Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[NH:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO.Cl.O.CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[N:5]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]2[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:4]1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2cc(S(=O)(=O)NCCO)ccc32)cc1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
(Scheme C). Amine 121 (75 mg, 0.19 mmol) was dissolved in MeOH/HCl(g) at room temperature and the solution was evaporated to dryness under reduced pressure. (E)-4-methoxycinnamic acid (41 mg, 0.23 mmol), EDCI (149 mg, 0.78 mmol), anhydrous TsOH (30 mg, 0.17 mmol) and dry DMA (3 mL) were then added and the mixture was sired at room temperature for 2 h. The mixture was poured into water and the precipitate was collected, washed with water, dried and dissolved in the minimum volume of DMW at room temperature. The solution was diluted with EtOAc, filtered and then diluted with hexane and refrigerated to give 37 (68 mg, 64%): mp 250-251° C.; 1H NMR [(CD3)2SO)] δ 9.35 (s, 1H), 8.83 (d, J=1.6 Hz, 1H), 8.38 (d, J=8.9 Hz, 1H) 8.00 (dd, J=8.9, 1.7 Hz, 1H), 7.90 (t, J=5.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.74 (d, J=15.3 Hz, 1H), 7.10 (d, J=15.3 z, 1H), 7.03 (d, J=8.81 Hz, 2H), 4.72-4.48 (m, 4 H), 4.13-4.06 (m, 2H), 3.83 (s, 3H), 3.38 (q, J=6.0 Hz, 2H), 2.87 (q, J=6.1 Hz, 2H). Anal. (C25H24ClN3O7S) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:19]([NH:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CNC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-methylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.01 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.68-7.61 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 7.16-7.03 (m, 3H), 6.68 (td, 1H, J=1.2 and 8.7 Hz), 2.90 (s, 3H); LCMS: purity: 95%; MS (m/e): 354(MH+).
Reaction SMILES: CC(C)=C[CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=C.[NH2-].[Li+].[CH3:13][O:14][C:15]([CH3:21])([O:17]CC#C)[CH3:16].BrCC>CCCCCC>[CH3:13][O:14][C:15]([CH3:21])([O:17][CH2:4][C:5]#[C:6][CH2:8][CH3:9])[CH3:16]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC(=C)CCC=C(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 232.6 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 15 minutes to 200 ml (8 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 12.6 g (91 mmol) of myrcene were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.0 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (90.8% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 157 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 15 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and concentrated under reduced pressure (40° C., 40 mbar). The crude product was analyzed by GC. 25.8 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained (yield 83.0% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]1[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=1)[CH3:15]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]2[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C1CN=C([C@H](C)N)O1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C1CN=C([C@H](C)NC(=O)Cc2cc(F)cc(F)c2)O1

Procedure:
Following General Procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[Cl:26]>>[Cl:18][C:19]1[CH:24]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Clc1ccc(I)cc1Cl
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,2-dichloro-4-iodobenzene according to the coupling protocol described in example 2. 1H NMR (DMSO-d6): δ 8.43 (s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.13 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (m, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.8, 2.7 Hz, 1H), 3.27 (s, 3H), 1.98 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCCCCC(=O)OCc1cc(Cl)ncn1
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCC(=O)OCc1cc(Oc2ccc3c(C(=O)OCC)csc3c2)ncn1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A suspension of 984 mg (4.05 mMol) hexanoic acid 6-chloro-pyrimidin-4-ylmethyl ester, 751 mg (3.38 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 1.43 g (6.76 mMol) K3PO4 in 20 ml NMP is stirred for 1.5 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; hexane/EtOAc 4:1→1:1) gives the title compound: MS: [M+1]+=429; TLC(hexane/EtOAc 4:1): Rf=0.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C@@H:53]([NH2:55])[CH3:54])=[CH:49][CH:48]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:55][C@H:53]([C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)[CH3:54])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (9 mg, yield 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O

Procedure:
82.2 g of 6A was dissolved in 300 ml of ethanol. 0.5 g of platinum oxide catalyst was added and the mixture was hydrogenated at 50 psig. Fresh portions of catalyst were added periodically. The reaction mixture was filtered, and the filtrate was concentrated. The residue was crystallized from water to give 2-amino-4-(trifluoromethyl)phenol (6B).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]([C:16](=[O:33])[CH:17]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.Cl.[NH2:36][OH:37].C(N(CC)CC)C>C(O)(C)C>[CH:27]1([CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:36][OH:37])=[CH:23][CH:24]=2)[C:16]([N:8]([CH2:7][C:6]([OH:34])=[O:5])[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(CC(C(=O)N(CC(=O)O)CC2CCCCC2)C2CCCCC2)cc1

Procedure:
{[3-(4-Cyano-phenyl)-2-(R,S)-cyclohexyl-propionyl]-cyclohexylmethyl-amino}-acetic acid tert-butyl ester (2.0 g, 4.29 mmol), hydroxylamine hydrochloride (0.89 g, 12.87 mmol) and triethylamine (1.3 g, 12.87 mmol) were stirred in isopropanol (80 ml) at room temperature for 24 hours. After evaporation, the residue was treated with potassium hydrogen sulfate solution and extracted with dichloromethane. The organic layer was dried and evaporated. Yield: 1.52 g (80%), MS m/z: 444.3 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:27]2[N:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)([C:6]([O:8]C)=[O:7])=[O:5]>O.O1CCOCC1>[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:27]2[N:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([OH:31])=[O:30])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)([C:6]([OH:8])=[O:7])=[O:5]
Reactant: CCCN(Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1)c1ncccc1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCN(Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)c1ncccc1C(=O)O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A solution of 350 mg of lithium hydroxide monohydrate dissolved in 10 ml of water was added to a solution of 0.70 g of ethyl 2-{N-[(2'-methoxalylbiphenyl-4-yl)methyl]-N-propylamino}nicotinate [prepared as described in step (a) above] dissolved in 5 ml of dioxane, and the resulting mixture was stirred at 70° C. for 4 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and 8.33 ml of 1N aqueous hydrochloric acid were added to the residual aqueous solution. The crystals thus precipitated were collected by filtration, to give 0.57 g of the title compound, melting at 179°-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[O:15]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][C:28]=1[O:35][CH3:36])[C@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18].N1CCCCC1>CO>[C@@H:16]1([O:15][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[C:11]3[S:10][C:9](=[S:14])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[C:12]3=[O:13])=[CH:29][C:28]=2[O:35][CH3:36])[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: O=C1CSC(=S)N1c1ccc(O)cc1
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1cc(C=C2SC(=S)N(c3ccc(O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
3-(4-Hydroxyphenyl)-2-thioxothiazolidin-4-one (0.23 g, 1.0 mmol) was added to a suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.32 g, 1.0 mmol) in methanol (20 ml) containing a drop of piperidine. The mixture, which rapidly turned yellow, was gently heated under reflux and deposited a thick precipitate after 30 min. The mixture was then cooled and filtered to give the required product (5c){0.12 g, 23%, m.p. decomp.>230° C., [α]D -34.4° (c 0.6, DMOS)}(Found: C, 53.04; H, 4.55; N, 2.81. C23H23NO9S2 requires C, 52.96; H, 4.44; N, 2.68%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([OH:23])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][C:27]([CH3:37])([CH3:36])[C:28](N1CCSC1=S)=[O:29].C(OCC)C>C1COCC1.C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([O:23][C:28](=[O:29])[C:27]([CH3:37])([CH3:36])[CH3:26])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)N1CCSC1=S
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(O)ccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1ccc2c3c(cnc2c1)CCCC3O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a suspension of Compound 141a (1.28 g, 3.88 mmol) in dry THF (50 mL) cooled in an ice-water bath was added NaH (60 percent, 163 mg, 4.08 mmol) followed by stirring for 10 minutes. A yellow-colored solution of Compound 226 (0.789 g, 3.88 mmol) in dry THF (10 mL) was added, and the mixture was then stirred at 25° C. for five minutes. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give a residue. Flash column chromatography of the residue (silica gel, 20 percent ethyl ether in benzene) provided Compound 142a (1.59 g, 99 percent): white powder; mp 125°-126.5° C.; Rf =0.49 (silica, 20 percent ethyl ether in benzene); IR (CHCl3) νmax 2957, 2934, 1750, 1261, 1131, 1116, 1027 cm-1 ; 1 H NMR (300 MHz, CDCl3) δ 8.58 (s, 1 H, H6), 7.98 (d, J=9.1 Hz, 1 H, H1), 7.67 (d, J=2.1 Hz, 1 H, H4), 7.21 (dd, J=9.1, 2.1 Hz, 1 H, H2), 5.33 (t, J=2.9 Hz, 1 H, H10), 2.90 (br dd, J=17.2, 3.3 Hz, 1 H, H7), 2.72 (ddd, J=17.2, 11.2, 5.7 Hz, 1 H, H7), 2.17-1.96 (m, 2 H, H8 or H9), 1.83-1.67 (m, 2 H, H8 or H9), 1.31 (s, 9 H, COC(CH3)3), 0.74 (s, 9 H, SiC(CH3)3), 0.12 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity) 414 (M+H, 100), 357 (9), 330 (12), 283 (5), 198 (10); HRMS for C24H36NO3Si (M+H), calcd 414.2464, found 414.2484. Anal. Calcd for C24H35NO3Si: C, 69.69; H, 8.53; N, 3.39. Found: C, 69.68; H, 8.44; N, 3.23.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:4]=[CH:3]1.C([N:13]([CH2:16][CH3:17])[CH2:14]C)C.[OH2:18]>>[CH2:16]([NH:13][C:14](=[O:18])[O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1)[C:17]1[CH:9]=[CH:8][CH:7]=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: O
Reactant: OCCCc1c[nH]cn1
Agent: Cl
Product: O=C(NCc1ccccc1)OCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 23 with 3-(1H-imidazol-4-yl)propanol hydrochloride and 5 mmol of triethylamine. The residual oil is taken up in a small amount of water. The title compound is crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:18]1([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:27].[N:18]1([CH:24]([C:14]2[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9]3)[CH2:25][CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCCN1CCCCC1
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N1CCCCC1

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and piperidinopropyl chloride hydrochloride were treated to obtain 5.0 g of 1-piperidinopropyl-3-phenyl-5-methylindazole hydrochloride (m.p. 222°-223° C).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CCOC(C)=O>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: Cc1ccccc1C(=O)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3C)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 8 %

Procedure:
A mixture of 2-phenyl-1-o-tolylethanone (commercially available) (200 mg, 0.95 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (183 mg, 0.86 mmol), urea (156 mg, 2.59 mmol), concentrated HCl (0.07 mL, 0.86 mmol) in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAc workup, then purified by preparative HPLC to give Compound 114 (31.75 mg, yield 8%). 1H NMR (DMSO-d6 400 MHz): δ 10.33 (br, 1H), 8.59 (s, 1H), 7.51-7.44 (m, 2H), 7.23-7.13 (m, 4H), 6.96-6.89 (m, 4H), 6.80-6.77 (m, 2H), 5.36-5.21 (m, 1H), 4.08-3.99 (m, 2H), 2.36 (s, 1.6H), 2.13 (s, 1.3H), 1.34-1.28 (m, 3H); MS (ESI): m/z 446.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:4]=1[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].O.O.[Sn](Cl)[Cl:30].[OH-].[K+]>C(O)C.O>[ClH:30].[NH2:24][C:21]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[C:4]([CH:20]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccc([N+](=O)[O-])cc1CSc1ccccc1NC(=O)C(C)(C)C
Reactant: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1CSc1ccccc1NC(=O)C(C)(C)C
Product: Cl

Procedure:
The product of Example 11 dissolved in ethanol and treated with 4 equivalents of Tin(II) dichloride dihydrate at reflux for 4 h. The reaction was cooled, diluted with water, made basic with potassium hydroxide and extracted with ethyl acetate (3×250 mL). The combined organics were washed with water then saturated sodium chloride solution. The solvent was removed in vacuo and the residue dissolved in diethyl ether. 4 N HCl in dioxane was added in excess and the resulting precipitate was filtered by suction to afford the product. 345.2 M+1
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH3:8][C:7]1[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccccc1
Yield: 96.4 %

Procedure:
In a schlenck tube, a mixture of 2-bromo-3-methyl-5-nitropyridine (4.6 mmol, 1.0 g), phenylboronic acid (4.6 mmol, 0.560 g), PdCl2dppf.DCM (0.47 mmol, 0.4 g), Cs2CO3 (13.8 mmol, 4.5 g) in a dioxane/water 4:1 mixture (18 ml) was heated at 100° C. for 14 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 3-methyl-5-nitro-2-phenylpyridine (0.95 g, yield 97%) as major product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[N-:12]=[N+:13]=[N-:14].[Na+]>CC#N>[N:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]1=[O:11])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2c(F)cccc21
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NC1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 4-fluoro-2,3-dihydro-1H-inden-1-one (1.29 g, 9.34 mmol) and HNIB (5.02 g, 12.1 mmol) in CH3CN (190.0 mL) was refluxed for 1.5 h, until the solution was clear yellow. Upon cooling to r.t., NaN3 (1.21 g, 18.7 mmol) was added and the solution was stirred at r.t. for 12 h. Additional NaN3 (0.50 g, 7.7 mmol) was added and the solution stirred further at r.t. for 4 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL). This solution was washed with H2O (75 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 5:1 hexanes/EtOAc) to give 1.61 g (96% yield) of 2-azido-4-fluoro-2,3-dihydro-1H-inden-1-one: 1H NMR (400 MHz, CDCl3): 7.59 (d, 1H), 7.41 (m, 1H), 7.32 (t, 1H), 4.15 (dd, 1H), 3.55 (dd, 1H), 2.89 (dd, 1H).