Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:22]#N)=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[PH2]([O-])=[O:25].[Na+]>N1C=CC=CC=1.O.[Ni]>[O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:25])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 6-((1R*,2S*)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazole-3-carbonitrile (1 g, 3.3 mmol) in pyridine (30 mL) acetic acid (8 mL) and water (8 mL) and Raney Nickel (1 g). Sodium hypophosphite (1.8 g, 21 mmol) was dissolved in water (10 mL) and added dropwise and the reaction was stirred overnight. The product was extracted into ethyl acetate (300 mL), washed with brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (300 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 10.17 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=8.5 Hz, 1H) 7.08-7.04 (m, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 3.38-3.34 (m, 1H), 2.27-2.17 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][I:12]>>[I-:12].[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:11]
Reactant: CI
Reactant: Cc1nc2ccccc2o1
Product: Cc1oc2ccccc2[n+]1C
Product: [I-]

Procedure:
A reaction of 26.6 g (0.2 mole) of 2-methylbenzoxazole and 34.6 g (0.24 mole) of methyl iodide was made in a sealed tube at 90° C. for a couple of hours. The resulted solid matters were pulverized and were then washed with acetone, so that the objective matter was obtained. The yield thereof was 50.4 g (91%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][C:15]([NH2:18])=[CH:16][N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[CH3:26][C:24]1[N:18]([C:15]2[S:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:12][CH:11]=3)=[N:17][CH:16]=2)[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1cnc(-c2ccc(N3CCOCC3)cc2)s1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cnc(-c3ccc(N4CCOCC4)cc3)s2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of 2-(4-morpholinophenyl)thiazol-5-amine (0.20 g, 0.77 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (2.3 mL, 4.6 mmol, 2 M in toluene) dropwise at rt. The reaction mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (132 mg, 0.84 mmol) in anhydrous CH2Cl2 (5 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound as a pale yellow solid (20 mg, 7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][N+]([O-])=O)=[CH:26][C:25]=1[Cl:35]>>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([Cl:35])[CH:26]=2)=[CH:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1Cl

Procedure:
The title compound (228.2 mg) was prepared from 0.49 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 268 μL of benzylamine, and 0.55 g of 1,2-dichloro-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.51-7.47 (m, 2H), 7.36-7.32 (m, 2H), 7.32-7.25 (m, 2H), 7.22 (s, 1H), 7.19-7.15 (m, 2H), 5.15 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO.C1COCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)O)CC1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (3.05 g, 8.64 mmol), 1 M aq LiOH (15 mL, 15 mmol), MeOH (15 mL), and THF (45 mL) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with satd citric acid, dried over MgSO4, concentrated, and triturated with ether to give the acid as a white solid (2.23 g, 76%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70].CO>C(Cl)Cl>[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[C:59]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:60][C:61]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:25]=3)[C:10]3[C:11](=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=3)[C:62]=2[CH:63]=1
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Reactant: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 988 %

Procedure:
In 40 mL of methylene chloride, 5.70 g (10 mmol) of 3,3′,4,4′-tetrakishexyloxybiphenyl and 15.3 g (31 mmol) of 1-(16-bromohexadecyl)-2-hexyloxybenzene were dissolved. Under argon, 10.0 g (62 mmol) of FeCl3 was added to the solution, and the solution was stirred at ambient temperature for three hours. The resulting reaction mixture was put into 800 mL of methanol and filtered to obtain 102 g of a solid. The solid was purified by silica-gel column chromatography to obtain a yellow solid. The yellow solid was recrystallized from ethanol and 8.2 g of a white solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-chloro-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (DMSO-d6): 11.31 (s, 1H), 9.02 (d, J=2.4, 1H), 8.96 (d, J=9.3, 1H), 8.31 (d, J=2.4, 1H), 8.24-8.20 (m, 1H), 7.73-7.69 (m, 1H), 7.54 (d, J=8.4, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O1CCOCC1>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To the suspension of ethyl 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.77 g, 1.9 mmol) in 1,4-dioxane (12 mL) was added aquoeous NaOH (1 N, 12 mL, 12 mmol). The mixture was stirred at rt for about 48 h. To the mixture was added EtOH (1 mL) and the mixture was heated at about 50° C. for about 24 h. The mixture was concentrated under reduced pressure and aqueous HCl (0.5 M, 10 mL) was added and the mixture extracted with EtOAc (25 mL). The solid in the organic layer was collected by vacuum filtration. The filtrate and aqueous layer were recombined and separated. The solid was dissolved in EtOAc (˜150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo and dried under reduced pressure at about rt to give 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.713 g, 99%): LC/MS (Table 2, Method b) Rt=2.74 min.; MS m/z: 390 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:14][C:13](O)=[N:12][N:11]=3)[S:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:38]2C=C[CH:41]=[CH:42][C:37]=2[N:36]=N1.CN(C=[O:58])C>CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:14][C:13]([NH:36][C@H:37]4[CH2:42][CH2:41][NH:34][C:38]4=[O:58])=[N:12][N:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NCC[C@@H]1Nc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Temperature: 35 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of Compound 51a (145 mg, 0.47 mmol) in DMF (4 mL) was added DIEA (0.243 mL, 1.39 mmol) followed by (S)-3-aminopyrrolidin-2-one, HCl (70 mg, 0.51 mmol). To the stirring solution was added BOP (247 mg, 0.56 mmol) and the reaction mixture stirred at 35° C. for 18 h. The reaction mixture was diluted with EtOAc and the solution washed with saturated NH4Cl. The aqueous portion was washed with EtOAc, and the combined organic extracts washed with brine. The organic portion was dried (Na2SO4), filtered and concentrated under reduced pressure then the residue purified on silica gel chromatography eluting with 0.5 to 12% MeOH to give Compound 51b (92 mg, 50% yield) as a light orange solid. LCMS=0.75 min using analytical method (M), 396.0 (M+H). 1H NMR (400 MHz CDCl3 containing CD3OD) δ 8.02 (d, J=1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 1.9 Hz, 1H), 4.26 (dd, J=10.4, 8.4 Hz, 1H), 3.43-3.38 (m, 1H), 2.68 (dddd, J=12.6, 8.3, 6.1, 2.0 Hz, 1H), 2.18-1.96 (m, 1H).
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.C[O:25][C:26](=O)[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>ClCCCl>[NH2:12][C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:10]=[CH:9][C:8]=1[NH:11][C:26](=[O:25])[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: CC(C)c1cc(N)c(N)cn1
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(C)c1cc(N)c(NC(=O)Cn2ccnc2-c2nccs2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 6-isopropyl-pyridine-3,4-diamine hydrochloride (265 mg, 1.41 mmol) in 1,2-dichloroethane (10 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (2.12 mL, 4.24 mmol). The mixture is stirred at room temperature for 45 min and then treated with a solution of (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (252 mg, 1.13 mmol) in 1,2-dichloroethane (2 mL) via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux for 20 h. After cooling, the reaction mixture is diluted with some MeOH (˜2 mL), followed by some water and then saturated aq NaHCO3. The resulting mixture is stirred vigorously for 15 min. The mixture is then extracted thrice with CHCl3 containing some (˜5%) MeOH. The combined extracts are dried over Na2SO4 and concentrated. The crude residue is then triturated with CHCl3, and the resulting mixture filtered. The solid is washed with a small amount of CHCl3 and dried, affording N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide as an off-white solid. 1H NMR (DMSO-ds, 300 MHz) δ 9.52 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.39 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 5.38 (s, 2H), 2.74 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm. The filtrate is concentrated and further purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH affords 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ 12.23 (br, 1H), 8.97 (br, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.23 (br, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04 (s, 1H), 5.82 (s, 2H), 3.14 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(OCC)C>CC(C)=O.O>[Cl:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: ClCCCBr
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In 5 ml of acetone, 853 mg of 2-piperazin-1-ylquinoline as synthesized in Step 7-1-A was dissolved and to which 160 mg of sodium hydroxide as dissolved in 5 ml of water was added. Into the mixed liquid 0.5 ml of 1-bromo-3-chloropropane was dropped, followed by stirring for an overnight at room temperature. After addition of diethyl ether, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 1.10 g (95%) of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1([CH2:41][OH:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[H-].[Na+]>CN(C=O)C.O>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([O:42][CH2:41][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCc1cccc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(OCc3cccc4ccccc34)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.200 g, 0.423 mmol) and 1-naphthalenemethanol (0.140 g, 0.888 mmol) in DMF (1 mL) was added sodium hydride (0.0355 g, 0.888 mmol) and stirred for 3 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0 to 20% EtOAc/hexanes) to afford the title compound (0.139 g, 55%).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[C:17]1([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution (70 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (2.20 g) and ethynylbenzene (1.3 ml) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (3.0 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-(5-phenyl-3-isoxazolyl)benzoate (2.47 g, yield 86%) as colorless crystals. melting point: 201–202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:7][C:6]=1[CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(NCCC(O)c1cc(Br)ccc1Cl)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1ccc(Cl)c(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(5-bromo-2-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 to give N-(3-(2-chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a pale yellow oil. Yield (1.03 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 9.42 (t, J=5.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, 2.0, 1H), 5.57 (d, J=4.0 Hz, 1H), 5.17 (s, 1H), 4.87-4.82 (m, 1H), 3.33-3.28 (m, 2H), 1.87-1.79 (m, 1H), 1.66-1.39 (m, 9H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([C:25]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:26])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(F)c(F)c1
Yield: 95 %

Procedure:
The title compound (oil) was prepared in 95% yield from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene and 3,4-difluorobenzoyl chloride by essentially following the procedure outlined in Example 81, Part C.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8]CCl.C(OC(=O)[NH:17][CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH2:21][O:20][CH2:19]1)(C)(C)C.Cl>[Cl-].[Zn+2].[Cl-]>[ClH:8].[CH3:3][C:2]([CH3:5])([CH3:4])[CH2:1][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH2:21][O:20][CH2:19][CH:18]2[NH2:17]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NC1COCc2ccc(Br)cc21
Reactant: CC(C)(C)C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C)Cc1ccc2c(c1)C(N)COC2
Yield: 273.7 %

Procedure:
Neo-pentylmagnesium bromide (10 mL, 9.1 mmol, 1.0 M in ether) was added dropwise to a solution of zinc chloride (18.2 mL, 0.5 M in tetrahydrofuran, 9.1 mmol) over 0.5 h and the reaction mixture stirred at RT for an additional 0.5 h. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (250 mg, 0.30 mmol) was added to the reaction mixture followed by (6-Bromo-isochroman-4-yl)-carbamic acid tert-butyl ester (1.00 g, 3.04 mmol) and the reaction mixture heated at reflux for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate and washed with water, sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography over silica (83:17 hexanes/ethyl acetate) yielded the desired protected amine (303 mg, 31%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 1H), 7.00 (d, J=6.3 Hz, 1H), 6.74 (s, 1H), 5.09-5.06 (m, 1H), 4.79-4.65 (m, 3H), 4.13-3.85 (m, 2H), 2.45 (s, 2H), 1.46 (s, 9H), 0.89 (s, 9H); ESI MS m/z 320 [C19H29NO3+H]+. A solution of protected amine (303 mg, 0.95 mmol) in hydrogen chloride (20 mL, 4 N in 1,4-dioxane, 80 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 6-(2,2-Dimethyl-propyl)-isochroman-4-ylamine hydrochloride (210 mg, quantitative) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6, 1.2 Hz, 1H), 6.73 (d, J=1.2 Hz, 1H), 4.75 (ABq, J=15.0 Hz, 2H), 3.96-3.80 (m, 3H), 2.44 (s, 2H), 1.73 (m, 2H), 0.89 (s, 9H); ESI MS m/z 220 [C14H21NO+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10](N)[C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1
Reactant: CC(C)(C)CN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)Cc1cc(Cl)nc(N)n1

Procedure:
A solution of 2-amino-4,6-dichloropyrimidine (1 mmol), neopentylamine (1.05 mmol), and triethylamine (2 mmol) in n-butanol was stirred at 110° C. for 12 h. Extraction and chromatography gave 2-amino-4-chloro-6-neopentylpyrimidine as a yellow solid. TLC: Rf=0.2, 30% EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([NH:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:19]([CH2:20][C:21]#[N:22])[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:24][CH:23]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: N#CCNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: N#CCN(C(=O)NC(=O)c1c(Cl)cccc1Cl)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
16.0 g of 2,6-dichlorobenzoylisocyanate are added in small portions to a solution of 11.66 g of p-chloroanilino-acetonitrile in 100 ml of dry benzene with moderate cooling. After some time a substance crystallizes out, which after about 12 hours is drawn off and washed with benzene. After drying the weight is 25.25 g, i.e. 93.7% the melting point being 185° C with spontaneous decomposition on the Kofler heating bench. Thin-layer chromatography (solvent either ethylacetae or chloroform) shows that the substance is pure, however, if desired, it may be recrystallized from 250 ml of benzene with a yield of 80%.