Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=NC2[N:53]([OH:56])N=NC=2C=1.CCN(C(C)C)C(C)C.[Si](ON)(C(C)(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:53][OH:56])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: On1nnc2cccnc21
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.5 %

Procedure:
A solution of (3S)-4-(((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.74 g, 1.36 mmol), EDC.HCl (0.31 g, 1.62 mmol), HOAt (185 mg, 1.36 mmol) and DIPEA (210 mg, 1.62 mmol) in DCM (20 mL) was stirred at −10° C. for 30 minutes. Then to the mixture was added a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.2 g, 1.36 mmol) in DCM (2.0 mL) slowly at −10° C. Then the mixture was warmed to 25° C. and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 10 mL), then the mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL) and water (100 mL), and the mixture was adjusted to pH 7 with aqueous ammonia. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (0.05 g, 6.5%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][CH2:16][Mg+].[Br-].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2([NH2:14])[CH2:16][CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of (R)-1-benzyl-3-cyanopyrrolidine (10 g, 53.4 mmol) in anhydrous ether (200 mL) was added Ti(OiPr)4 (17.2 mL, 58.8 mmol) and the resulting solution was cooled to −78° C. EtMgBr (3.0 M in Et2O, 35 mL, 105 mmol, Aldrich) was added drop-wise during a period of 40 min at −78° C. Anhydrous THF* (50 mL) was added to the resultant yellow suspension to facilitate stirring and the solution was stirred for 20 min at −78° C. The reaction mixture was allowed slowly to warm up to room temperature, then BF3-Et2O (13.4 mL, 107 mmol) was added and the resultant dark brown suspension was stirred at room temperature for 2 hrs. Both 1N HCl (100 mL) and Et2O (200 mL) were introduced subsequently to the reaction mixture and stirring was kept for 20 min until both organic and aqueous phases became clear. It was basified using aqueous 20% NaOH (100 mL) and stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with Et2O (2×100 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give (R)-1-(1-benzyl-pyrrolidin-3-yl)-cyclopropylamine as brown oil (10.5 g, 90%), which was vacuum distilled to give a colorless liquid (9 g, 77%). The product is sufficiently pure to use in next step. For characterization, a small amount of sample was purified by PTLC using solvent NH4OH/MeOH/CH2Cl2 (1/60/340): [α]23 −10.0° (c=2.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 3.62 (d, JAB=12.8 Hz, 1H), 3.56 (d, JAB=12.8 Hz, 1H), 2.66-2.57 (m, 3H), 2.40-2.37 (m, 1H), 1.96-1.91 (m, 2H), 1.69-1.62 (m, 1H), 0.55-0.48 (m, 2H), 0.41-0.36 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].[CH3:39][P:40]([NH2:43])(=[O:42])[O-:41].C([N:47]([CH:50](C)C)CC)(C)C>CN(C=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:50]([NH2:47])=[NH:43].[CH3:39][P:40]([NH2:43])(=[O:41])[O-:42]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CP(N)(=O)[O-]
Solvent: CN(C)C=O
Product: N=C(N)NCCCC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of (15) (0.131 g, 0.216 mmol) stirring at room temperature under argon in anhydrous DMF (2.0 ml), 1-H-pyrazole-1-carboxamidine•HCl (32 mg, 0.216 mmol) was added followed by diisopropylethylamine (28 ml, 0.216 mmol). The reaction mixture was stripped slightly on a rotovap then rotated overnight without vacuum at room temperature. After removing DMF in vacuo the reaction residue was dissolved in dichloromethane and applied to a flash silica gel column. An isocratic system of 20% MeOH/dichloromethane, 2% NH4OH followed by treatment with Dowex OH− (300 mg) in MeOH gave 80 mg of desired product (yield, 57%). 31P NMR (s, 31.99 ppm), mass spec. calcd=648.91, Found=649.48.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: CCOC(=O)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2nc(C(=O)O)cs2)ccc1-n1cnc(C)c1
Temperature: 90 °C
Yield: 232.4 %

Procedure:
A mixture of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-4-carboxylic acid ethyl ester (210 mg, 0.586 mmol), KOH (3M in water, 1172 1, 3.52 mmol) and ethanol (3 ml) was heated to 90° C. for 12 h and then cooled to 0° C. An aqueous HCl solution (1 N) was added until pH7. The solvents were evaporated, toluene was added to the residue and evaporated again to yield the title compound as light brown solid (450 mg (purity 43%), 100%) .
Reaction SMILES: C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:3](=[O:4])C1.[CH2:19]([NH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[C:24]=1[NH2:30])[CH:20]=[CH2:21]>C(#N)C>[CH2:19]([N:22]1[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[C:24]=2[NH:30][C:3]1=[O:4])[CH:20]=[CH2:21]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: C=CCNc1ccnc(Cl)c1N
Solvent: CC#N
Product: C=CCn1c(=O)[nH]c2c(Cl)nccc21
Yield: 70 %

Procedure:
A 400 ml acetonitrile solution of 4.46 g of N,N′-disuccinimidyl carbonate was added to an acetonitrile solution containing 2.88 g of N*4*-allyl-2-chloropyridine-3,4-diamine, and the mixture was heated under reflux for 70 hours. The solvent was concentrated under reduced pressure, and the residue was dissolved in a mixture consisting of 500 ml of ethyl acetate and 300 ml of water. The organic layer was washed twice with 100 ml of 1N hydrochloric acid and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.30 g of the title compound was obtained from the fraction eluted with ethyl acetate-dichloromethane (1:1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([CH2:21][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: OC(COc1cccc2[nH]ccc12)CN1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from 4-(oxiranylmethoxy)-1H-indole and 4-phenylmethylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 52% overall yield. FDMS m/e=364 (M+ of free base). mp 105°-107°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([S:9][CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.CN1CCOCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[C:16]([O:15][C:13]([NH:12][C@H:11]1[CH2:10][S:9][CH:3]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][NH:1][C:20]1=[O:22])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(CN)c1cccs1)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CSC(c2cccs2)CNC1=O
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 150 g of S-[2-amino-1-(2-thienyl)ethyl]-N-t-butoxycarbonyl-L-cysteine [prepared as described in step (b) above] and 52 ml of N-methylmorpholine in 1 liter of dimethylformamide was added to a solution of 108.4 ml of diphenylphosphoryl azide in 500 ml of dimethylformamide at 10° C., over a period of 4 hours, and the mixture was left to stand at room temperature overnight. At the end of this time, 1.5 liters of ethyl acetate and 1.5 liters of water were added, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the resulting extracts were combined with the separated organic layer. The resulting organic mixture was washed twice, each time with an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, after which the solvent was evaporated off. The residue was subjected to silica gel column chromatography, using a 1:4 by volume mixture of ethyl acetate and methylene chloride as eluent, to give 112.5 g of the title compound as a gummy substance.
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:14]2[CH:10]([CH2:11][C:12]3[S:19][CH:18]=[CH:17][C:13]=32)[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[S:19]1[C:12]2[CH2:11][CH:10]3[CH:14]([C:13]=2[CH:17]=[CH:18]1)[CH2:15][CH2:16][NH:8][CH2:9]3
Reactant: c1ccc(CN2CCC3c4ccsc4CC3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: c1cc2c(s1)CC1CNCCC21
Temperature: 22 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
The product from step g) (279 mg, 1.04 mmol) in dichloroethane (5.2 ml) was treated with K2CO3 (574 mg, 4.16 mmol) and Ace-Cl (451 μl, 4.16 mmol) at 80° C. for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 hour at 22° C. The MeOH was concentrated and triturated with ether to give 135 mg (60%) of the subtitle compound. MS calculated for C10H13NS+H 180, observed 180.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][OH:17])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CC(C)=O>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: CON=C(C(N)=O)c1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (253 mg, E/Z≠65/35), potassium carbonate (177 mg), 95% dimethyl sulfate (148 mg) and acetone (4.0 ml) was stirred at room temperature for 4 hours. A few pieces of ice were added, and the mixture was stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to obtain the title compound (194 mg, E/Z≠79/21, yield: 72.4%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:24]1[O:28][N:27]=[C:26]([CH3:29])[N:25]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.Cl>>[Cl:23][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH:8]([NH2:7])[C:24]3[O:28][N:27]=[C:26]([CH3:29])[N:25]=3)=[CH:11][CH:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Product: Cc1noc(C(N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Yield: 99.5 %

Procedure:
2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (33 mg) was prepared from [2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (43 mg, 0.1 mmol) and hydrochloric acid (0.5 mL, 4.0 M. solution in dioxane) following the typical Boc deprotection procedure N.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC1CCC(=O)CC1
Yield: 82.9 %

Procedure:
To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate (from Step 1, Example 77, 4.71 g, 19.44 mmol) in acetonitrile (45 mL) was added 6N HCl aqueous solution (45 mL). The resulting mixtures was stirred at rt for 2 h and neutralized with solid NaHCO3 to pH 8, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4. Filtration and evaporation to dryness gave the ketone product as colorless oil (2.97 g, 78.1%).
Reaction SMILES: O1C=C(CN)N=C1.[S:8]1[C:12]([CH2:13][NH2:14])=[CH:11][N:10]=[CH:9]1.[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29]([NH:14][CH2:13][C:12]3[S:8][CH:9]=[N:10][CH:11]=3)=[O:30])[C:22]2=[O:35])=[CH:36][CH:37]=1
Reactant: NCc1cncs1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: O=C(NCc1cncs1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 43 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with thiazol-5-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-5-ylmethyl)isonicotinamide was obtained as a colorless solid in 43% yield: mp 148-150° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.39 (t, J=5.7 Hz, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.35-7.29 (m, 3H), 7.19-7.13 (m, 2H), 4.64 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 3.93 (t, J=8.0 Hz, 2H), 3.34 (t, J=8.0 Hz, 2H); MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC1.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>CCOCC.C1COCC1.Cl.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyllithium (10 ml of a 2.0M solution in a 7:3 mixture of cyclohexane and ether, 20 mmol) was added dropwise to zinc chloride (20 ml of a 1.0M solution in ether, 20 mmol) at room temperature. The resulting mixture was stirred for 2 hours, then a solution of 4-iodo-2-nitrotoluene (2.63 g, 10 mmol) in THF (20 ml) and tetrakis(triphenylphosphine)palladium (0.3 g, 0.26 mmol) were added successively. The reaction mixture was stirred for 3 hours then diluted with 0.5M hydrochloric acid (40 ml) and extracted with ether (3×70 ml). The ether extracts were washed with brine, dried, concentrated then purified by column chromatography using petrol (60°-80° C.)-ethyl acetate (9:1) on silica gel to give 4-phenyl-2-nitrotoluene (1.8 g, 85% yield) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][OH:17]>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:15][CH2:16][OH:17])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: OCCBr
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2CCO
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 19.1 mmol) in DMF (40 mL) was added sodium hydride (60%, 1.53 g, 38.3 mmol) and the reaction mixture was stirred for 20 min. 2-Bromoethanol (1.50 mL, 21.1 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to ambient temperature and concentrated to afford a brown sludge. Ice water (50 mL) was added and the resulting precipitate was collected by filtration, rinsed with water (50 mL) and ether (50 mL), and dried in vacuo to afford 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-ethanol as a beige solid (4.30 g, 14.1 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 8.19 (1H, s), 4.84 (1H, t, J=5.8 Hz), 4.30 (1H, t, J=5.8 Hz), and 3.77 (2H, app q, J=5.6 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 7.35 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C1COCC1>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-thienyl)phenol in anhyd. THF (10 mL) was added Et3N (0.9 mL, 6.5 mmol), followed by TMSCl (0.4 mL, 3.2 mmol). The reaction mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to give 2-(4-trimethylsilyloxyphenyl)thiophene: TLC (20% EtOAc/hex) Rf 0.69. This material was used without further purification.
Reaction SMILES: [BH3-]C#N.[Na+].[N:5]1([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:27][N:8]2[CH2:7][CH2:6][N:5]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:10][CH2:9]2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C1CC(N2CCN(CC3CC3)CC2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (20.0 mmol) NaBH3CN were added in 4 batches at RT to a solution of 1.71 g (5.0 mmol) tert. butyl 4-piperazin-1-yl-piperidine-1-carboxylate and 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde in 100 mL of EtOH and the reaction mixture was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in saturated NaHCO3 solution, extracted exhaustively with EtOAc and the organic phase was dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:0.5).
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:40]C(Br)C.[BrH:44].C(O)(=O)C>>[BrH:40].[BrH:44].[C:1]1([CH3:39])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Reactant: CC(Br)Br
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1

Procedure:
From N,N′,N″-Tris(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.3.13.31) prepared from 1.3.13.18, dibromoethane and base) and HBr/acetic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][N:12]1[CH:21]=[C:20]2[C:14]([CH2:15][N:16]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:18]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=32)=[N:13]1)C.O>CCOCC.O1CCCC1.C(Cl)Cl>[Cl:26][C:24]1[CH:23]=[CH:22][C:19]2[C:20]3[C:14](=[N:13][N:12]([CH2:11][CH2:10][OH:9])[CH:21]=3)[CH2:15][N:16]=[C:17]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:18]=2[CH:25]=1
Reactant: CCOC(=O)Cn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: OCCn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reaction time: 0.25 h

Procedure:
A solution of 0.4 g (0.01 mol) of lithium aluminum hydride in 80 ml of ether was cooled to -30°. A solution of 0.8 g (2.1 mmol) of 8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acid ethyl ester in 5 ml of tetrahydrofuran was added and the mixture was stirred at -10° to -5° for 15 min. The reaction mixture was hydrolized by addition of 2 ml of water, diluted with methylene chloride and filtrated over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield colorless crystals which were recrystallized for analysis from ethyl acetate, hexane, mp 173°-175°.