Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH2:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH:28][C:10]([CH:8]3[CH2:9][CH:7]3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: O=C(Cl)C1CC1c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask was 2-(pyridin-4-yl)cyclopropanecarbonyl chloride (7D, 190 mg, 1.05 mmol) added in Pyridine (2 mL) to give a yellow suspension. 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 213 mg, 0.951 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. The reaction was quenched with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure (3×100 mL). The reaction mixture was filtered and purified by preparatory, 5-95% (10 mM NH4HCO3 (aq)/10 mM NH4HCO3 in 20/80 (v/v) H2O/MeCN). Received 9 mg (3%) of yellow solid. 1H NMR (DMSO-d6) δ: 11.32 (s, 1H), 8.46 (d, J=6.1 Hz, 2H), 7.94-8.06 (m, 2H), 7.88 (s, 1H), 7.53-7.67 (m, 3H), 7.15-7.26 (m, 2H), 6.33 (s, 1H), 2.37 (s, 3H), 1.50-1.66 (m, 2H). ESI-MS: m/z 370.0 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:5]2[CH2:6][CH2:7][NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1.CC(C)([O-])C.[Na+].Br[C:19]1[CH:24]=[N:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][N:20]=1.O>CS(C)=O>[CH:25]1([C:22]2[N:23]=[CH:24][C:19]([O:1][CH:2]3[CH2:11][N:5]4[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]4[CH2:3]3)=[N:20][CH:21]=2)[CH2:27][CH2:26]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: O=C1NCCN2C[C@H](O)C[C@@H]12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Temperature: 25 °C
Reaction time: 0.4 h
Yield: 23.7 %

Procedure:
In a 4 mL vial were combined (7R,8aS)-7-hydroxyhexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (180 mg, 1.152 mmol) from Step 2 and sodium tert-butoxide (188 mg, 1.959 mmol) in dimethyl sulfoxide (1 mL). The mixture was stirred at room temperature for 0.4 hours followed by the addition of 2-bromo-5-cyclopropyl-pyrazine (229 mg, 1.152 mmol). After stirring at room temperature for 8 hours, water was added, and the solution was extracted with ethyl acetate. The extract was concentrated in vacuo, and the resulting solid was purified using an Agilent Technologies SuperFlash SF-15-12 g cartridge eluted with a gradient of 0-8% methanol/dichloromethane over 20 minutes to give 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (75 mg, 0.273 mmol, 23.72% yield) as an oil in a 3:1 (7R,8aS: 7R,8aR) diastereomer ratio. 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=32.4 Hz, 1H), 8.19 (dd, J=14.4, 0.9 Hz, 1H), 8.12-8.05 (m, 1H), 5.54-5.41 (m, 1H), 3.77 (t, J=8.0 Hz, 0.5H), 3.54 (dddd, J=12.4, 10.1, 8.1, 4.0 Hz, 1H), 3.49-3.35 (m, 1H), 3.30-3.19 (m, 1.5H), 3.02 (ddd, J=16.9, 9.2, 4.7 Hz, 1H), 2.91 (dt, J=7.7, 4.2 Hz, 1H), 2.89-2.80 (m, 1H), 2.80-2.66 (m, 1H), 2.60-2.51 (m, 1H), 2.00 (qt, J=9.5, 4.8 Hz, 1H), 1.12-1.02 (m, 2H), 0.96-0.86 (m, 2H); MS (ESI+) m/z 275 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A solution of ethyl 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (for a preparation see Intermediate 27)(240 mg, 0.557 mmol) in ethanol (5 mL) was treated with aqueous lithium hydroxide (1N, 1.115 mL, 1.115 mmol) and the resulting mixture was stirred at room temperature. After 1 h most of the ethanol was removed in vacuo, the residue was diluted with water (ca 2 mL) and the “cloudy” mixture was treated with acetic acid (0.064 mL, 1.115 mmol). The precipitate formed was isolated by filtration, washed with Et2O and dried at 60° C. for 16 h to give 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotin ic acid (150 mg, 0.373 mmol, 66.9% yield) as a pale yellow solid which was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.61 min, MH+=403.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:7])=[N:4][O:5][N:6]=1.C(OCC)C.[Cl-].[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:7][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[N:4][O:5][N:6]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1nonc1N
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1nonc1NC(=O)C1CC1
Reaction time: 0.5 h

Procedure:
5 g (about 0.05 moles) of 4-methyl-3-aminofurazan, 50 ml of ethyl ether and 4 ml of pyridine are then loaded into a 100 ml glass reactor. This is cooled to a temperature of from 0° to 10° C. and 5 ml (0.06 moles) of the chloride of cyclopropanecarboxylic acid are added under agitation. Heating is then carried out under reflux for about one hour. After cooling of the reaction mass, the ether is evaporated and the residual solid is transferred into about 100 ml of water. Slight heating is effected for about 30 minutes and then the mass is cooled and filtered, the solid being washed with water. The solid obtained is dried in an oven at 90° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 96.2 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.96 g, 8.5 mmol) and potassium phthalimide (2.37 g, 12.8 mmol) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (4.72 g, 96.3%) as crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][C@H:33]([CH:36]([CH3:38])[CH3:37])[C:34]#[N:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH:36]([CH3:38])[CH3:37])#[N:35]
Reactant: CC(C)[C@@H](N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol), (R)-2-amino-3-methylbutanenitrile (Int-VII, 9.10 mg, 0.093 mmol), HATU (45.8 mg, 0.121 mmol), and 4-methylmorpholine (37.5 mg, 0.371 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=30.3 min) to provide single enantiomer N—((R)-1-cyano-2-methylpropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 40.1% yield): LCMS=512.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, d, J=8.58 Hz), 8.13-8.26 (2 H, m), 7.50-7.81 (7 H, m), 5.21 (1 H, s), 4.54-4.69 (1 H, m), 2.05-2.25 (1 H, m), 1.09 (3 H, d, J=6.82 Hz), 0.98 (3 H, d, J=6.60 Hz); HPLC peak RT=10.5 min (Method A).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.C(OC(C)C)(C)C>C(O)C>[C:3]1([CH3:13])[C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.1 g (11 mmol ) of p-toluenesulfonic acid in 5 ml of ethanol was added dropwise to a solution of 5 g (9.3 mmol) of α-(2,2-dimethylpropanoyloxy)ethyl 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 32 ml of ethanol. After stirring at room temperature for 30 minutes, a total of 280 ml of diisopropyl ether were added to the crystal magma formed and the mixture was briefly stirred. The precipitate formed was then filtered off with suction and washed with a little diisopropyl ether, and the residue was dried in vacuo over calcium chloride/paraffin. 5.4 g of the desired crystalline title compound were obtained, which consisted of an approximately 1:1 mixture of the two diastereomers according to HPLC and was identical in its physical and chemical properties with the product from working example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:24][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:27])([CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH:24]=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:26])([CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
A solution of 7-(1-hydroxymethyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.27 g, 3.38 mmole) in 10 mL of dichloromethane was added to a suspension of 1.1 g of pyridinium chlorochromate in 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 6 hours, diluted with 50 mL of ether and filtered through a pad of Celite. The volatiles were removed in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.91 g of 7-(l-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 85.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.40 g, 2.6 mmol), 3-ethoxy-4-hydroxybenzaldehyde (0.43 g, 2.6 mmol) and cesium carbonate (0.84 g, 2.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 20 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (1×), 0.5N sodium hydroxide solution (1×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 86%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1(C)C=CC=CC=1.OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH2:21][C:22]2([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(CC2=Cc3cccc(-c4ccc(C(C)(C)C)cc4)c3C2)CCCCC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
27.9 g of crude 4-(4-tert-butyl-phenyl)-2-[(1-methylcyclohexyl)methyl]-indan-1-one (˜83% purity), 2.82 g (74.5 mmol) of NaBH4 and 70.5 ml of toluene are charged in a flask equipped with reflux condenser, dropping funnel and magnetic stirring bar. The mixture is warmed to 50° C. and 14 ml of methanol are slowly added with stirring and stirring is continued for 2.5 h to ensure a complete reaction. Excess NaBH4 is carefully hydrolyzed with approx. 40 ml of 2n H2SO4. The organic phase is separated and the water phase is washed with another 35 ml of toluene. The combined organic phases are twice extracted with 2n H2SO4 and dried over anhydrous MgSO4. Most of the solvent is removed in a vacuum and replaced by fresh toluene up to a total volume of 100 ml and 0.3 g of p-toluenesulfonic acid are added. The reaction flask is fitted with a water separator and the reaction mixture is heated to reflux for 1.5 h. The conversion can be monitored by TLC. Once the dehydration is complete, the solution is washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent is thoroughly removed in a vacuum and 25.85 g of a brown oil is obtained. Purification of the indene is carried out via a column chromatography. Yield: 18.85 g (˜85%) of 7-(4-tert-Butyl-phenyl)-2-[(1-methylcyclohexyl)methyl]-1H-indene.
Reaction SMILES: O=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[P:8]([OH:11])([OH:10])[OH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:6][C:5](=[CH2:7])[CH:4]=[C:2]([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3]
Reactant: OP(O)O
Reactant: CC(=O)C=C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C)C=C(C)P(=O)(O)O

Procedure:
For example, mesityl oxide was reacted with phosphorous acid in the presence of acetic anhydride and acetic acid under mild conditions to yield 4-methylpenta-2,4-diene-2-phosphonic acid in more than 90% purity.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(OC(=O)C)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 13 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0015 ml of acetic anhydride was added. Next, 0.0045 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.04 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 16% and phenethyltriethoxysilane was produced at a yield of 13%. The yield of (α-methylbenzyl) triethoxysilane was 2%.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[N:22]=1
Reactant: OCc1cccc(-c2cccc(Cl)c2)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
433 mg (0.264 ml, 3.64 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 400 mg (1.82 mmol) [6-(3-Chloro-phenyl)-pyridin-2-yl]-methanol in 25 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (409 mg, 94%) used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16]Cl)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[I-:22].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][I:22])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(C(=O)OCCl)cc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C(=O)OCI)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-(4-methoxybenzyloxy)benzoate (0.77 g, 2.5 mmole) in 15 ml dry acetone was added sodium iodide (1.87 g, 12.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield 0.86 g=86%
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[C:21](=O)[CH:20]2[NH:23][C:24](=O)[CH:15]1[CH2:16][CH:17]=[CH:18][CH2:19]2.CC(C[Al]CC(C)C)C>C1COCC1.C(OCC)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[CH2:21][CH:20]2[NH:23][CH2:24][CH:15]1[CH2:16][CH:17]=[CH:18][CH2:19]2
Reactant: O=C1NC2CC=CCC1N(c1ccc3c(c1)Cc1ccccc1-3)C2=O
Agent: CC(C)C[Al]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CCC2CNC(C1)CN2c1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
7-(9H-Fluoren-2-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (310 mg, 0.94 mmol) in THF (4 mL) was placed in a μW tube. Dibal-H (4 mL, 4 mmol, [1M] in THF) was then added to the reaction mixture with venting under argon flow. When all H2 evolution was completed, the reaction mixture was heated to 130° C. for 900 sec. The reaction mixture was then diluted with a saturated Rochelle's solution (30 mL) and diethyl ether (30 mL) followed by stirring vigorously overnight. The layers were separated and the organic solution was dried with magnesium sulfate, filtered and the solvent removed by reduced pressure to yield the title compound as a residue.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][C@H:5]1[OH:13])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([OH:13])[CH2:6]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CC[C@H](N=[N+]=[N-])[C@H](O)C1
Reaction time: 10 h

Procedure:
A solution of cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was treated at −20° C. dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) in dichloromethane (5 mL). The temperature was allowed to reach 0° C. and kept at 0° C. for 10 hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was codistilled with dry DMF (10 mL) without heating. This crude preparation of the mesylate was used without further purification directly for the next step.