Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27](I)=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:41]5[CH:40]=[C:39]([F:38])[CH:44]=[CH:43][C:42]=5[O:48][CH3:49])=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 5-fluoro-2-methoxyphenylboronic acid (20 mg, 0.118 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.9 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone as a light yellow oil. MS: m/z 633.3 (M+H+).
Reaction SMILES: [NH:1]=[C:2]=N.[CH3:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[C:17]=1[O:29][Si](C(C)(C)C)(C)C)=S.CS(Cl)(=O)=O.C([N:44](CC)CC)C>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]([C:2]#[N:1])[C:13]([NH:12][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=2[CH3:4])=[NH:44])=[C:17]([OH:29])[C:18]=1[S:23]([N:26]([CH3:27])[CH3:28])(=[O:24])=[O:25]
Reactant: N=C=N
Reactant: CCN(CC)CC
Reactant: Cc1c(F)cccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Product: Cc1c(F)cccc1NC(=N)N(C#N)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1O

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2-methyl-3-fluorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (330 mg, 0.62 mmol), methanesulfonyl chloride (0.12 mL, 1.38 mmol) and triethylamine (0.2 mL, 1.04 mmol) were reacted to form the desired product (320 mg, crude). 1H NMR (CDCl3) δ 0.38 (s, 6H), 1.05 (s, 9H), 2.28 (s, 3H), 2.85 (s, 6H), 6.89 (t, 1H), 6.93 (d, 1H), 7.05 (d, 1H), 7.13 (m, 1H), 7.19 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O:17]O)(C)(C)C>ClCCl.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:17])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CCc2ccc(Br)cc21
Agent: [Cr+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan 8g (4 g, 17.8 mmol) was dissolved in 40 mL of anhydrous dichloromethane, followed by addition of chromium oxide (280 mg, 1.8 mmol) and slowly dropwise addition of tert-butyl hydroperoxide (19 mL, 190 mmol). The reaction system was sealed and stirred overnight at room temperature after the reaction solution was crimson and the generated gas was released. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of water and extracted with dichloromethane (100 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-bromo-3,3-dimethyl-indan-1-one 19a (3.5 g, 82.3%) as a white solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCl)(C)(C)C.C[O-].[Na+].C(#[N:33])C>CO.C(Cl)Cl>[NH2:33][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][CH:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CSc2ccccc2)cc1
Reactant: Nc1ccccc1
Reactant: CC#N
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccccc1SC(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a rapidly stirred solution of 2.3 g. (0.025 mole) of aniline and 10.0 g. (0.050 mole) of benzylphenylsulfide in 300 ml. of dry acetonitrile and 100 ml. of methylene chloride under nitrogen at -40° C., was added dropwise 3.5 g. (0.032 mole, 28% excess) of tert-butylhypochlorite in 25 ml. of methylene chloride at -78° C. in diffuse light. The reaction mixture was stirred 4 hours at -40° C. then allowed to warm slowly to -20° C. over 3 hours. Sodium methoxide (7.0 g., 0.13 mole) in 50 ml. of dry methanol (at 25°C) was added quickly. The reaction mixture was stirred for 1 hour as it warmed to room temperature. The solution was concentrated in vacuo, 100 ml. of water was added, and extracted with 5 × 100 ml. of chloroform. The combined organic phases were washed with 50 ml. of 5% aqueous sodium hydroxide, 100 ml. of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. Solvent was removed in vacuo giving a dark brown oil which was chromatographed on 300 g. of Fisher basic alumina (Act I) using etherpentane as eluant. Recovered was 5.2 g. (72% yield based on starting aniline) of 2-aminodiphenylthiophenoxymethane. Recrystallization from ethanol-water gave light yellow crystals, m.p. 65°-65.5° ; ir (cm-1) (CCl4) 3480, 3380, 3090, 1620, 1580, 1490, 1450, 1310, 1270, 1160, 1080, 1070, 1025, 690; NMR (CCl4) τ: 2.4-3.7 (14H, m), 4.51 (1H, s), 6.0-6.4 (2H, br s).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH3:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCNC
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 72 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.38–7.25 (m, 5H), 7.03–6.97 (m, 3H), 6.49 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.98–2.94 (m, 2H), 2.55–2.49 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.01–1.95 (m, 4H), 1.86–0.162 (m, 10H); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[F:41].N1C=CC=CC=1>CN(C)C=O.ClCCl.CN(C)C1C=CN=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:22])[NH:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[F:41])[CH:23]([CH3:24])[CH3:25])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N#Cc1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(C#N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyric acid (2.5 g, 7.37 mmol) and a few drops of N,N-dimethylformamide in dichloromethane (20 mL) was slowly added oxalyl chloride (1.3 mL, 14.74 mmol) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred for 15 minutes at 0° C. and 2 hours at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane (20 mL) and to the resulting solution was added 4-amino-3-fluoro-benzonitrile (840 mg, 6.14 mmol), 4-dimethylaminopyridine (150 mg, 1.2 mmol) and pyridine (0.78 mL, 9.21 mmol) at 0° C. The mixture was stirred for 2 hrs at 0° C. and overnight at room temperature. The reaction was quenched with 1 M aqueous citric acid solution and then extracted with dichloromethane (three times). The combined organic extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(4-cyano-2-fluoro-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (2.15 mg, 77%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([OH:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC[N:22]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:22])=[O:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(C(=O)O)c1-c1ccc(F)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Yield: 87.5 %

Procedure:
A solution of the compound (16.87 g, 64.32 mmol) obtained in step 2, WSC (16.03 g, 83.62 mmol), HOBt (11.30 g, 83.62 mmol), TEA (11.65 mL, 83.62 mmol) and ammonium chloride (4.47 g, 83.62 mmol) in DMF (200 mL) was stirred at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→85% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (14.72 g, 56.3 mmol, 88%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution was washed with water (2×20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquors were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1)→ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 12%). 1H NMR (250 MHz, CDCl3): δ1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 (m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, 1H), 5.61 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 7.18 (s, 1H). MS (ESP): 423.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:21]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:9]=1)=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
6-Nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (8.1 g, 20.5 mmol) was dissolved in DMF (75 mL) at 23° C. under an atmosphere of argon. SnCl2 (12.9 g, 67.7 mmol) was added followed by water (1.7 mL, 92.2 mmol) and the resulting mixture was heated to 50° C. After 4 h, 3N NaOH (45 mL, 135 mmol) was added followed by EtOAc (100 mL). The resulting emulsion was filtered hot through Celite and the bed of Celite was washed with hot EtOAc (3×100 mL). The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to give a solid. The crude material was purified by silica gel chromatography (2:8→7:3 ethyl acetate:hexane), to give 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine as a yellow solid (5.1 g, 68% yield). MS (FAB) [M+H]/z Calc'd 366, found 366.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:53]4[C:58]([CH3:59])=[CH:57][C:56]([CH3:60])=[CH:55][C:54]=4[CH3:61])=[C:18]4[N:52]=[C:21]([C:22]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=5)=[C:23]5[NH:41][C:26](=[C:27]([CH:33]6OCC(C)(C)C[O:34]6)[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:53]4[C:54]([CH3:61])=[CH:55][C:56]([CH3:60])=[CH:57][C:58]=4[CH3:59])=[C:18]4[N:52]=[C:21]([C:22]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=5)=[C:23]5[NH:41][C:26](=[C:27]([CH:33]=[O:34])[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C(C)(C)C)cc4)c4ccc([nH]4)c(C4OCC(C)(C)CO4)c4nc(c(-c5ccc(C(C)(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C(C)(C)C)cc4)c4ccc([nH]4)c(C=O)c4nc(c(-c5ccc(C(C)(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
Following a general procedure,22 a solution of 4 (43 mg, 0.05 mmol) in CH2Cl2 (5 mL) was treated with TFA/water (0.5 mL, 1:1) to give a biphasic solution. After stirring at room temperature for 2.5 h, CH2Cl2 was added. The organic layer was washed (saturated aqueous NaHCO3 and brine), dried (Na2SO4), concentrated, and chromatographed (silica, CH2Cl2/hexanes) to give a purple solid (34.8 mg, 92%): IR (neat) 1674, 1557, 1110 cm−1; 1H NMR δ −1.90 (s, 2H), 1.61 (s, 18H), 1.84 (s, 6H), 2.61 (s, 3H), 7.26 (s, 2H), 7.75-7.78 (m, 4H), 8.08-8.11 (m, 4H), 8.59 (d, J=4.4 Hz, 2H), 8.69 (d, J=4.4 Hz, 2H), 9.01 (d, J=5.2 Hz, 2H), 10.03 (br s, 2H), 12.50 (s, 1H); 13C NMR δ 195.1, 151.2, 139.2, 138.7, 138.3, 137.7, 134.2, 128.0, 124.4, 124.0, 122.6, 107.7, 35.2, 31.9, 29.9, 21.8, 21.7; LD-MS obsd 721.86; FAB-MS obsd 721.3931, calcd 720.3828 (C50H48N4O); λabs 428, 528, 567, 600, 657 nm.
Reaction SMILES: [Cl-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[N:9][N+:10]2[CH:14]=[CH:13][N:12]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:11]=2[CH3:26])=[CH:6][CH:5]=1.[CH3:30][N:31]([CH3:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.N1CCCCC1>C(O)C>[Cl-:1].[CH3:25][N:23]([CH3:24])[C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[N:15][N+:12]2[CH:13]=[CH:14][N:10]([N:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH3:2])[CH3:29])=[CH:28][CH:27]=3)[C:11]=2[CH:26]=[CH:36][C:35]2[CH:38]=[CH:39][C:32]([N:31]([CH3:40])[CH3:30])=[CH:33][CH:34]=2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C=Cc2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Reaction time: 20 h

Procedure:
0.82 g of 1,3-bis[[p-(dimethylamino)-benzylidene]amino]-2-methylimidazolium chloride is suspended in 30 ml of ethanol, whereupon the suspension is treated with 0.3 g of 4-dimethylaminobenzaldehyde and 0.17 g of piperidine and heated to boiling under reflux. A deep red solution results. After 20 hours it is left to cool. The precipitated product is removed by filtration and re-precipitated from methylene chloride/ether. After recrystallization from toluene there is obtained 1.3-bis[[p-(dimethyl-amino)benzylidene]amino]-2-[p-(dimethylamino)styryl]imidazolium chloride as a red solid of melting point 238°-240°.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[C:38]([OH:45])[CH:37]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:46](OCC)(=O)C>C1COCC1.[Pd]>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:16]([O:31][CH2:32][CH:33]([CH3:46])[CH2:35][CH3:34])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([OH:45])[CH:37]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc([N+](=O)[O-])c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)COc1cccc(OCc2ccc(OC)cc2)c1-c1cc(-c2ccc(N)c(O)c2)c(C(=O)OC(C)(C)C)c(N)n1

Procedure:
A solution of tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(3-hydroxy-4-nitrophenyl)nicotinate (2.32 g, 3.78 mmol) in ethyl acetate (15.0 mL) and THF (15.0 mL) was hydrogenated at 1 atm in the presence of palladium on charcoal (10%, 0.10 g) overnight. The resulting mixture was filtered on Celite and washed with ethyl acetate and THF. The combined filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-4-(4-amino-3-hydroxyphenyl)-6-[2-[(4-methoxybenzyl)oxy]-6-(2-methylbutoxy)phenyl]nicotinate. (2.21 g, 100%); LC-MS (m/z=584, M+1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])=[O:21]
Reactant: OCc1cccc2nnsc12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc2nnsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.23 g of 7-hydroxymethylbenzo-1,2,3-thiadiazole, 3.1 ml of triethylamine and 0.2 g of 4-dimethylaminopyridine in 50 ml of methylene chloride there is added dropwise with cooling at -5° to 0° C. a solution of 2.23 g of methanesulfonyl chloride in 15 ml of dichloromethane, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then treated with ice-water and extracted several times using dichloromethane. The combined extracts are washed with water, dried and evaporated. Chromatographic purification on silica gel (CH2Cl2) gives the title compound as a viscous resin.