Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([Cl:16])=[C:11]([F:17])[CH:10]=1)[CH2:2][CH2:3][CH3:4].C>[Br-].[Zn+2].[Br-].[Pd].CC(=O)OCC>[CH2:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([Cl:16])=[C:11]([F:17])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C=Cc1cc(F)c(Cl)c(F)c1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCc1cc(F)c(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-(4-chloro-3,5-difluoro-phenyl)-acrylic acid butyl ester (5.000 g; 18.202 mmol), zinc bromide (0.819 g; 3.640 mmol), and 10% palladium over activated charcoal (0.320 g) was placed under nitrogen before EA (140 ml) was added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 22 h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(4-chloro-3,5-difluoro-phenyl)-propionic acid butyl ester as a slightly yellow oil which was further dried under HV (5.020 g; 98%). LC-MS: tR=1.14 min.; [M+H]+: no ionisation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([OH:29])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([O:29][CH2:2][C:3]4[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=4)[C:6]#[N:7])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(COc2cc3n(n2)CCN(C(=O)c2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
3-(bromomethyl)benzonitrile (0.086 g, 0.44 mmol) was added to a stirred suspension of 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.105 g, 0.4 mmol) and Cs2CO3 (0.261 g, 0.8 mmol) in ACN (2 mL). The mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 3-[({5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl}oxy)methyl]benzonitrile (0.089 g, 59% yield) as a white solid. C21H17FN4O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.08 (br. s., 4 H), 4.74 (br. s., 2 H), 5.22 (s, 2 H), 5.51 (br. s., 1 H), 7.15 (t, J=8.5 Hz, 2 H), 7.44-7.51 (m, 3 H), 7.60 (d, J=7.8 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H), 7.74 (s, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[C:21]1([CH2:27][CH2:28][SH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:29][CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: SCCc1ccccc1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Product: Cc1c(SCCCSCCc2ccccc2)ccnc1CSc1ccncc1
Yield: 49 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-phenylethyl mercaptan gives, after silica gel chromatography and crystallization from diisopropyl ether, the title compound as a colorless powder; m.p. 48-50° C.; yield 49% of theory.
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:14])[CH3:13])[P:5](Cl)[O:6][CH2:7][CH2:8][C:9]#[N:10])([CH3:3])[CH3:2].[C:15]([O:18][CH:19]([O:58][C:59](=[O:61])[CH3:60])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([OH:57])[CH2:32][O:33][C:34]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)C(C)C)(C)C.O.C(OCC)(=O)C.CCCCCC>[C:15]([O:18][CH:19]([O:58][C:59](=[O:61])[CH3:60])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:57][P:5]([N:4]([CH:12]([CH3:14])[CH3:13])[CH:1]([CH3:3])[CH3:2])[O:6][CH2:7][CH2:8][C:9]#[N:10])[CH2:32][O:33][C:34]([C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: COc1ccc(C(OCC(O)CCCCOc2ccc(C(OC(C)=O)OC(C)=O)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C(OCC(CCCCOc2ccc(C(OC(C)=O)OC(C)=O)cc2)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Cyanoethyl diisopropylchlorophosphoramidite (0.49 ml, 2.19 mmol) was added to a solution of 9 (0.83 g, 1.29 mmol) dissolved in 32 ml of anhydrous methylene chloride containing 0.67 ml of N,N-diisopropylethylamine. The reaction solution was stirred for 1.0 h at 25° C. under argon and then treated with 1.0 ml of methanol and poured into 300 ml of 5% sodium bicarbonate solution. The mixture was extracted with ethyl acetate (300 ml) and the extract was dried over sodium sulfate and evaporated. The crude product was purified by silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexane (2% triethylamine). The pure phosphoramidite fractions were evaporated affording a homogenous oil: 0.61 g (56%) yield; TLC (1:1, ethyl acetate/hexane), Rf=0.62; 31P NMR (DMSO-d6) 147.82 (singlet). Anal. Calcd for C47H59N2O10P0.2 H2O: C, 66.68; H, 7.07; N, 3.31. Found: C, 66.46; H, 7.27; N, 2.94.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:50])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][C:36]=1[CH2:42][NH:43]C(OC(C)C)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:50])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:26])=[CH:37][C:36]=1[CH:42]([C:32]([O:31][CH:27]([CH3:29])[CH3:28])=[O:50])[NH2:43])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(N)C(=O)OC(C)C)c1
Yield: 127.1 %

Procedure:
Toluene-4-sulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (5.06 g, 11.6 mmol) and 3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (3.01 g, 8.92 mmol) were coupled using Standard procedure A to give the title compound as a white solid (3.41 g, 64%). MS [ES] m/z 601.603 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[NH:18][C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].S(Cl)([Cl:35])=O>C(OCC)(=O)C.ClCCl.CCCCCCC.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[NH:18][C:19](=[O:27])[CH:20]([Cl:35])[C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)ccc1NC(=O)CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)ccc1NC(=O)C(Cl)C(=O)C(C)(C)C
Temperature: -5 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Compound D (130 g, 0.344 mol) and anhydrous sodium acetate (42.4 g, 0.516 mol) were combined in 300 miL dichloromethane in a 1 L three-neck flask fitted with a thermometer, addition funnel, and a gas inlet/outlet tube connected to a water aspirator acting as a gas scrubber. The stirred slurry was cooled to −5° C. in an ice/acetone bath under nitrogen. Thionyl chloride (46.5 g, 0.344 mol) was added dropwise to the stirred slurry, keeping the temperature below 5° C. TLC (50:45:5 heptane: dichloromethane:ethyl acetate) at the end of the addition showed some starting material. An additional 4 g thionyl chloride was added in 1 g portions, analyzing for residual Compound D after each addition. The final TLC showed only product and a trace of the dichlorinated product. The reaction mixture was slowly partitioned between 500 mL ethyl acetate and 1 L water containing 40 g sodium acetate. The aqueous layer was extracted with 200 ethyl acetate. The ethyl acetate layers were combined with 200 mL more ethyl acetate, and the solution extracted with 2×300 mL brine. The solution was dried over MgSO4, filtered, and evaporated to an orange-brown oil. Heptane (250 mL) was added and the solution evaporated to remove some residual acetic acid. The oil was chromatographed through 0.9 L silica gel in a 1 L sintered glass filter funnel. Heptane: dichloromethane (2:8) was used to remove most of the product, and then dichloromethane to remove the rest. The combined product fractions were evaporated to an orange oil. The oil was dissolved in 250 mL heptane, seeded, and left at room temperature overnight. The mixture was then cooled for 30 min in an ice bath and filtered to give 125 g colorless solid. The filtrate was evaporated and the residue crystallized from 35 mL cold heptane to give an additional 6.0 g off-white solid, pure by TLC. Total yield compound E: 131 g, 92%.
Reaction SMILES: [N:1]12[CH2:8][C:5]([CH2:9][OH:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C([Li])CCC.CCCCCC.N1([C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[N:30]=2)=[O:28])C=CNC1>O1CCCC1>[N:1]12[CH2:8][C:5]([CH2:9][O:10][C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[N:30]=3)=[O:28])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Cn1nc(C(=O)N2C=CNC2)c2ccccc21
Reactant: OCC12CCCN(CC1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nc(C(=O)OCC23CCCN(CC2)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A cooled (0° C.) solution of 1-azabicyclo[3.2.1]oct-5-ylmethanol (1.70 g, 12 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was treated (via syringe) with 2.45N n-butyllithium/hexane (12 mmol), then stirred at room temperature for thirty minutes and concentrated in vacuo to remove all hexane. Anhydrous tetrahydrofuran (15 mL) was added, followed by 3-(3H-imidazol-1-ylcarbonyl)-1-methyl-1H-indazole (2.49 g, 11 mmol), and the mixture was stirred under nitrogen at room temperature for 18 hours, then at 60° C. for three hours, and concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (75 mL) and toluene (125 mL) containing some 2-propanol, and the organic layer was set aside. The aqueous solution was extracted with toluene (2×50 mL) containing some 2-propanol, and the combined organic solution was rinsed with water to remove imidazole, then dried azeotropically with toluene. The residue was filtered through alumina (eluted with 15% methanol/tetrahydrofuran), concentrated in vacuo, and triturated from ether/petroleum ethers (30°-60°), then recrystallized from ether/petroleum ethers (30°-60°) to afford 1.75 g (53%) of the product as a colorless solid; mp. 93°-95° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH:23]=[O:24])[CH3:21])[CH3:16]>>[CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH:23]([OH:24])[CH2:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:15]([CH3:14])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CBr)COCc1ccccc1
Reactant: CC(C)=CCCC(C)CC=O
Product: CC(C)=CCCC(C)CC(O)CC(C)COCc1ccccc1

Procedure:
This compound was prepared starting from the rac. 3-benzyloxy-2-methyl-1-propyl bromide and racemic citronellal using the procedure described in Example 4. Rac.-1-benzyloxy-2,6,10-trimethyl-9-undecen-4-ol was obtained as a colorless oil, b.p. 145°-150° C. (bath temperature) (0.01 mm Hg.)
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.IC1C=CC(C2N=[C:19]([C@H:23]([N:25](C)[C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)C)N(C)C=2)=CC=1.[C:37]([O-:40])([OH:39])=O.[Na+]>O1CCOCC1>[NH:25]([C:26]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])[C@@H:23]([C:37]([OH:40])=[O:39])[CH3:19]
Reactant: O=C([O-])O
Reactant: C[C@H](c1nc(-c2ccc(I)cc2)cn1C)N(C)C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC showed no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.Cl.COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: Cl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCNCC1)O2
Yield: 76.5 %

Procedure:
(E)-3-{1′-tert-Butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.20 g, 3.0 mmol) was deprotected with HCl according to the procedure for preparation of Intermediate 1, Step C, giving (E)-3-{-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (694 mg) as its hydrochloride salt.
Reaction SMILES: [I-].[K+].[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20]Cl)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>O1CCCC1>[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20][NH:32][CH:29]4[CH2:31][CH2:30]4)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, a potassium iodide and 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 7-(ethylthio)-1-[(cyclopropylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[O:19]CC1>CC#N>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:19]
Reactant: C1CCOC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
O,O-Dibenzoyl tartaric acid monohydrate (18.8 g, 50 mmole) was dissolved in 250 ml CH3CN and the solvent was removed in vacuo. This process was repeated. The resulting oil was dissolved in 250 ml THF and dicyclohexylcarbodiimide (DCC) (10.6 g, 50 mmole) dissolved in 50 ml THF was added. A precipitate started forming in a few minutes. After stirring for 18 hr at 20° C. the reaction mixture was filtered, and the precipitate washed with a little THF. The precipitate was then dried in high vacuum to give 10.8 g (100%, 50 mmole) dicyclohexylurea (DCHU). To the combined filtrate was added 2-(N-methyl)aminoethanol (4.0 ml, 50 mmole) and the reaction mixture was stirred for 1 hr at 20° C. Then, DCC (10.6 g, 50 mmole) in 50 ml THF was added; a small precipitate was formed. After about 1 hr, 2-(N-methyl)aminoethanol (4.0 ml, 50 mmole) was added and the reaction mixture stirred for 18 hours at 20° C.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.O>O1CCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C=C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1
Yield: 99 %

Procedure:
1,550 ml (2.0 mol) of a 1.29 M solution of vinylmagnesium chloride in tetrahydrofuran were introduced into a 4 l stirred flask under nitrogen. Subsequently, while stirring under nitrogen at 30°-35° C., a solution of 222.0 g (1,764 mol) of 4-fluorobenzaldehyde in 2,000 ml of tetrahydrofuran was added over the course of 30 min, cooling the reaction mixture with ice. The mixture was then stirred at room temperature under nitrogen for 2.5 h. Subsequently, while stirring and cooling with ice, 180 ml of water were added, the mixture was filtered with suction, and the residue from the filter was washed 3x with 150 ml of tetrahydrofuran. The filtrates were combined, dried with sodium sulfate and concentrated. 265.7 g (99%) of product were obtained in the form of a yellow-brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7]O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:25].[Li+]>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][Br:25])[CH3:2]
Reactant: [Br-]
Reactant: CCOc1ccccc1CCO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1.35 g (8.12 mmol) of 2-ethoxyphenethyl alcohol and 2.05 g (20.03 mmol) of triethylamine in 15 ml of dichloromethane was slowly added 1.86 g (16.24 mmol) of methanesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 2 h and was poured into 200 ml of mixed solution of hexanelether(1:1). It was washed with 30 ml of water, dried over MgSO4, filtered through a plug of silica gel and concentrated. The residue was dissolved in 30 ml of acetone and 2.82 g (32.48 mmol) of lithium bromide was added slowly at 0° C. The reaction mixture was refluxed for 5 h and volatiles were removed. The residue was added 150 ml of ether, washed with water (30 ml ×2), dried over MgSO4, filtered through a plug of silica gel and concentrated to give 2-ethoxyphenethyl bromide as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH2:36])[N:28]=1>CO.C(Cl)Cl>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH2:36])[N:28]=2)[N:10]=1
Reactant: NCCNc1ncc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(NCCNc2ncc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Yield: 60 %

Procedure:
Using the conditions described in Example 139, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]amine and 10.6 mg (0.061 mmol) of 2-chloro-5-nitro-6-aminopyridine afforded 191 mg (60%) of [4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine as a yellow solid following chromatography (silica gel, 5% methanol/methylene chloride).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].COCCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1nn(-c2ccccc2)cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: COCCO
Product: Nc1ccc(-c2cn(-c3ccccc3)nc2CC(=O)O)cc1

Procedure:
210 mg. of [4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl]acetic acid are reacted with 20 ml. of glycol monomethyl ether and 1 g. of Raney nickel and hydrogenated at room temperature under normal pressure. The reaction is worked up as described in Example 17(c). [4-(4-Aminophenyl)-1-phenyl-3-pyrazolyl]acetic acid is obtained.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([P:10](C(F)(F)C(F)(F)F)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])([F:9])[C:5]([F:8])([F:7])[F:6].Br>C(OCC)C>[F:3][C:4]([P:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[OH:1])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: CCOCC
Product: OP(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
29 mmol of a 1.5 molar aqueous sodium hydroxide solution are added to a solution of 5.2 g (13.3 mmol) of tris(pentafluoroethyl)phosphine in 50 ml of diethyl ether, and the mixture is stirred at room temperature for 15 minutes. After removal of the aqueous phase, 50 ml of 1,6-dibromohexane are added, and all volatile constituents are removed overnight in vacuo. The reaction mixture is reacted with 13 mmol of HBr, and the product is separated off from the reaction mixture by means of fractional condensation (3 cold traps at −30° C., −78° C. and −196° C.). The compound is stable at room temperature under inert-gas conditions.
Reaction SMILES: [F:1][C:2]([F:29])([S:25]([NH2:28])(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[OH-].[Li+:31]>O>[C:2]([S:25]([NH:28][Li:31])(=[O:27])=[O:26])([C:3]([C:4]([C:5]([C:6]([C:7]([C:8]([C:9]([F:12])([F:11])[F:10])([F:14])[F:13])([F:16])[F:15])([F:18])[F:17])([F:19])[F:20])([F:22])[F:21])([F:23])[F:24])([F:1])[F:29]
Reactant: [Li+]
Reactant: NS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Solvent: O
Product: [Li]NS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
49.4 g (0.099 mol) of perfluorooctane sulphonamide and 2.37 g (0.099 mol) of lithium hydroxide were introduced into 448 g of water and dissolved at ca. about 50° C. with stirring. A 10% solution of C8F17SO2NHLi was obtained.