Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C=O)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCl)cc1
Temperature: 40 °C
Yield: 58 %

Procedure:
A solution of 3-[(4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one (0.945 g, 3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg, 1.5 equiv.) and 1-bromo-3-chloropropane (1.1 equiv.). The reaction mixture is heated to 40° C. for 3 h. The reaction mixture is partitioned between EtOAc and water. The organic layer is collected and washed sequentially with H2O (1×), saturated aqueous NaHCO3 solution (1×), and brine (1×). The organic phase was dried and concentrated to give an oil. The oil was purified by preparative chromatography (silica gel; 1:1 EtOAc:hexane) to give the named compound as a yellow solid (711 mg, 58%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:16]([C:12]12[CH2:11][O:10][C:7]([CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])([O:9][CH2:15]1)[O:8][CH2:13]2)[CH2:17][CH3:18]
Reactant: CCCC1(CO)COC1
Reactant: C#CCOCCC(=O)O
Product: C#CCOCCC12OCC(CCC)(CO1)CO2

Procedure:
4-n-Propyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-trioxabicyclo[2.2.2] octane was prepared from 3-(prop-2-ynyloxy)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To admixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.38 g, 77%) of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1.C(NC(C)C)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>ClCCl>[C:21]([C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]=1[OH:20])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:34](=[O:35])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2NC(=O)Oc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 1095.8 %

Procedure:
N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (0.85 g) and diisopropylamine (0.39 ml) were suspended in dichloromethane (20 ml) and a solution of phenyl chloroformate (16.8 g) in dichloromethane (30 ml) was added dropwise under ice-cooling. After stirring the mixture overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Purification of the residue by a silica gel column chromatography (chloroform:ethyl acetate=10:1) followed by crystallization from hexane/ethyl acetate afforded phenyl N-[2-(3,5-di-t-butyl-4-hydroxybenzoylamino)phenyl]carbamate (12.6 g, 49%).
Reaction SMILES: [CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C@H:26]([OH:35])([C:32]([OH:34])=[O:33])[C@@H:27]([OH:31])[C:28]([OH:30])=[O:29].CO>C(#N)C>[CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:28]([C@@H:27]([C@H:26]([C:32]([O-:34])=[O:33])[OH:35])[OH:31])([O-:30])=[O:29]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Solvent: CO
Solvent: CC#N
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 1.007 g (2 mmol) of (R,R)-arformoterol tartrate Form A and 65 mL of methanol was heated to the reflux temperature of the solvent for 30 min. Then, the solution obtained was cooled to 50° C. in 30 min, followed by addition of 90 mL of acetonitrile at the same temperature for 10 minutes. Afterwards, the solution was cooled to 30° C. in 30 minutes and stirred at room temperature for 2 hours. The product was collected by filtration, washed with acetonitrile and dried under vacuum (2-3 mbar, equivalent to 1.5-2.25 mm Hg) at 40° C. for 17 hours to provide acetonitrile solvate of (R,R)-Formoterol-L-tartrate, which contained about 2.7% (w/w) of acetonitrile, as determined by TGA analysis.
Reaction SMILES: [CH3:1][NH:2][OH:3].Cl.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>C(N(CC)CC)C.O1CCCC1>[CH3:1][N:2]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[OH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.02 Grams of N-methylhydroxylamine.HCl was suspended with 70 ml of tetrahydrofuran and 6.70 g of triethylamine was added to the solution. After stirring at room temperature for 0.5 hour, 5.73 g of p-toluenesulfonyl chloride was added to the reaction solution and stirred at room temperature over night. The saturated sodium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and N-methyl-N-(p-toluenesulfonyl)hydroxylamine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.IC1C=CC=CC=1.I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([O:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: Cc1cc(C)cc(O)c1
Reactant: N#Cc1ccc(I)cc1
Solvent: Ic1ccccc1
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2)c1

Procedure:
Example 3.1 was repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmoles) and the iodobenzene with 595 mg of 4-iodobenzonitrile (2.6 mmoles), the latter being added at the same time as the 3,5-dimethylphenol.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[N:3][N:4]=[C:5]([CH3:7])[CH3:6].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C.O1CCCC1>[CH3:6][C:5]([NH:4][N:3]=[C:2]([CH3:8])[CH3:1])([CH3:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(C)=NN=C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=NNC(C)(C)Cc1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
Acetone azine (1.50 g, 13.4 mmol) was dissolved in 10 mL of diethyl ether, mixed with 32 mL (19.2 mmol) of 0.6 M benzylmagnesium bromide in tetrahydrofuran and stirred at 45° C. for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 ml), and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (9:1 to 6:1) as the eluent to give 710 mg of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH3:9])[C:6]#[N:7].O.[NH2:16][NH2:17]>C(O)C>[CH3:9][C:8]1[C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[CH3:1])=[C:6]([NH2:7])[NH:17][N:16]=1
Reactant: CC(=O)C(C#N)Cc1ccccc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccccc1Cc1c(C)n[nH]c1N
Temperature: 25 °C
Yield: 37.8 %

Procedure:
To a solution of 2-(2-methylbenzyl)-3-oxobutanenitrile (7.39 g, 39.5 mmol) in ethanol (400 mL) was added hydrazine hydrate (1.97 g, 39.5 mmol) and stirred under reflux for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1 then DCM:methanol=40:1) to provide the titled compound (3.005 g, 38%) as a yellow solid; LC/MS: MS (ES+) m/e 202 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.12 (s, 3H), 2.33 (s, 3H), 3.63 (s, 2H), 7.07-7.17 (m, 4H).
Reaction SMILES: O1C2C(=CC=CC=2)[C@H]([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C@H:24]4[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:34][CH2:33][CH2:32]5)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:25]4)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])CC1.C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1C[C@@H](C2C=C3C(C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=CC=2)C[C@H]1C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)=O)=O)=O)(C)(C)C.[C:154]1([CH2:160][C@@H:161]([C:163]2[NH:167][N:166]=[N:165][N:164]=2)N)[CH:159]=[CH:158][CH:157]=[CH:156][CH:155]=1.C(O)(C(F)(F)F)=O>>[CH3:46][C:44]([CH3:47])([CH3:45])[C@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:42]([N:26]1[CH:27]([C:29]([NH:30][C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[O:41])[CH2:18][C:19]2[C:24](=[CH:28][C:22]([C@H:17]3[CH2:23][C@@H:14]([C:12](=[O:13])[NH:11][C@H:161]([C:163]4[NH:167][N:166]=[N:165][N:164]=4)[CH2:160][C:154]4[CH:159]=[CH:158][CH:157]=[CH:156][CH:155]=4)[N:15]([C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:59])([CH3:61])[CH3:60])[CH2:16]3)=[CH:21][CH:20]=2)[CH2:25]1)=[O:55]
Reactant: N[C@@H](Cc1ccccc1)c1nnn[nH]1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H](Cc4ccccc4)c4nnn[nH]4)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2CC1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Yield: 33 %

Procedure:
Following procedures analogous to those for the preparation of Compounds F and G of Example 46, (S)-2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoic acid (Compound D of Example 46, 30 mg, 0.030 mmol) and (S)-2-phenyl-1-(1H-tetrazol-5-yl)ethanamine, TFA (17 mg, 0.059 mmol) were converted to the title compound (10 mg, 33% over 2 steps). MS (ESI+) m/z 987.8 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)[NH2:13]>C(O)C.O>[CH3:25][NH:24][S:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:12][N:13]=[CH:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:16]=1)(=[O:23])=[O:22]
Reactant: O=CCSc1ccccc1
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(NN=CCSc2ccccc2)cc1
Reaction time: 14 h
Yield: 78.9 %

Procedure:
A solution of (phenylthio)acetaldehyde (6.05 g) in absolute ethanol (180 ml) was added over 10 min to a solution of 4-hydrazino-N-methylbenzenemethanesulphonamide hydrochloride (10 g) in water (180 ml) with cooling. After addition of the aldehyde was complete, the mixture was stirred at 5° for a period of 14 h. The precipitated solid was filtered off, washed with water (200 ml), hexane (200 ml) and dried in vacuo to give the title compound (10.95 g), m.p. 110°-112°. T.l.c. (B) Rf 0.5 (KMnO4)
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=O)[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:36][O:37][NH2:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=[N:38][O:37][CH3:36])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: CON
Agent: Cl
Product: CON=C(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-(methoxyimino)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methyl propanoic acid and O-methylhydroxylamine hydrochloride according to general procedure I.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:27][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(CN[C@H]2CCCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
3,5-bis(Trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in ethanol (25 mL). Triethylamine (1.78 mL, 12.6 mmol) was added and the mixture was heated at 80° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 7.6 mmol, 60%) as a white solid. δH (d6-DMSO) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH2:30])=[CH:21]1.C(N(CC)CC)C>C(O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])=[CH:21]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1=CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4=CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 22.3 %

Procedure:
A reaction mixture of 1.4 g of 6-chloropurine riboside, 1.6 g of [1H-inden-3-yl]methylamine as prepared in Example E hereinafter and 1.5 g of triethylamine in 150 ml ethanol is refluxed for 24 hours. Volatiles are evaporated under reduced pressure and residue is purified on Prep-500A using one prepacked silica gel column and 10% methanoldichloromethane as an eluant at a rate of 150 ml/min. Evaporation of solvent from pure fractions affords 0.43 g (22%) of N6 -[1H-inden-3-yl]methyl adenosine having a melting point of 200°-202° C. Anals. calcd. for C20H21N5O4.0.3 CH3OH; Found: C=60.20; H=5.53; N=17.29; C=60.49; H=5.44; N=17.25.
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:28]1([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with piperidine and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(piperidin-1-yl-)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]4[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]4)=[N:16][C:15]=23)[CH:2]=1.C([Sn](CCCC)(CCCC)[C:50]([O:52][CH2:53][CH3:54])=[CH2:51])CCC>O1CCOCC1.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>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])=[C:18]([C:50]([O:52][CH2:53][CH3:54])=[CH2:51])[C:17]([CH:37]4[CH2:38][CH2:39][S:40](=[O:44])(=[O:43])[CH2:41][CH2:42]4)=[N:16][C:15]=23)[CH:2]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A mixture of 3-(quinolin-3-yl)-5-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-2b, 210 mg, 0.28 mmol), tributyl(1-ethoxyvinyl)stannane (310 mg, 0.84 mmol) and Pd(Ph3P)4 (31 mg, 0.028 mmol) in anhydrous dioxane (5.0 mL) was heated under argon at 100° C. for 24 h, cooled and concentrated. The residue purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1) to give 169 mg (83%) of the title compound as a light brown solid. LC/MS RT=2.58 min (5 min method). Mass calculated for, M+H 724.33, observed 724.33.
Reaction SMILES: C([C:3]1[C:4]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:5][CH:6]=[C:7]([CH:9]([Cl:11])[Cl:10])[N:8]=1)=O.Cl.[NH2:24][OH:25].O>CS(C)=O>[N:24](=[C:3]1[N:8]=[C:7]([CH:9]([Cl:11])[Cl:10])[CH:6]=[N:5][CH:4]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[OH:25]
Reactant: NO
Reactant: O=Cc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1C1N=CC(C(Cl)Cl)=NC1=NO
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of 10 g of 3-formyl-5-dichloromethyl-2-phthalimidopyrazine in 50 ml of dimethyl sulfoxide was heated at 50° C., 7 g of hydroxylamine hydrochloride were added, and the mixture was stirred for 15 minutes at 70° C. Thereafter, 700 ml of water were added to the reaction solution, the mixture was filtered and the filtrate was washed with a little diethyl ether. 6.8 g of colorless crystals (65%) of 3-oximinodichloromethyl-2-phthalimidopyrazine were obtained. 1H-NMR (270 MHz, DMSO-d6): δ7.7 (s, 1H), 8.0 (m, 4H), 8.3 (s, 1HO), 9.1 (s, 1H), 12.0 (s, OH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]C1C=CC=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C[Mg]Br
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: Cc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-methylbenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=388.
Reaction SMILES: C(N)(=[S:8])C1C=CC=CC=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.CC1C=CC(C(N)=O)=C([N+]([O-])=O)C=1>>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[S:8])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: NC(=S)c1ccccc1
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cc1ccc(C(N)=O)c([N+](=O)[O-])c1
Product: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
The thio-benzamide, was prepared as described in Example 14-1, starting from 4-methyl-2-nitro-benzonitrile via 4-methyl-2-nitro-benzamide which gave the title compound (1.03 g, 98%). LC/MS: (Method I): tR=0.54 min, >80%, m/z (ESI)=180 (M-NH2)+.