Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][PH:17](=[O:23])[O:18]CC(C)C)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.C1COCC1>[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][PH:17](=[O:18])[OH:23])=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CO[PH](=O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[PH](O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
8.70 g (2127.5 mmol) of NaOH in 40 ml of water were added dropwise at 23° C. to a solution of 34.52 g (87 mmol) of isobutyl (4-diphenylphosphino-phenyl)methylphosphinate in 50 ml of THF. After heating under reflux for 6 hours, 18.1 ml (218 mmol) of concentrated hydrochloric acid were added dropwise at 23° C., the mixture was stirred for 10 minutes at 23° C. and completely evaporated on a rotary evaporator. The residue is taken up in methylene chloride, the solution was dried over Na2SO4 and completely evaporated. Drying under reduced pressure gave 28.3 g of (4-diphenylphosphinophenyl)methylphosphinic acid (90% of theory) in the form of a pale yellow solid having a melting point of 40° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[CH2:52][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:54][C:55]#[N:56]>C1COCC1>[C:55]([CH2:54][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][NH:68][C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:52][N:47]1[CH2:48][CH2:49][N:50]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:51][C@H:46]1[CH3:45])#[N:56]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: C[C@@H]1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
A mixture of 4-cyano-2-fluorobenzoic acid (50.4 mg, 0.305 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (107 mg, 0.282 mmol) and triethylamine (196 uL, 1.41 mmol) in THF (2.8 mL) was stirred for 15 minutes, followed by the addition of the diastereomeric 4-[(2R)-2-methylpiperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride salt (130 mg, 0.23 mmol). After stirring for 2 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. To separate diastereomers, preparative HPLC-MS was used: Waters mass directed fractionation system, Waters SunFire C18 column, 5 μm particle size, 30×100 mm, mobile phase system: Aq(0.1% TFA)/AcN; flow rate 60 mL/min; separating gradient: 30.4-48.4% B in 12 minutes. Peak 1 (first to elute), and Peak 2 (second to elute) were subjected to the deprotection step separately: stirred for 1 hour in a 1:1 mixture of DCM/TFA, concentrated, then stirred for 30 minutes in a solution of ethylenediamine (0.2 mL) in methanol (1.5 mL). Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product (peak 1: 19 mg, peak 2: 23 mg, total 36% of theoretical). Peak 1: 1H NMR (400 MHz, d6-dmso) (rotamers): δ 12.11 (br s, 1H), 8.81 (d, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.99-7.93 (m, 1H), 7.79-7.68 (m, 1H), 7.62-7.54 (m, 2H), 6.97 (dd, 1H), 4.93-4.83 (m, 1H), 3.85-3.66 (m, 1H), 3.36-2.08 (m, 10H), 0.90 and 0.71 ((each as d) together=3H); LCMS (M+H)+: 498.1. Peak 2: 1H NMR (400 MHz, d6-dmso) (rotamers): δ □12.08 (br s, 1H), 8.82 (d, 1H), 8.68 (d, 1H), 8.37 (d, 1H), 8.01-7.93 (m, 1H), 7.80-7.71 (m, 1H), 7.63-7.54 (m, 2H), 6.98 (t, 1H), 4.94-4.81 (m, 1H), 3.87-2.26 (m, 11H), 1.05 and 0.87 ((each as d) together=3H); LCMS (M+H)+: 498.1.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:7][C:8]2[O:12][C:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][C:9]=2[C:23]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.CC(C)([O-])C.[K+]>CCCCCCC>[C:24]([C:23]1[C:9]2[CH2:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:12][C:8]=2[CH:7]=[C:6]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:5]=1[OH:4])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To 22 mL of heptane, 5-acetoxy-4,6-di-tert-butyl-2,2-dipentyl-2,3-dihydrobenzofuran and 1.68 g (15.0 mmol) of potassium tert-butoxide were added and the interior of the reaction vessel was argon-purged by a process consisting of depressurizing the reaction vessel and blowing it with argon. The mixture was heated on an oil bath at 120° C., refluxed for 2 hours in an argon atmosphere and cooled down to room temperature, followed by adding 30 mL of 10% hydrochloric acid dropwise. Further, the mixture was vigorously agitated for 15 minutes and then left to stand still; the organic layer was subjected to HPLC analysis and the generation of 4,6-di-tert-butyl-5-hydroxy-2,2-dipentyl-2,3-dihydrobenzofuran was confirmed by retention time (99.36% in purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 17.5 g. of p-chlorobenzoyl chloride are reacted. The benzene is evaporated and the dark purple residue is dissolved in 200 ml. of chloroform and washed successively with 5% sodium carbonate, 0.5N Hydrochloric acid and then with water and dried over sodium sulfate giving a dark purple oil. The oil is extracted with ether giving the product as grey crystals, mp 98°-100° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[CH3:12][O:13]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH:38]=[CH:39][C:40]=1[CH3:41]>C1COCC1.Cl>[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH:12]=[O:13])[CH:38]=[CH:39][C:40]=1[CH3:41]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CC(C)(C)C=O)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(CC(C)(C)CC=O)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Lithium bis(trimethylsilyl)amide solution (55 ml, 55 mmol, 1M in THF) was added to a mixture methoxy methyl triphenyl phosphonium chloride (18.9 g, 55 mmol) in 65 ml THF dropwise at 0° C. and stirred for 15 min and it was added to a mixture of the product of STEP 3 (7.3 g, 34.7 mmol ) in 35 ml THF dropwise at 0° C. After 5 min, the reaction was quenched with H2O. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with H2O, brine, dried with Na0.2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=5/95) to give a yellow liquid in 6.3 g. It was dissolved in 100 ml THF and 100 ml 2N HCl. The reaction was heated at reflux for 30 min and cooled to room temperature. THF was evaporated. The product was extracted with ethyl acetate and washed H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=15/85) to yield a colorless oil in 3.8 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [F:1][C:2]([F:31])([O:16][C:17]1[CH:18]=[C:19]([C:27]([O:29]C)=[O:28])[CH:20]=[C:21]([CH:26]=1)[C:22]([O:24]C)=[O:23])[CH:3]([F:15])[O:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[OH-].[K+].Cl>O>[F:1][C:2]([F:31])([O:16][C:17]1[CH:26]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=[C:19]([CH:18]=1)[C:27]([OH:29])=[O:28])[CH:3]([F:15])[O:4][C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:8])([F:10])[F:9]
Reactant: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
Dimethyl 5-(1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)isophthalate (47.6 g, 0.10 mol) was added to a solution of water (1.00 L) and KOH (206 g, 3.5 mol). The resulting solution was heated to reflux for about 48 hours. The reaction was cooled to room temperature and then acidified to a pH of about 1 with concentrated HCl. The precipitate material was filtered and then dried under vacuum for 4 days to give 38.51 g of product.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1OS(C(F)(F)F)(=O)=O)=[O:5])C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26]([NH:33][C:34]([NH2:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:26]([N:33]1[C:4](=[O:5])[C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[NH:36][C:34]1=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)c1sc(C)nc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethanesulfonyloxy)thiazole-5-carboxylic acid ethyl ester (6.38 g, 20 mmol) in dioxane (80 mL) under an atmosphere of N2 was added cesium carbonate (13.0 g, 40 mmol), benzylurea (3.3 g, 22 mmol), Xantphos (0.58 g, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.46 g, 0.5 mmol). The resulting mixture was stirred at 60° C. for 18 h, cooled to RT, then poured onto water (500 mL) and stirred for 15 min. The resulting mixture was filtered, the filtrate collected and reduced in volume in vacuo to approximately one-third. The resultant precipitate was collected by filtration, washed with ether and dried in vacuo to give the title compound as a white solid (3.9 g, 72%).
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH3:6])[CH:8]=2)[N:17]=1
Reactant: Br
Reactant: Cc1cccc(C(=O)CSC#N)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (20 ml) solution was added to a solution of 2-(3-methylphenyl)-2-oxoethyl thiocyanate (2.29 g, 12.0 mmol) in acetic acid (20 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.03 g (66.8%) of the desired product as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[O:24]1[C:2]2([CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:3]2)[O:1][CH2:22][CH2:23]1
Reactant: OCCO
Reactant: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC3(CCO2)OCCO3)cc1
Yield: 101.9 %

Procedure:
4-Nitro-benzenesulfonic acid 4-oxo-tetrahydro-pyran-2-ylmethyl ester (0.5 g, 1.59 mmol), ethylene glycol (986 mg, 15.9 mmol) and p-toluene sulfonic acid (61 mg, 0.32 mmol) were refluxed in benzene (20 ml) for 20 hours. The solvent was removed in vacuo to afford a solid. The solid was dissolved in dichloromethane (30 ml) and successively washed with a saturated aqueous solution of sodium bicarbonate (2×5 ml) and water (2×5 ml). The organic phase was dried (Na2SO4), filtered and the solvent removal in vacuo afforded 582 mg (100%) of 4-nitro-benzenesulfonic acid 1,4,8-trioxa-spiro[4.5]dec-7-ylmethyl ester as a solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(C(=O)N2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (200 mg, 0.48 mmol), 2-piperidin-4-ylpropan-2-ol (78 mg, 0.55 mmol), HATU (205 mg, 0.54 mmol) and DIPEA (96 μL, 0.55 mmol) in DCM (5 mL) was allowed to stir at r.t. for 19 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) then (Si—PCC, MeOH:EtOAc, 0-5%) affording 798 as a white solid (138 mg, 53%). LCMS (method G): RT 7.50 min, [M+H]+ 545.4. 1H NMR (CDCl3, 400 MHz): δ 7.97-7.96 (1 H, m), 7.68-7.67 (1 H, m), 7.28-7.20 (2 H, s), 4.91-4.82 (1 H, m), 4.68-4.65 (1 H, m), 4.40 (4 H, brd s), 3.97 (3 H, s), 3.86 (4 H, t, J=4.70 Hz), 3.18-3.10 (1 H, m), 2.84-2.83 (2 H, m), 1.94-1.92 (2 H, m), 1.64-1.62 (1 H, m), 1.44-1.43 (2 H, m), 1.35-1.34 (2 H, m), 1.24-1.22 (7 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N+:12]=1[O-:18].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:6]([O-:9])=[O:7])[C:14]([CH3:17])=[CH:13][N+:12]=1[O-:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a nitrating mixture of sulphuric acid (24 mL) and nitric acid (12 mL) cooled to 0° C. was added 2,5-dimethyl-1-oxido-pyridin-1-ium (CAS: 4986-05-4) (8.4 g, 68.21 mmol). The solution was allowed to warm to room temperature and stirred over 30 mins then heated to 110° C. and stirred over 5 hrs. The reaction mixture was cooled and poured onto ice. The aqueous solution was made basic with solid sodium carbonate, giving a precipitate. The aqueous was extracted into DCM (3x), and the combined extracts were dried over magnesium sulphate, filtered and evaporated to yield a yellow solid, 2,5-dimethyl-4-nitro-1-oxido-pyridin-1-ium (D135) (9.8 g, 58.3 mmol, 85.4% yield);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][C:11]=1[N+:23]([O-])=O.ClC1N=C(NC2C=CC=C[C:35]=2[O:40]C)C([N+]([O-])=O)=CC=1.OC1C=C(B(O)O)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:22][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:10]3[N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[C:35](=[O:40])[NH:23][C:11]3=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1-n1c(=O)[nH]c2ccc(-c3cccc(O)c3)nc21
Temperature: 98 °C
Yield: 59 %

Procedure:
3-(6-(2-Methoxyphenylamino)-5-nitropyridin-2-yl)phenol. 6-Chloro-N-(2-methoxy-phenyl)-3-nitropyridin-2-amine (2.03 g, 7.27 mmol), 3-hydroxyphenylboronic acid (1.50 g, 10.90 mmol), palladium (II) acetate (0.489 g, 0.727 mmol), 1,1′-(bis(di-tertbutyl)phosphine)ferrocene (0.344 g, 0.727 mmol) and potassium phosphate (4.62 g, 21.81 mmol) were combined in dioxane and heated to 98° C. under nitrogen conditions for 16 h. Upon consumption consumption of starting material (monitored by TLC), the reaction mixture was filtered through celite. The filtrate was condensed under reduced pressure to afford the crude product. The crude material was purified using Biotage silica gel chromatography (10-40% ethyl acetate in hexanes) to afford the title compound (1.48 g, 59%). MS (ESI) m/z 338.4 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH3:20][CH:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:23](=[O:24])[CH2:22][CH:21]([CH3:26])[CH3:20])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CC(C)CC(=O)Cl
Product: CCc1noc(-c2sc(NC(=O)CC(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and 3-methyl-butyryl chloride.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc2ccccc2c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-(bromomethyl)naphthalene were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(O)C.[ClH:48]>O1CCCC1>[ClH:48].[ClH:48].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH:26]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(Cc2cc(C(C)(C)C)cc(-c3ccc(C(F)(F)F)nc3)c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and 1-methyl piperazine (0.14 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was then concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-((4-methylpiperazin-1-yl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (0.26 g, 53% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of nitrobenzene 198 (2.07 g) and NH4Cl (1.84 g) in EtOH (40 ml)-H2O (10 ml), was added iron powder (1.92 g). The mixture was heated to reflux for 1 hr. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat. NaHCO3 (30 ml) and extacted with AcOEt (30 ml). The combined organic layers were washed with brine (30 ml) and dried over Na2SO4. Concentration of the solvent afforded the aniline 199 (1.77 g, 95%) as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][C:23]=1[N+:24]([O-])=O)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2)=[N+]=[N-]>CCO.[Pd]>[NH2:24][C:23]1[CH:22]=[C:21]2[C:8](=[CH:7][C:6]=1[CH2:5][CH2:4][NH2:1])[CH2:9][C@@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:20]2
Reactant: [N-]=[N+]=NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: [Pd]
Solvent: CCO
Product: NCCc1cc2c(cc1N)C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 5 h

Procedure:
To a solution of (2S)-5-(2-azidoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step F (236 mg, 0.67 mmol) in EtOH (15 mL) was added 10% Pd/C (172 mg). The reaction mixture was stirred under a hydrogen atmosphere (ca. 1 atm) for 5 h, then filtered through a Celite pad, washing with MeOH, and the filtrate was concentrated under reduced pressure to give the title compound. MS: m/z/z 295 (M+1).