Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:26]Br.S([O-])(O)=O.[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:26][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]3([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:14]=2[CH:15]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)-c1ccccc1C21c2ccccc2-c2ccccc21
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Reaction time: 3 h
Yield: 97.2 %

Procedure:
In a two-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 1 L of water, three drops of a surfactant, 10.7 g (0.0395 mol) of anhydrous iron (III) chloride, and 253 g (0.8 mol) of 9,9′-spirobifluorene were placed and stirred to mix. By adding 102 g (0.638 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at room temperature for 3 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a solid, was filtered and washed with water. Thus, 298 g of a crude product was obtained. The crude product was recrystallized using dioxane, thus resulting in 245 g (0.62 mol, yield of 78%) of a white solid, which is the target product. This product was subjected to gas chromatography and the purity of the product was 99%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH:15]=[C:16]([N:21]=[N+]=[N-])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:25]=[C:24]2[C:14]([CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[NH:21]2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(=Cc1ccc(OCCOCCOCCO)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2ccc(OCCOCCOCCO)cc2[nH]1

Procedure:
Methyl 4-[(2-(2-hydroxyethoxy)ethoxy)ethoxyl-α-azidocinnamate (IV, EXAMPLE 2, 3.0 g) is dissolved in xylene (86 ml) and quickly heated to reflux. TLC indicates disappearance of starting material, the reaction is cooled to 20°-25° and the material is purified by flash column chromatography eluting with ethyl acetate/hexane (75/25). The appropriate tractions are pooled and concentrated to give the title compound, MS theory=323.1369, found =323.1366.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[CH2:17]([OH:20])[CH2:18][OH:19].N1C(C)=CC=CC=1C.CO>O.[B-](F)(F)(F)F.[Ag+]>[OH:19][CH2:18][CH2:17][O:20][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: OCCO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(OCCO)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29° C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (λmmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatography of the residue on silica gel gives an oil, λmax.MeOH =216 mμ(8350); νmax.=3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm-1 (olefin group).
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.Cl.[CH2:37]([O:39][N:40]=[C:41]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:42](Cl)=[O:43])[CH3:38].C(OCC)(=O)C>O1CCCC1>[CH2:37]([O:39][N:40]=[C:41]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:42]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12)=[O:43])[CH3:38]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12)c1nsc(N)n1
Yield: 74.1 %

Procedure:
To a solution of benzhydryl 7-amino-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (3 g) in tetrahydrofuran (30 ml) containing monotrimethylsilyl acetamide (5 g) was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (1.8 g) under stirring at -10°-0° C. The reaction mixture was stirred at the same temperature for 30 minutes. After addition of ethyl acetate (150 ml) and a small amount of water, the separated organic layer was washed in turn with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.1 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH:40]=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:53]>CO>[ClH:53].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[C:39]([O:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[CH:38]=[CH:37]3)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cc(OCCN4CCOCC4)ccc3c2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(COCCCOc2ccc(C3CCNCC3OCc3ccc4cc(OCCN5CCOCC5)ccc4c3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[6-(2-morpholin-4-yl-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 4-[2-[6-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl]-naphthalen-2-yloxy]-ethyl]-morpholine hydrochloride (1:2) in the form of colourless crystals; M: 611 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1.I[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2cnc(-c3c(-c4ccccc4F)noc3C)c2)cc1
Temperature: 90 °C
Yield: 4 %

Procedure:
To a solution of 3-(2-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) in DMSO (2 mL) was added copper(I) iodide (7.9 mg, 0.04 mmol), 4-iodoanisole (57 mg, 0.45 mmol), L-proline (9.5 mg, 0.08 mmol) and potassium carbonate (113.6 mg, 0.82 mmol) and the resulting mixture heated at 90° C. for 3 days. After cooling to room temperature the resulting mixture was poured into water and extracted with ethyl acetate. The organic extracts were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title compound (5.7 mg, 4%) which was obtained as a light brown gum. MS: m/e=350.5 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH2:12]([C:19]1([N:26]([CH3:28])[CH3:27])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:47]>ClCCCl.CC(=O)CC.C(O)C.O>[ClH:47].[ClH:47].[CH2:12]([C:19]1([N:26]([CH3:27])[CH3:28])[CH2:24][CH2:23][CH:22]([NH:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CN(C)C1(Cc2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
292 mg C-(1H-indol-3-yl)-methylamine were partly dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 463 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 72 hours at room temperature. For working up, water (10 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was extracted twice with ether and then rendered strongly alkaline with sodium hydroxide solution. The mixture was extracted again with ethyl acetate (4×10 ml). A pale precipitate precipitated out of the combined ethyl acetate phases even during the processing. After cooling, this was filtered off with suction, washed twice with cold ethyl acetate and dried. The product obtained in this way (235 mg) was white and solid (m.p. 194-198° C.). 217 mg were dissolved hot in 2-butanone/ethanol (30+10 ml), and saturated ethanolic hydrochloric acid (1.5 ml; 1.85 M) was added at RT, while stirring. After two hours, no precipitate had yet precipitated out. Even after reducing the amount of solvent and cooling, no hydrochloride precipitated out. The mixture was therefore evaporated to dryness at 40° C. in vacuo and excess HCl was driven off. 260 mg 1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride were obtained as the residue as a pale pink-colored solid of m.p. 170-174° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[C:7]#[N:8])([O-])=O.[ClH:14]>[Pd].CO>[NH2:8][CH2:7][C:6]1[C:5]([F:13])=[C:4]([C:11]([F:12])=[CH:10][CH:9]=1)[NH2:1].[ClH:14]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-nitro-2,4-difluoro-benzonitrile (500 mg, 2.72 mmol), Pd/C (200 mg), conc. HCl (1.50 mL, 18.0 mmol) and MeOH (25 mL) is stirred at rt overnight under a hydrogen atmosphere (3.2 bar). The catalyst is removed by filtration, the filtrate is concentrated and evaporated twice from EtOH to give the sub-title compound as HCl salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH:19]1[CH2:24][CH2:23][N:22](C(OCC)=O)[CH2:21][CH2:20]1)[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BrH:30].C(=O)=O>>[BrH:30].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2c(C)cccc2C)CC1
Agent: Br
Agent: O=C=O
Product: Cc1cccc(C)c1N(C(=O)Cc1ccccc1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
A mixture of 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate in 60 parts of hydrobromic acid solution 48% is warmed until the evolution of carbon dioxide is ceased. Heating is continued for 15 minutes at a temperature between 80°-120° C. The reaction mixture is evaporated. The solid residue is washed successively with methylbenzene and 2-propanone and dried, yielding 4.1 parts of N-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide hydrobromide; mp. 251.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:11])=[C:5](C)[CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)=[CH:8][CH:7]=1)=[O:11])[CH2:22][CH3:23]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.1 %

Procedure:
The compound (195.6 mg) obtained in Example 12-2 was dissolved in anhydrous methanol (7.8 ml) and added with 2-imidazole carboxaldehyde (88.4 mg) and trimethyl orthoformate (0.200 ml) and the whole was stirred at room temperature for 14 hours. Then, the solution was added with sodium borohydride (69.2 mg) and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The resultant was added with water and subjected to extraction with chloroform. The extract was washed with a saturated saline solution and dried with magnesium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (101 mg) as a colorless oily substance.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:26][CH2:27][CH:28]=[O:29])=[CH:21][CH:20]=1>O.CO>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([F:30])([F:17])[F:31])=[CH:20][CH:21]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
19.72 Grams of methyl acetoacetate were dissolved in 30 ml of water, and 25.33 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.98 g of sodium acetate and then an additional concentrated aqueous hydrochloric acid solution were added to the mixture so that the mixture had a pH of 6.9. And 40 ml of methanol and then 23.44 g of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The resulting mixture was stirred at 45°-50° C. for 10 hours. The mixture was concentrated under reduced pressure, and the residue obtained was extracted three times with ethyl acetate. The organic layers were combined, washed twice with a 5% aqueous acetic acid solution and then twice with a saturated aqueous sodium chloride solution and thereafter dried over anhydrous magnesium sulfate. Removing the solvent from the washed layer under reduced pressure gave 22.64 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone (purity: 89.6%, yield: 69.4%).
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CC(C)Oc1ccc(B(O)O)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1Cl
Temperature: 105 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (600 mg, 1.96 mmol, 1.00 equiv), [3-chloro-4-(propan-2-yloxy)phenyl]boronic acid (671 mg, 3.13 mmol, 1.60 equiv), Pd(dppf)Cl2 (430 mg, 0.59 mmol, 0.30 equiv) and potassium carbonate (811 mg, 5.87 mmol, 2.99 equiv) in 1,4-dioxane (50 mL) and water (5 mL) was stirred under nitrogen at 105° C. for 8 h. The solid material was removed by filtration and the filtrate was extracted with ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-16% ethyl acetate in petroleum ether to give 600 mg (88%) of 3-(3-chloro-4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde as a yellow oil. LCMS (method C, ESI): RT=0.98 min, m/z=371.0 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[Li][CH2:25]CCC.CI.Cl>C1COCC1.O>[CH2:1]([CH:3]1[CH2:4][CH2:5][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH3:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:7][CH2:8]1)[CH2:2][CH3:25]
Reactant: [Li]CCCC
Reactant: C#Cc1ccc(C2CCC(C3CCC(CCC)CC3)CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC#Cc1ccc(C2CCC(C3CCC(CCC)CC3)CC2)cc1
Reaction time: 3 h

Procedure:
3.0 g (9.7 mmol) of 4′-(4-ethynylphenyl)-4-propylbicyclohexyl are initially introduced in 25 ml of THF at −20° C., and 7.3 ml (11.7 mmol) of n-BuLi (15% soln. in hexane) are added dropwise. After 1 h at this temperature, 0.73 ml (11.7 mmol) of methyl iodide is metered in, and the batch is left in the cooling bath to thaw for 3 h. Water and dil. hydrochloric acid are added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln., and the solution is dried using sodium sulfate. The crude product obtained after removal of the solvents is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from n-heptane. This gives 4-propyl-4′-(4-prop-1-ynylphenyl)bicyclohexyl as a colourless solid having an m.p. of 82° C.
Reaction SMILES: BrN1C(=O)C2C(=CC=CC=2)C1=O.[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][S:43][CH3:44])[CH:37]=2)[N:29]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:45]#[C:46][NH2:47].CC([O-])(C)C.[K+]>CO.C(Cl)Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[CH2:42][S:43](=[N:47][C:46]#[N:45])[CH3:44])[N:29]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CN
Reactant: CSCc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1
Agent: CC(C)(C)[O-]
Agent: O=C1c2ccccc2C(=O)N1Br
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CO
Product: CS(Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1)=NC#N
Reaction time: 4 h

Procedure:
2-Bromo-1H-isoindole-1,3(2H)-dione (22.0 mg; 0.12 mmol) was added to a solution of 4-[2-(benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(methylsulfanyl)methyl]phenyl}pyrimidin-2-amine (37.0 mg; 0.08 mmol), cyanamide (4.5 mg; 0.11 mmol) and potassium 2-methylpropan-2-olate (11.1 mg; 0.10 mmol) in MeOH (0.44 mL) at RT. The batch was stirred for 4 hours before it was diluted with DCM and aqueous sodium thiosulfate solution. The batch was extracted with DCM (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give crude (rac)-[[3-({4-[2-(benzyloxy)-4-fluorophenyl]-5-fluoropyrimidin-2-yl}amino)benzyl](methyl)-λ4-sulfanylidene]-cyanamide that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([Cl:16])[CH:4]=[N:3]1.Cl[C:18]1[N:23]=[CH:22][C:21]2[C:24](=[O:48])[N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:26][C:20]=2[CH:19]=1.C(N(CC)C(C)C)(C)C.NN>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCCC1.CO>[NH2:29][CH2:28][C@@H:27]([N:25]1[CH2:26][C:20]2[CH:19]=[C:18]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[Cl:16])[N:23]=[CH:22][C:21]=2[C:24]1=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Cl)ncc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc2c(cn1)C(=O)N([C@H](CN)Cc1cccc(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg, 0.0800 mmol), bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol), 2-[(2S)-2-(6-chloro-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (30.0 mg, 0.0667 mmol) and N,N-diisopropylethylamine (34.8 μL, 0.200 mmol) in 1,4-dioxane (1 mL) and water (50 μL) was microwaved at 110° C. for 15 minutes. Filtered through a pad of celite and concentrated, the residue was purified by combi-flash chromatography eluted with EtOAc/hexane (50-100%). To the purified intermediate was added methanol (0.4 mL), tetrahydrofuran (0.4 mL) and hydrazine (0.2 mL, 6 mmol). The solution was stirred at room temperature overnight. Purification by prep.—HPLC (pH=10) gave the desired product as white solid. LC-MS found: 400.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.95 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.23 (m, 1H), 6.98 (m, 2H), 6.95 (dt, J1=9.30 Hz, J2=1.80 Hz, 1H), 4.59 (s, 2H), 4.41 (m, 1H), 3.93 (s, 3H), 3.02 (dd, J1=14.40 Hz, J2=5.10 Hz, 1H), 2.89 (m, 1H), 2.81 (d, J=6.60 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.[CH2:11](O)CCC>O>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.[CH4:11]
Reactant: CCCCO
Agent: C=C(C)[C@H]1CC=C(C)CC1
Solvent: O
Product: C
Reaction time: 11 h

Procedure:
A 32-fluid ounce d-limonene fluid mixture was prepared by combining 7.7 fluid ounces of d-limonene and approximately 1.0 ml of Triton® X-114 in a blender. The mixture was then agitated until bonded. Next, about 20.8 fluid ounces of butyl alcohol was added to the d-limonene/surfactant mixture and blended, afterwhich the temperature of the resulting mixture decreased and then increased again. Once the mixture bonded, about 3.5 fluid ounces of water was slowly added to the mixture. The mixture was blended until warm and then allowed to stand. After approximately 10 to 12 hours, the mixture was completely solubilized; i.e. the mixture had changed from a hazy mixture having separate layers to a clear, single phase mixture with only about 0.5 residue remaining on the bottom. This residue was filtered away from the final product. The resulting fluid mixture exhibited VOC emissions of 0.016 pounds per start resulting from charcoal ignition, which was in compliance with the South Coast Air Quality Management District standard.