 (1.78 g, 25.8 mmol) in H2O (10 mL). The reaction mixture was stirred at 0° C. for another 0.5 hours. Then HPF6 solution (40 mL) was added in two batches. The precipitate obtained by filtration was then heated under infrared light about 130-150° C. while grey solid slowly burned to dark viscous oil. The reaction process was monitored by TLC. The obtained dark oil was purified by chromatography on silica gel to afford 1-tert-butyl-2-fluoro-4-nitrobenzene (600 mg, 12.0% yield). NMR (400 MHz, CDCl3) δ 7.96 (dd, J=2.4, 8.8 Hz, 1H), 7.87 (dd, J=2.4, 12.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C=O)C.O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CCl)no1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CN=[N+]=[N-])no1
Yield: 73.7 %

Procedure:
3-Chloromethyl-5-methylisoxazole (500 mg, 3.8 mmol) and sodium azide (494 mg, 7.6 mmol) were heated in DMF (10 ml) at 60° C. for 6 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (MgSO4) and the volatiles removed by evaporation to give the title compound (387 mg, 73%) as an oil. NMR (DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([OH:13])=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH:32]1[CH2:35][O:34][CH2:33]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([O:13][CH2:31][CH:32]3[CH2:35][O:34][CH2:33]3)=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ICC1COC1
Reactant: Cc1ccc(S(=O)(=O)n2nc(O)c3cc([N+](=O)[O-])cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2nc(OCC3COC3)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
5-Nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-ol (0.05 g, 0.150 mmol) was dissolved in DMF (1.5 mL). Cesium carbonate (0.146 g, 0.450 mmole) was added, and then 3-(iodomethyl)oxetane (0.030 g, 0.150 mmol; prepared according to US 2008/0021032) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water and extracted with EtOAc (2×50 mL), and the extracts were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Preparative TLC (0.5 mm plate, 1:1 ethyl acetate/hexanes) afforded 5-nitro-3-(oxetan-3-ylmethoxy)-1-tosyl-1H-pyrazolo[3,4-b]pyridine (15 mg, 19%) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.54-9.52 (m, 1H), 8.83-8.81 (m, 1H), 8.05-7.99 (m, 2H), 7.34-7.28 (m, 2H), 4.93-4.86 (m, 2H), 4.78-4.72 (m, 2H), 4.62-4.55 (m, 2H), 3.57-3.48 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:21].[CH2:22](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[C:18]3[CH:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:21]=[CH:22]1
Reactant: COc1ccc2ncc(N)c(Nc3ccccc3Cl)c2c1
Reactant: CCOC(OCC)OCC
Product: COc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1

Procedure:
0.2 g (0.66 mmol) of N4-(2-chloro-phenyl)-6-methoxy-quinoline-3,4-diamine (Example 44i) in 6 ml triethylorthoformate are heated under reflux for 4 h. The solvent is evaporated almost to dryness, the dark residue is dissolved in ca. 1 ml ethyl acetate and the compound is precipitated by adding ca. 30 ml of hexane. The desired title compound is filtered off, and is dried for 16 h at 60° C. (high-vacuum). mp: 202-205° C.; MS: 310 (M++1); HPLC: tret=70.56 min (Grad 1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([NH:32][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[O:13])=[CH:7][C:6]=1[C:22]([F:23])([F:25])[F:24])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2cnccn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 50 mg, 0.13 mmol) in methylene chloride (1 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.OM solution of oxalyl chloride in methylene chloride (0.08 mL, 0.156 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (1 mL) and was treated dropwise with a solution of 2-aminopyrazine (15 mg, 0156 mmol) in tetrahydrofuran (1 mL) and 2,6-lutidine (0.02 mL, 0.157 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with methylene chloride 3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-pyran-2-yl)-propionamide (13 mg, 22%) as a colorless gum: EI-HRMS m/e calcd for C20H22F3N3O4S (M+Na)+ 480.1175. found 480.1177.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:18])[C@H:12]([OH:17])[C@@H:13]([CH2:15][OH:16])[O:14][C@H:8]3[N:7]([CH2:19][CH:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21])[C:6]=2[CH:27]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C.CO>[Si:33]([O:16][CH2:15][C@H:13]1[O:14][C@@H:8]2[C@@H:9]([S:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][C:6]=3[N:7]2[CH2:19][CH:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21])[C@@H:11]([OH:18])[C@@H:12]1[OH:17])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCN(CC)C(C)CN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)C(C)CN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]21
Temperature: 25 °C
Reaction time: 23 h
Yield: 9.4 %

Procedure:
To the solution of 1.51 g of the compound (10) obtained in Example 10 and 0.48 g of imidazole in 3.5 ml of dimethylformamide, 0.55 g of tert-butyldimethylsilyl chloride was added dropwise, and the mixture was stirred for 23 hours at room temperature. Chloroform was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography, and 180 mg (yield: 9.4%) of the title compound was obtained from the fraction of ethyl acetate-methanol (19:1).