Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ncn1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 38.2 %

Procedure:
A solution of 4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.0 g, 4.31 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (1.75 g, 6.46 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.86 g, 6.46 mmol), and triethylamine (1.20 mL, 8.61 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (800 mg, 38.3%). LCMS calculated for C23H35F3N5O3: (M+1) 486.2; found 486.2.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=O)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(C)(N)CO
Reactant: COc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(CC2=NC(C)(C)CO2)cc1[N+](=O)[O-]

Procedure:
A mixture of 2-amino-2-methyl-1-propanol, 7.2 g (0.05 mol), (Aldrich Chemical Company) and 4-methoxy-3-nitrobenzeneacetic acid, 16.7 g (0.079 mol), (Journal of the American Chemical Society, Vol. 70, pp. 2837-2843, (1948)) is refluxed overnight in xylene, 100 ml, under a water separator. The mixture is diluted with toluene, filtered, washed with an aqueous solution of potassium bicarbonate and water. The organic layer is separated and evaporated. The resulting gum is chromatographed over silica gel and eluted with ethyl acetate to give 7.6 g of 4,5-dihydro-2-[(4-methoxy-3-nitrophenyl)methyl]-4,4-dimethyloxazole after recrystallization from hexane; mp 88°-90° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]I>>[CH3:10][C:11]([CH3:20])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCC(C)(C)CI
Reactant: O=Cc1ccccc1O
Product: CCCCCCC(C)(C)COc1ccccc1C=O

Procedure:
2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane to yield 2-(2,2-dimethyl octyloxy)benzaldehyde which was reduced to 2-(2,2-dimethyl, octyloxy)benzyl alcohol and then converted to [[2-(2,2-dimethyloctyloxy)phenyl]methyl]triphenylphosphonium bromide as in Example 1. Condensation of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[(2,2-dimethyl-octyl)oxy]phenyl]-2,4,5,8-non-atetraenoic acid mp 113°-117° (from dichloromethane/hexane mixture).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29]O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Reactant: C1COCCN1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCOCC2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and morpholine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.19 min, m/z=511.2; 1H NMR (CDCl3) 1.49 (t, 3H), 2.05-2.11 (m, 3H), 2.16 (m, 1H), 2.23-2.41 (m, 5H), 2.51 (m, 1H), 2.71 (m, 1H), 3.61 (m, 4H), 5.61 (m, 1H), 6.83 (d, 2H), 7.20-7.32 (m, 4H), 7.31 (m, 5H), 7.43 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([Sn:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)C>[CH2:2]([Sn:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a three-necked flask, a solution of 1-bromobutane (34.25 g, 250 mmol) in diethyl oxide was added on magnesium (7.3 g, 300 mmol) covered with dry diethyl oxide. When the addition was completed, the mixture was refluxed during one hour. This solution was then added to triphenyltin chloride (42.6 g, 110 mmol) in 150 mL of diethyl oxide and refluxed for 3 hours. The mixture was hydrolysed with a minimum of water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated. Crystallization of the crude product in methanol gave a white solid (32.3 g, 93 mmol).
Reaction SMILES: C(N1CCN(C(=O)C(C2C3C(=C(OC)N=CC=3OC)NC=2)=O)CC1)(=[O:8])C1C=CC=CC=1.C(N1CCN([C:46](=[O:58])[C:47]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)=[O:48])[C@H](C)C1)(=O)C1C=CC=CC=1.COC1C=NC(OC)=C2C=1C(C(=O)C([O-])=O)=CN2.[K+:78]>>[NH:51]1[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][N:53]=2)[C:49]([C:47](=[O:48])[C:46]([O-:58])=[O:8])=[CH:50]1.[K+:78]
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12
Agent: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Agent: [K+]
Product: O=C([O-])C(=O)c1c[nH]c2ncccc12

Procedure:
Compound IVa, N-(benzoyl)-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]piperazine, was prepared by the same method used to prepare compound 5a but the starting material was Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate. The compound was purified by silica gel chromatography using EtOAc as the eluting solvent to give a white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H), 8.15 (s, 1H), 7.40 (m, 6H), 4.00 (s, 3H), 3.83 (s, 3H), 3.63-3.34 (m, 8H); 13C NMR (125 MHz, DMSO-d6) δ 185.5, 169.3, 166.5, 146.2, 145.7, 136.6, 135.3, 129.6, 128.4, 126.9, 122.2, 122.1, 119.2, 114.4, 56.8, 52.9, 45.5, 39.9. MS m/z: (M+H)+ calcd for C22H23N4O5: 423.17; found 423.19. HPLC retention time: 1.33 minutes (column B). Anal. Calcd. For C22H21N4O5: C, 62.7; H, 5.02; N, 13.29. Found: C, 61.92; H, 5.41; 13.01. Melting Point: 229.5-232° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[CH3:56][C:55]1[CH:54]=[C:53]([CH3:57])[NH:52][C:51](=[O:58])[C:50]=1[CH2:49][NH:48][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1cccc(F)c1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cccc(F)c2C(F)(F)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-fluoro-2-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DMF (25 ml) cooled in an ice bath was added HATU (2.19 g, 5.77 mmol) and DIPEA (1.67 ml, 9.61 mmol). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 904 mg, 5.29 mmol) was added and the reaction was warmed room temperature for 4 h. The reaction mixture was then poured onto distilled water (300 ml) and stirred for 1 h after which time the precipitate was collected via vacuum filtration using microfibre paper. The resulting solid was triturated using diethyl ether and filtered to afford the title compound as a pale brown solid (1.19 g, 72%). LC-MS 100%, m/z=343.0, 1H NMR (500 MHz, DMSO) δ 11.48 (s, 1H), 8.54 (t, J=4.8 Hz, 1H), 7.71 (dd, J=13.3, 8.0 Hz, 1H), 7.56-7.45 (m, 1H), 7.20 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 4.25 (d, J=4.9 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH2:4][CH2:5]1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 3 g (23.2 mmol) trans-4-Methylamino-cyclohexanol in 120 ml CH2Cl2 were added 4.2 ml (24.4 mmol, 1.05 eq) N,N-diisopropylethylamine followed by 5.96 g (24.4 mmol, 1.05 eq) 4-(trifluoromethyl)-benzenesulfonyl chloride in 50 ml CH2Cl2. The mixture was stirred at RT over night and the organic phase extracted with 1M KHSO4, followed by 5% NaHCO3 and brine. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane:EtOAc 1:1 yielded 6.0 g (77%) trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white solid, MS: 338 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Piperazine (6.0 g, 69 mmol) was dissolved in dimethylsulfoxide (50 ml), 2-fluorobenzonitrile (0.95 ml, 9 mmol) and potassium carbonate (2.2 g, 17 mmol) were added and the mixture was stirred at room temperature for 16 h. Water (100 ml) was added and the mixture was extracted with toluene (2×100 ml). The combined organic extracts were washed with 1N sodium hydroxide (3×75 ml), dried (MgSO4) and concentrated in vacuo to give 1.48 g (88%) 2-(1-piperazinyl)benzonitrile as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.5 mmol) in DMF (160 mL), was added iodomethane (35.7 g, 248 mmol) and sodium carbonate (26.3 g, 248 mmol). The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrates were concentrated under vacuum till dry and re-dissolved in ethyl acetate before washing with 5% sodium bicarbonate solution (700 mL) followed by 5M HCl solution (300 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-bromo-2-methyl-3-nitrobenzoate (16 g, 94.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[CH3:32]>>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:27][C:26]=1[CH3:32]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Cl)cc3)c2)o1
Reactant: COc1ccc(N)cc1C
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1C

Procedure:
N-(4-Methoxy-3-methylphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride and 4-methoxy-3-methylaniline using method K. NMR; δH [2H6]—DMSO 10.14,(1H, b), 8.05,(2H, d), 7.90,(1H, dd), 7.57-7.55,(5H, m), 6.92,(1H, d), 3.77,(3H, s), 2.57,(3H, s), 2.33,(3H, s), 2.16,(3H, s). LCMS; retention time 3.53 min, MH+ 414.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](C)OCC
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCO[SiH](CCCc1ccccc1)OCC
Temperature: 80 °C
Yield: 63 %

Procedure:
Comparative Example 5. The platinum-catalyzed reaction of styrene and methyldiethoxysilane in the absence of a hydro(acyloxy)silane compound. A 212 mg sample of styrene (2 mmoles) and 279 mg of methyldiethoxysilane (HSi(CH3)(OEt)2, 2.1 mmoles) were placed in a glass reaction tube. This was followed by the addition of 0.001 mL of a toluene solution (platinum content=0.4 wt %) of a zero-valent platinum complex with divinylsiloxane. The reaction tube was subsequently sealed with Teflon™ tape, placed in an oil bath heated to 80° C., and heated for 1 hour. After cooling, analysis of the contents by gas chromatography showed an approximately 65% conversion of the vinyl group in the styrene. The hydrosilylate yield was 63% phenethylmethyldiethoxysilane. The α-phenethyl adduct: β-phenethyl adduct ratio was 1:1.65.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:30][OH:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][O:31][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecylglycerine and 0.16 ml of triethylamine in 2 ml of chloroform is added dropwise to a solution, cooled to 0° C., of 0.16 ml of 4-chlorobutyryl chloride in 1 ml of chloroform. The reaction mixture is stirred at room temperature, diluted with 5 ml of chloroform and washed in succession with 5 ml of 1N sodium hydroxide and 3×10 ml of water. The organic phase is dried and concentrated. The residue is chromatographed on silica gel while eluting with hexane-ether (19:1). There is obtained (R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in the form of an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Br:15])=[C:11](Br)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[Br:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In 35 ml of N,N-dimethylformamide were dissolved 1.5 g (4.1 m mol) of 2-(4-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone and 0.59 g (4.1 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.27 g of powdery potassium hydroxide. The reaction mixture was stirred for one day at room temperature. The resulting solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The crystals thus obtained were recrystallized from ethyl acetate-benzene to give 1.4 g of the intended compound.
Reaction SMILES: [CH2:1]([C:12]([CH3:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:15][NH:16]Cl.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12](=[N:16][OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ONCl
Reactant: CCCCCCCCCCCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC(C)=NO
Yield: 93 %

Procedure:
A solution of 40 g of methyl undecyl ketone and 18 g of hydroxylamino hydrochloride in 200 ml of ethanol, 60 ml of water and 10 g of NaOH is refluxed for 5 hours and thereafter cooled. The ethanol is distilled off in vacuo and the reaction mixture is then diluted with water, extracted with ether and the ethereal extract is dried over Na2SO4. The ether is distilled off and the solid residue is then distilled in vacuo, affording 40 g of 2-tridecanone oxime. Melting point (after recrystallisation from ether); 51°-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.[NH2:38][CH2:39][CH2:40][C:41]#[N:42].[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:28][CH2:29][CH:30]([NH:42][CH2:41][CH2:40][C:39]#[N:38])[CH2:31][CH2:32]3)[N:9]=2)[CH:7]=1
Reactant: N#CCCN
Reactant: O=C1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CCCNC1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Yield: 2 %

Procedure:
To solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (300.0 mg, 0.569 mmol) in methanol (30 mL) was added 3-aminopropanenitrile (199.5 mg, 2.85 mmol). The resulting solution was stirred at room temperature for 3. Then NaBH3CN (71.56 mg, 1.14 mmol) was added. The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with ethyl acetate. The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/0.05% NH4HCO3=30% increasing to ACN/0.05% NH4HCO3=55% within 8 min; Detector, UV 254 nm. 6.7 mg product was obtained. This resulted in 6.7 mg (2%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 34) [M+H]+=581.4, RT=2.44 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.68-8.66 (m, 2H), 8.27 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d, 1H, J=8.1 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 5.45 (t, 1H, J=6.9 Hz), 4.80 (d, 2H, J=7.2 Hz), 2.79-2.72 (m, 3H), 2.71-2.57 (m, 5H), 2.10-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.23-1.16 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[O:22][C:21]2[C:16](=[C:17]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:18]=[CH:19][CH:20]=2)[O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[O:22][CH2:14][O:15][C:16]=34)[CH2:26][CH2:27]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: c1cc(CCC2CCNCC2)c2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2cc1CN1CCC(CCc2cccc3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 0.24 g of 2-oxo-1,2-dihydro-3-quinolinecarboxaldehyde and 0.3 g of 4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine. To the mixture were added 0.5 ml of acetic acid and 0.42 g of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature for 12 hours. An aqueous saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was collected by filtration, to give 130 mg of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[I:17]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:17][C:8]1[CH:7]=[C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)CC(C)(C)c1ccc(OC)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC(C)(C)c1ccc(OC)c(I)c1
Temperature: 25 °C

Procedure:
Methyl 3-(4-methoxyphenyl)-3-methylbutanoate (475 mg, 2.137 mmol) was dissolved in ethanol (20 mL). Iodine (542 mg, 2.137 mmol) and silver sulfate (666 mg, 2.137 mmol) were added and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was then diluted with ethyl acetate (40 mL) and filtered. The filtrate was washed with sodium bisulfite (2×50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford methyl 3-(3-iodo-4-methoxyphenyl)-3-methylbutanoate. 1H NMR (CDCl3, 500 MHz) δ 7.73 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.6, 2.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.55 (s, 3H), 2.57 (s, 2H), 1.41 (s, 6H).