Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:40][C@H:41]([C:51]1[NH:52][C:53]([I:56])=[CH:54][N:55]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48]>CN(C=O)C>[I:56][C:53]1[NH:52][C:51]([C@@H:41]([NH:40][C:6]([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:8])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48])=[N:55][CH:54]=1
Reactant: O=C(O)c1cncs1
Reactant: CNC(=O)CCCCC[C@H](N)c1ncc(I)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(I)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of thiazole-5-carboxylic acid (1.5 eq.) in DMF (1 M) was treated with EDC.HCl (1.5 eq.), HOBt (1.5 eq.) and DIPEA (1.5 eq.), Reaction mixture was stirred at room temperature for 10 min and then added to a solution of D7 in DMF (0.33 M). The reaction mixture was stirred at room temperature for 1 h and subsequently partitioned between DCM and sat. aq. NaHCO3. The organic phase was separated and the aqueous phase extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude that was purified by flash chromatography (Biotage; 25M; DCM/MeOH) to afford the title compound as a white powder. 1H-NMR (400 MHz, 300K, DMSO-d6) δ 12.25 (br s, 1H), 9.23 (s, 1H), 9.02 (d, 1H, J 8.0 Hz), 8.58 (s, 1H), 7.65 (br s, 1H), 7.23 (s, 1H), 5.05 (m, 1H), 2.55 (d, 3H, J 5.2 Hz), 2.02 (t, 2H, J 7.6 Hz), 1.97 (m, 1H), 1.82 (m, 1H), 1.47 (m, 2H), 1.25 (m, 4H); MS (ES+) C15H20IN5O2S: 462 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[C:14]([CH3:16])[O:13][N:12]=2)[CH:6]=1)(=O)C>Cl>[CH3:16][C:14]1[O:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=2)[N:15]=1
Reactant: CC(=O)Oc1cccc(-c2noc(C)n2)c1
Agent: Cl
Product: Cc1nc(-c2cccc(O)c2)no1
Reaction time: 8 h

Procedure:
A solution of 8.55 g (39.18 mmol) of the product obtained in Step C above in 120 ml of 1N HCl solution is heated at reflux for 90 minutes and is then left at ambient temperature overnight, with stirring. The precipitate is filtered off to yield the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH:16]=[CH2:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl.P([O-])([O-])([O-])=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH2:15][CH:16]2[CH2:17][O:26]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A solution of 4-allyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 12.8 mmol, prepared according to J. Comb. Chem. 2002, 4, 125) in DCM and 0.3 M phosphate buffer (pH 8, 150 mL) was treated with mCPBA (3.5 g, 1.1 eq, 70%) and the mixture vigorously stirred at rt overnight. Further 3.5 g of mCPBA were added. After a total of 24 h, the phases were separated, the org. phase dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1:1 to EA) gave the desired intermediate as colourless oil (0.88 g, 26%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CCO.C1COCC1.[Pd]>[NH2:16][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: COCCOCOc1cc([N+](=O)[O-])ccc1C#N
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCOc1cc(N)ccc1C#N
Reaction time: 18 h

Procedure:
To a solution of 2-(2-Methoxy-ethoxymethoxy)-4-nitro-benzonitrile (2.35 g; 9 mmol) in EtOH/THF (25 mL/1 mL) was added a catalytic amount of 5% Pd/C. The reaction mixture was stirred under H2 atmosphere for 18 hours, filtered through kiselguhr evaporated to dryness and purified by column chromatography (SiO2—MeOH/CH2Cl2=0:1 to 5:95) to yield after evaporation 1.8 g (88%).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.B.CSC.[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][CH2:30][C:31]2=[O:36]>C(Cl)Cl>[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][CH2:30][C@@H:31]2[OH:36]
Reactant: O=C1CCc2c(Br)cccc21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: ClCCl
Solvent: CSC
Product: O[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a 100 mL 3-neck flask equipped with an internal thermometer and an addition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1.6 ml, 1M solution in toluene) and borane-dimethylsulfide (150 uL) under N2. The reaction was stirred at room temperature for 10 min then diluted with DCM (10 mL). Borane-dimethylsulfide (6.0 mL) was added and the reaction cooled to −20° C. A solution of 4-Bromo-2,3-dihydro-1H-inden-1-one (2.5 g, 11.8 mmol) in DCM (10 mL) was added dropwise over 20 min while maintaining the reaction temperature at −20±5° C. The reaction was stirred for 2 h after the addition was complete, then quenched by the dropwise addition of MeOH (10 mL). The reaction mixture was diluted with MeOH (20 mL) and the solvent distilled at atmospheric pressure. MeOH (30 mL) was added in two portions and the distillation was repeated twice. All the solvent was evaporated to give a solid which was purified by silica gel column chromatography (EA/hexanes) and recrystallization from 5:1 hexane/EA (30 mL) to provide 1.56 g (62%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a white powder IND INT-1. LCMS-ESI (m/z) calculated for C9H9BrO: 213.1; found 196.9 [M-OH]+, tR=3.06 min. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.9 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 5.29 (dd, J=12.6, 6.9 Hz, 1H), 3.05 (ddd, J=16.6, 8.7, 4.6 Hz, 1H), 2.87-2.71 (m, 1H), 2.50 (dddd, J=13.2, 8.4, 7.0, 4.6 Hz, 1H), 1.94 (dddd, J=13.5, 8.8, 6.6, 5.5 Hz, 1H), 1.80 (d, J=7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 146.82, 143.50, 131.24, 128.58, 123.21, 120.25, 76.83, 34.69, 31.19. Chiral HPLC: (S)-4-bromo-2,3-dihydro-1H-inden-1-ol was eluted using 10% IPA in hexanes: >99.9% % ee, tR=6.27 min.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:10]=[CH:9][N:8]=[C:7]5[C:3]=4[N:4]=[C:5]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[N:6]5[CH3:11])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[CH2:19][CH2:20]1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: c1cc(N2CCNCC2)ccc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(-c2nc3c(N4CCN(c5ccc(OCC6CC6)cc5)CC4)ncnc3n2C)cn1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 1-(4-(cyclopropylmethoxy)phenyl)piperazine (34.8 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 16.1 mg (30% yield) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:31](=[O:32])[CH2:30][CH2:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1ccc2ncnc(N)c2c1
Reactant: O=C(Cl)CCC1CCCC1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A mixture of 4,6-diaminoquinazoline hydrochloride (10 g) and tripropylamine (26.4 g) in dry pyridine (100 ml) was stirred in an ice-bath for 20 minutes. To the mixture was added dropwise during 1.5 hours 3-cyclopentylpropionyl chloride (12.2 g). The mixture was stirred in an ice-bath for 1.5 hours. Crushed ice was added to the reaction mixture. The mixture was stirred for 5 minutes and concentrated under reduced pressure. After addition of water, sodium hydrogen carbonate was added in small portions to the mixture to give precipitates which were separated by filtration, washed with water and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After the filtration of insoluble materials, the filtrate was treated with activated charcoal and concentrated under reduced pressure to give a residue. The residue was suspended in ethyl acetate. The suspension was stirred for 1 hour under heating and filtered to give crystalline 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.2 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[OH:22]CC12CCN(CC1)CC2=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]2)[CH2:18][C:19]3=[O:22])=[O:11])=[CH:2]1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C1CN2CCC1(CO)CC2
Product: O=C(OCC12CCN(CC1)CC2=O)c1c[nH]c2ccccc12

Procedure:
(3-oxoquinuclidin-4-yl)methyl 1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 4-(Hydroxymethyl)quinuclidin-3-one as the nucleophile.
Reaction SMILES: [C:1]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:53])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:52])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]3[CH:35]=[C:34]([C:36](=[O:51])[N:37]([CH2:39][CH2:40][CH2:41][N:42](C(OC(C)(C)C)=O)[CH3:43])[CH3:38])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.CO>>[C:1]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:53])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:52])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]3[CH:35]=[C:34]([C:36](=[O:51])[N:37]([CH3:38])[CH2:39][CH2:40][CH2:41][NH:42][CH3:43])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1nc2ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc2s1
Agent: Cl
Solvent: CO
Product: CNCCCN(C)C(=O)c1ccc2nc(NCCCCCC(=O)N(C)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)sc2c1
Yield: 73 %

Procedure:
The compound (157 mg, 0.190 mmol) obtained in Example 93c and 2 N hydrochloric acid-methanol (1.90 mL, 3.79 mmol) were used to give the title compound (101 mg; yield, 73%) as a white solid according to the method described in Example 89e.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 89.4 %

Procedure:
To a mixture of ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate (0.66 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid as pale-yellow crystals (0.56 g, yield 89%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 204-205° C.
Reaction SMILES: ClC1C=C(C2N(C3C=CC(F)=CC=3)N=C(C(O)=O)C=2)C=CC=1.Cl[C:24]1[CH:25]=[C:26]([N:31]2[C:35]([C:36]3[CH:41]=[C:40](F)[CH:39]=[C:38]([Cl:43])[CH:37]=3)=[CH:34][C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])=[N:32]2)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:43][C:38]1[CH:37]=[C:36]([C:35]2[N:31]([C:26]3[CH:25]=[CH:24][C:29]([F:30])=[CH:28][CH:27]=3)[N:32]=[C:33]([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:45])[CH:34]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)cc2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3ccc(F)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 85A in analogy to the synthesis of the compound of Example 1. 53 mg (42% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].N#N.[OH-].[Na+].[CH2:17](Cl)[CH:18]=[CH2:19]>O.CC(O)C>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: C=CCCl
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C=CCOc1ccc(CC=C)cc1OC
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A multi-necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and dropping funnel was charged with 150 g of eugenol, 400 ml of 2-propanol and a gentle flow of N2 was introduced. A 40% NaOH solution (43.9 g NaOH, 1.1 mole in 66 g H2O) was added slowly to the externally cooled reaction vessel at a rate to maintain the internal temperature below 35° C. The mixture was stirred for 10 minutes and 113 ml (1.38 mole) of allyl chloride was added to the flask and heated to maintain a gentle reflux for 1 hour, at which time the reaction was complete (GC analysis). The flask was charged with 300 ml water. A Dean-Stark Trap and steam bath were used to azeotropically remove the 2-propanol. The distillation ceased when the temperature reached 94° C. and after cooling, 300 ml of hexane was added and the water layer separated. The organic layer was washed with water until the pH of the water wash was neutral, the layer was then dried over MgSO4, filtered and the solvent removed under vacuum. The product was vacuum distilled to yield 155 g (84%) of a pale yellow 3-[2-methoxy-4-(2-propenyl)phenoxy]propene.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10].[ClH:14]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[C:4]([C:3]([Cl:14])=[N:2][OH:1])[CH:5]=[CH:6][C:7]=1[O:12][CH3:13])#[N:10]
Reactant: COc1ccc(C=NO)cc1C#N
Reactant: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(Cl)=NO)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[(Hydroxyimino)methyl]-2-methoxybenzonitrile, 4 M hydrochloric acid and Oxon (registered trade name) were dissolved in a DMF solution, followed by stirring at room temperature for 12 hours to obtain 3-cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride. NMRC: 7.01 (1H, d), 8.03 (1H, dd), 8.07 (1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCOCC1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(C(=O)NC2CCOCC2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a mixture of 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide (360 mg, 1.439 mmol), ammonium formate (272 mg, 4.32 mmol) in methanol (20 ml) at 0° C., was added Pd/C (10%, 0.04 g) and the reaction mixture was stirred at 60° C. for 1 hrs. The reaction mixture was cooled to room temperature and filtered through celite, the filtrate was concentrated under vacuum. The residue was taken in ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated under vacuum to afford the title compound (300 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OC(O)C)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(C)O
Product: Nc1ccc(-c2nc3cc(N)ccc3o2)cc1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
2-(4-Nitrophenyl)-5-nitrobenzoxazole (30 g, 0.105 mol), ethoxyethanol (300 mL) and 10 percent Pd/C (300 mg) were placed in a 600 mL Parr Reactor. The reactor was heated to 70° C. at 50 psi hydrogen (340 kPa) for 3 hours, then 90° C. at 150 psi hydrogen (1033 kPa) for an additional 16 hours. After the hydrogen was vented off, the solution was filtered hot under nitrogen. A portion of the solvent (100 mL) was removed from the solution and deionized water (100 mL) was added thereto, causing product to precipitate. The solution containing the precipitated product was stirred and refluxed for 1 hour. The solution was cooled to room temperature, and the product was filtered and washed with methanol (50 mL). The product was dried and 20.7 g (87 percent yield) of an off-white solid having a melting point of 226° C. to 228° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:26]O>>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([OH:26])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1F
Reactant: OO
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 12. Quantities: 3-fluoro-4-octoxybiphenyl-4'-yl-boronic acid (11) (4.40 g, 0.012 mol), 10% hydrogen peroxide (16 ml, 0.036 mol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[F:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39]>CO>[F:36][C:37]([F:44])([F:43])[C:38]([NH:21][C@@H:19]([CH3:20])[C@H:18]([S:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@H](N)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-amine (0.024 g, 0.06 mmol) in MeOH (2.5 mL), 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) and ethyl trifluoroacetate (0.114 mL, 0.95 mmol) was added and the mixture was stirred at rt O/N and than submitted to purification on HPLC. The relevant fractions were collected freezdried to give 16 mg of product (53% yield) which was analysed by LC/MS and NMR.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][N:16]2COCC[Si](C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.N1C=CC=CC=1.[CH3:41][C:42](OC(C)=O)=[O:43].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[C:5]([NH:9][C:42](=[O:43])[CH3:41])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N(C)c2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
N-Methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine, prepared in Example 11 (34 mg, 0.041 mmol) was suspended in CH2Cl2 (0.5 mL) at 23° C. under an atmosphere of argon. Pyridine (81 μL, 1.0 mmol), Ac2O (94 μl, 1.0 mmol) and DMAP (cat.) were added. The reaction became homogeneous immediately. After 1 h, TLC analysis (CH2Cl2:EtOAc 4:1) indicated no starting material. The reaction was quenched with saturated NaHCO3(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to an oil. The oil was suspended in MeOH (2 mL) and K2CO3 (83 mg, 0.6 mmol) was added. The resulting mixture was stirred at 23° C. under an atmosphere of argon. After 1 h, the reaction was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure. The crude material was purified by semi-prep HPLC to give N-{3-[methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-acetamide (8.4 mg, 22%). 1H NMR (300 MHz, CDCl3) δ 7.86 (d, 1H, J=8.68 Hz), 7.58 (d, 1H, J=7.17 Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, J=8.29 Hz), 6.98 (m, 1H), 6.95 (d, 1H, J=1.92 Hz), 6.8 (dd, 1H, J=1.16, 8.05 Hz), 3.37 (s, 3H), 2.14 (s, 3H). LCMS (ESI) [M+H]/z Calc'd 383, Found 383. Anal. Calc'd: C, 75.37; H, 5.80; N, 14.65. Found: C, 73.53; H, 6.01; N, 13.73.