Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][C:8]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1.[Zn]>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:17][C:8]1[CH:9]=[C:10]([OH:13])[C:11]([C:25](=[O:27])[CH3:26])=[CH:12][C:7]=1[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(OCC(=O)OCC)c1
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(O)c(C(C)=O)cc1OCC(=O)OCC

Procedure:
The compound of example 65c (38 g; 112.5 mmol) was heated with acetyl chloride (9.74 ml; 137 mmol) and activated Zn (7.46 g) in toluene (250 ml) for 5 h (Synth. Commun, 1998, 28, 2203). to obtain the title compound which was processed as is routinely done and purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 30 g (78.3%); MS (CI): 409 (M++29), 381(M+); analysis: C16H20O8 requires C, 56.47; H, 5.92; found: C, 56.05; H, 5.59%.
Reaction SMILES: [NH2:1][C@H:2]([CH3:17])[CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]2.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:33]Br)=[CH:28][C:27]=1[CH2:43][OH:44])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[NH3:1].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:33][NH:1][C@H:2]([CH3:17])[CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]3)=[CH:28][C:27]=1[CH2:43][OH:44])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cc2cc(C[C@@H](C)N)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)ccc2[nH]1
Product: N
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A solution of methyl 5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate (Preparation 14, 5.00 g, 21.5 mmol) and [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 20, 4.86 g, 10.8 mmol) in dichloromethane (50 ml) was heated to 90° C. allowing the dichloromethane to evaporate gradually. The resulting melt was left at 90° C. for 16 h under nitrogen. The reaction mixture was then cooled to room temperature and the resulting solid triturated with dichloromethane. The solid was filtered off and the solvent removed in vacuo to give a pale orange oil. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (99:1:0.1 by volume) to give the title compound as a pale yellow oil (3.90 g).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.CO.C(Cl)(Cl)Cl>ClCCl>[O:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:27][CH:26]=2)[CH2:30]1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(CC2CCOC2)s1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NC(C(=O)O)c1ccc(CC2CCOC2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(tetrahydrofuran-3-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 47) by the procedure described in Example 24 except that the eluent used was 10% methanol in dichloromethane. vmax (CHCl3) 3409, 3293, 1648 and 1603 cm-1. δ (CD3SOCD3) 1.44-1.61 (1H, m), 1.70-1.82 (1H, m), 1.85-2.03 (1H, m), 2.30-2.80 (8H, m), 3.29-3.40 (2H, m), 3.53-3.76 (3H, m), 5.13 and 5.25 (1H, two d's, J 6.55 Hz), 5.70 and 5.77 (1H, two s's), 6.64 (1H, d, J 3.23 Hz), 6.74-6.84 (1H, m), 7.11-7.31 (5H, m), 7.87 and 8.12 (1H, two d's, J 6.68 Hz).
Reaction SMILES: [SiH3][OH:2].[C:3]1(Br)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.Cl[Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O>[C:3]1([Si:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O[SiH3]
Reactant: Brc1cccc2ccccc12
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O[Si](c1ccccc1)(c1ccccc1)c1cccc2ccccc12

Procedure:
For preparation of the silanol, 60 mmol 1-naphthyl bromide are metallized with the equimolar amount of n-butyllithium (2 M solution in cyclohexane, 60 mmol) at −20° C. in 400 ml diethyl ether and 60 mmol dichlorodiphenylsilane is then added, in accordance with Example 2.1. After addition of the dichlorodiphenylsilane, the reaction mixture is heated under reflux for 3 h and then hydrolysed by addition of water (100 g). After the organic phase which has been separated off has been washed neutral, the solution is concentrated in vacuo and the crude product is obtained as a white solid. Crude yield: 21.17 g, content: 84% (GC-MS).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH3:19][N:20]=[C:21]=[O:22]>>[CH3:19][NH:20][C:21]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1)=[O:22]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: CN=C=O
Product: CNC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
Following the procedure of Example 1 3-[2-(4-aminopiperidyl) ethyl]indole is reacted with methyl isocyanate to give the title compound which is converted to the hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][NH:26][N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:26]2[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)=[N:25]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
A mixture of 4-benzyloxybenzyl chloride (11.60 g), ethyl 3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (11.70 g), potassium carbonate (13.80 g) and N,N-dimethylformamide (150 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain ethyl 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (16.90 g, yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 103–104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH3:23])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:21]=1[CH3:22].ClCCCl.N1C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:40](Cl)=[O:41]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH3:23])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:40](=[O:41])[C:39]4[CH:38]=[C:37]([O:36][CH3:35])[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=4)[CH2:19][CH2:20]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:21]=1[CH3:22]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCN(CCC3(C)CCc4c(C)c(OC)c(C)c(C)c4O3)CC2)cc(OC)c1OC
Yield: 62.8 %

Procedure:
A solution composed of 2.0 g (6.02 mmol) of the 3,4-dihydro-6-methoxy-2-[2-(piperazin-1-yl)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained by the process of Example 12, 50 ml of 1,2-dichloroethane and 0.57 g of pyridine was ice-cooled in a nitrogen atmosphere and, to this solution, 1.67 g of 3,4,5-trimethoxybenzoyl chloride was added dropwise. The resultant mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate. Low-boiling substances were distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 1.99 g of 3,4-dihydro-6-methoxy-2-[2-[4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl]ethyl]-2,5,7,8-tetramethyl-2H-benzopyran [Compound (17)] having the following physical characteristics.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[NH2:16][C:17]1[C:18](=[O:31])[N:19]([CH2:28][CH2:29][CH3:30])[C:20](=[O:27])[N:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[NH2:23].C(N=C=NC(C)C)(C)C>CO>[NH2:23][C:22]1[N:21]([CH2:24][CH2:25][CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH3:30])[C:18](=[O:31])[C:17]=1[NH:16][C:11]([C:6]1([NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14])[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:13]
Reactant: O=C(NC1(C(=O)O)CCCC1)C(F)(F)F
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CO
Product: CCCn1c(N)c(NC(=O)C2(NC(=O)C(F)(F)F)CCCC2)c(=O)n(CCC)c1=O
Temperature: 4 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A mixture of 11.4 g of 1-trifluoroacetylaminocyclopentanecarboxylic acid and 10.4 g of 5,6-diamino-1,3-dipropyluracil in 120 ml of methanol was treated with 8.7 ml of diisopropylcarbodiimide (DIPC). After 2 hours stirring at room temperature and 1 h at 4° C., the formed precipitate is filtered under vacuum, washed and dried, thereby obtaining 15.1 g of 6-amino-1,3-dipropyl-5-(1-trifluoroacetylamino cyclopentanecarboxamido)uracil m.p. 203°-4° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:23](C1C(N[C@@H]2C3C(=CC=CC=3)CC[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:23][C@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3CC[C@H]2O)n1
Product: CCc1nc(N[C@@H]2c3ccccc3CC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (trans)-1-[(3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.30 (m, 6H), 1.95 (m, 1H), 2.25 (m, 1H), 2.64 (dd, J=7.5, 15.1 Hz, 2H), 2.84 (dd, J=7.6, 15.2 Hz, 2H), 2.94 (m, 2H), 4.03 (m, 1H), 4.74 (d, J=6.7 Hz, 1H), 5.08 (s, 1H) 5.16 (dd, J=6.7, 7.2 Hz, 1H), 7.2 (m, 1H), 7.28 (m, 2H), 7.35 (m, 1H); MS (EI) m/z (rel. intensity) 375 (M+, 9), 359 (68), 357 (67), 230 (45), 146 (35), 129 (69), 128 (56), 118 (55), 117 (99), 115 (68), 91 (45). HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1029. Anal. Calcd for C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 57.61; H, 5.88; N, 10.70.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:17]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:24].[CH2:17]([N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccnc1CNC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: Cc1ccc[n+](Cc2ccccc2)c1CNC(=O)OC(C)(C)C
Product: [Br-]

Procedure:
A solution of tert-butyl ((3-methylpyridin-2-yl)methyl)carbamate (9.2 g, 41 mmol) and benzyl bromide (9.9 mL, 83 mmol) in 150 ml of acetonitrile was heated in a sealed vessel at reflux overnight and then concentrated in vacuo to give the title compound which was used without further purification. MS (ESI) 313 (M+H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.C([Sn](Cl)(CCCC)CCCC)CCC.[NH2:26][C:27]1[N:32]=[C:31](Br)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1>C1COCC1.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:26][C:27]1[N:32]=[C:31]([C:6]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]=2)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1
Reactant: C1=COCCC1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CSc1nc(N)nc(C2=CCCCO2)c1C#N

Procedure:
From 3,4-dihydro-2H-pyran, tert-butyllithium and tributyltin chloride in THF. Then treatment with 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile and bis(triphenylphosphine)palladium(II) chloride in dioxane. ES-MS m/e (%): 271 (M+Na+, 39), 249 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:27]=1[OH:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[O:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Cl)ccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Oc3ccc(N)cc3F)ccnc21
Temperature: 185 °C
Yield: 7.4 %

Procedure:
A mixture of 4-chloro-2-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (3.2 g, 8.9 mmol), 2-fluoro-4-nitrophenol (2.79 g, 17.8 mmol), and DIPEA (3.5 mL, 20 mmol) in NMP (15 mL) was heated in a sealed tube at 185° C. for 3 days. The mixture was diluted with EtOAc and filtered through a short pad of Celite® (EtOAc). The filtrate was washed with 5% aq. Na2CO3 solution and dried over MgSO4. The title compound was purified by flash column chromatography (silica gel, 100% CH2Cl2 to 50% EtOAc/CH2Cl2) to afford the desired product (295 mg, 7.4%) as a light brown solid. LC/MS(ESI+) m/z 451 (M+H)+.
Reaction SMILES: C(Br)C.[Mg].[OH:5][C:6]([CH3:16])([CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14])[C:7]#[CH:8].[CH3:17][C:18]1([CH3:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[C:19]1=[O:25].[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[OH:5][C:6]([CH3:16])([CH2:7][CH2:8][C:19]1([OH:25])[CH:20]([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]1([CH3:26])[CH3:17])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: C#CC(C)(O)C=CC=C(C)C=C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Solvent: c1ccccc1
Product: C=CC(C)=CC=CC(C)(O)CCC1(O)C(C)CCCC1(C)C

Procedure:
A solution of ethyl bromide (1.75 g.) in diethyl ether was added to a suspension of magnesium (0.385 g.) in ether and the mixture was heated to reflux for 30 minutes. A solution of the alcohol, 3-hydroxy-3,7-dimethyl-nona-4,6,8-trien-1-yne, (1.0 g.) in dry benzene was added and the mixture refluxed 30 minutes. A solution of 2,2,6-trimethylcyclohexanone (1.12 g.) in benzene was added and the mixture refluxed for 15 minutes and poured into saturated aqueous ammonium chloride solution. The organic phase was washed with brine dried and concentrated to give 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethylcyclohexyl)-nona-1,3,5-trien-3-yne which was chromatographed on activity III alumina to give pure 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethylcyclohexyl)-nona-1,3,5-trien-8-yne.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH2:15]([CH:17]([NH2:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16].C1(C)C=CC=CC=1.C(C(N1C(=O)C2=C(N=[N+]=[N-])C=CC=C2C1=O)CCCCCCCCC(C)(C)CO)C>CN(C)C=O>[CH2:15]([CH:17]([N:31]1[C:10](=[O:11])[C:5]2=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]1=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCC(N)CCCCCCCCC(C)(C)CO
Agent: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 99.9 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 9.6 g (0.05 mol) of 3-nitrophthalic anhydride, 12.9 g (0.055 mol) of 1-ethyl-10,10-dimethyl-11-hydroxy-1-aminoundecane, 150 ml of toluene and 250 ml of dimethylformamide is heated to the boil, the water formed being removed azeotropically. The reaction mixture is then evaporated to dryness. The residue is dissolved in 150 ml of methylene chloride and the solution is extracted with three times 50 ml of 10% sodium carbonate solution. The methylene chloride solution is then dried over anhydrous sodium sulphate and evaporated. 20.9 g (about 100% of theory) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-nitrophthalimide are obtained in the form of a viscous oil which gradually crystallises after standing for several weeks; melting point 66°-68° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:23])[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccc3c(N)ncnn23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 192.3 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (325 mg, 1.07 mmol) in DMF (5 mL) and AcOH (1 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (153 mg, 0.54 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 3 h. Aqueous K2CO3 (5%, 20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide 397 mg (97%) of the desired product, which contained minor impurities. ES-MS m/z 382.08 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][OH:35].Cl.NO>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[OH:35][NH:34][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])=[O:21]
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCNC(=O)c1ccc2ccccc2c1)NO
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
(Method J5C) A solution of 6-[(naphthalene-2-carbonyl)amino]hexanoic acid (4/53) (0.618 g, 2.17 mmol) in dry tetrahydrofuran (6 ml) was cooled in ice bath under argon atmosphere and 1,1′-carbonyldiimidazole (0.422 g, 2.6 mmol) was added. The mixture was stirred for 30 min. and a solution of hydroxylamine (4.35 mmol) in dry dimethylformamide (3 ml) [the solution of hydroxylamine was made from hydroxylamine hydrochloride (0.302 g, 4.35 mmol) and triethylamine (0.61 ml) in dimethylformamide (3 ml) and filtered] was added. After stirring overnight the reaction mixture was diluted with saturated NaH2PO4 (30 ml) and extracted with ethyl acetate (3×30 ml). The organic phase was evaporated under reduced pressure by adding several times of benzene to remove traces of water. The crude product was crystallized successively from ethyl acetate and acetonitrile to give of the title compound (0.260 g, 40%), m.p. 96-98° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.21-1.45 (2H, m); 1.46-1.73 (4H, m); 1.89-2.05 (2H, m); 3.25-3.37 (2H, m); 7.65-7.81 (2H, m); 7.86-8.04 (4H, m); 8.42 (1H, s); 8.56-8.72 (2H, m); 10.32 (1H, s). HPLC analysis on Symmetry C8 column: impurities <1% (column size 3.9×150 mm; mobile phase 40% acetonitrile+60% 0.1% H3PO4; detector UV 220 nm; sample concentration 0.145 mg/ml). Anal. Calcd, %: C, 67.98; H, 6.71; N, 9.33; Found, %: C, 68.29; H, 6.97; N, 8.99.
Reaction SMILES: C(C1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#N.[OH-:18].[K+].[O:20]1[CH2:25][CH2:24]OCC1>>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:24]([C:25]([OH:20])=[O:18])[CH:17]=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: [OH-]
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Reactant: C1COCCO1
Agent: [K+]
Product: CCNC(=O)Nc1nc2ccc(C(=O)O)cc2s1

Procedure:
About 60 mg N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 5 mL of about a 1:1 mixture of about 2N aq KOH and dioxane. The reaction mixture was then brought to reflux for about 12–24 hours. Upon cooling, the reaction mixture was poured into about 25 mL of dilute aqueous acid. The white precipitate was collected by filtration and was washed well with water. 1H NMR 1.09 (t, 3H), 3.19 (m, 2H), 6.79 (br s, 1H), 7.65 (d, 1H), 7.92 (m, 1H), 8.48 (d, 1H), 11.0 (br s, 1H), 12.8 (br s, 1H); LC/MS 2.12 min, 266 (M+1), 264 (M−1), lab LC retention time 4.7 minutes.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[CH:6][C:3]=1[C:4]#[N:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 51.6 %

Procedure:
A portion of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1; 0.8 g, 2.8 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.8 g, 5.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA (0.5 g, 3.7 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hrs, then cooled to 25° C. and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.55 g, 50%). 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]+ 381.