Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)=[O:8]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of 5-bromo-2-hydroxy-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 5; 720 mg, 2.28 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (1102 mg, 7.97 mmol) and 4-fluorobenzyl bromide (0.62 ml, 5.01 mmol). The mixture was heated at 50° C. for 2 hours, cooled and the solvent removed in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (15 ml). The organic layer was separated, washed further with water (2×5 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column (SiO2, 6:1-1:1 cyclohexane/ethyl acetate) gave the product as a pale yellow oil. 544 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](O)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:38][O:39][C:40](=[O:52])[NH:41][CH:42]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH2:43]1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][CH:42]([NH:41][C:40]([O:39][CH3:38])=[O:52])[CH2:43]2)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC(=O)O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)NC1CNc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)C1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
8.88 ml of triethylamine are added to a solution of 6.67 g of 4(S)-(3-carboxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester in 200 ml of methylene chloride under argon. The mixture is cooled to 15° C. and 5.54 g of bis(2-oxo-3-oxazolidinyl)phosphinic chloride are added. The mixture is stirred at room temperature for 2 hours. A solution of 4.36 g of (1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester [177202-73-2] in 100 ml of methylene chloride is added, followed by addition of 2.11 g of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 17 hours. The mixture is poured into 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a slightly yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.39 (1:3 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]([N:11]([CH2:14]C)CC)C.Cl[PH:17][O:18][CH2:19]N(C)C>C1COCC1.C(Cl)Cl>[CH3:9][N:11]([P:17]([O:18][CH3:19])[C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: CN(C)COPCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COP(c1nc([N+](=O)[O-])n[nH]1)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.86 g, 25.1 mmol) and triethylamine (14.0 mL, 10.2 g, 101 mmol) in THF (40 mL) was added dropwise Chloro(N,N-dimethylamino)methoxyphosphine (3.55 g, 25.1 mmol) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a yellow oil (4.56 g, 83%) 31P NMR (CDCl3) δ 134.9.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1.[C:29](=O)=[O:30].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])N>C(#N)C>[CH2:1]([N:9]=[C:29]=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: O=C=O
Agent: NC(=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A Fischer-Porter bottle was charged with 0.65 g (5 mmol) of octyl amine, 1.17 g of P1 -tBu (5 mmol), 1 02 g (10 mmol) of triethylamine, 25 mL of acetonitrile and 154 mg (1 mmol) of biphenyl as an internal standard. The bottle was pressurized to 80 psig with carbon dioxide and the solution was stirred for 30 min. at room temperature. A second Fischer-Porter bottle was charged with 0.71 g (5 mmol) of phosphorus pentoxide, and 25 mL of acetonitrile then pressurized to 80 psig with CO2. The carbamate solution was added rapidly to the P2O5 suspension at room temperature causing the P2O5 to dissolve. An aliquot taken after three minutes gave a 22% yield of octyl isocyanate by G.C. analysis. The reaction was monitored for a total of 18 hrs during which time the yield of octyl isocyanate increased to a maximum of 27% (1 hr) and then steadily decreased with formation of the symmetric urea.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Product: COC(=O)COc1cc(C(=O)OC)nc2cc(Cl)ccc12

Procedure:
The purified methyl 7-chloro-4-hydroxy-2-quinolinecarboxylate was alkylated with methyl bromoacetate as described in example 2 to produce methyl 7-chloro-4- methoxycarbonylmethyloxy-2-quinolinecarboxylate as a white solid having a melting point of 153.5°-154.5° C.
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1cc(OC(C)=O)ccc1C#Cc1ccccc1
Reaction time: 1 h

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5(3H,4H)dione, the product of Example 1A, (10.0 g, 34 mmole) and acetic anhydride (25 mL) were placed in a 100 mL flask and heated at reflux overnight under argon. Heating was stopped and the reaction was treated with water (25 mL) and stirred for 1 hr. The reaction was poured into water and extracted with Et2O. The combined ether extracts were washed with water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to yield 9.4 g of crude product. Chromatography of the crude product over silica gel, using methylene chloride as eluent, gave 4.2 g of pure 1-[5-Acetoxy-2-(phenylethynyl)phenyl]-2-propanone product as a viscous oil.
Reaction SMILES: [CH2:1]([N:6]([CH2:12]Cl)[C:7](=[O:11])[CH:8]([Cl:10])[Cl:9])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:14]([O:16][CH2:17][CH2:18][OH:19])[CH3:15].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:1]([N:6]([CH2:12][O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:7](=[O:11])[CH:8]([Cl:10])[Cl:9])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN(CCl)C(=O)C(Cl)Cl
Reactant: CCOCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOCCOCN(CCC(C)C)C(=O)C(Cl)Cl

Procedure:
The solution of N-isopentyl-N-chloromethyldichloroacetamide (24.7 g., 0.1 mole) and 2-ethoxyethanol (9.9 g., 10.7 ml., 0.11 mole) in dry benzene (70 ml) is weighed in a four-necked, round-bottom flask of 250 ml, equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1 g., 13.9 ml., 0.1 mole) is added to this solution under stirring and cooling by water in such a rate that the temperature is maintained below 40° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×100 ml.) to remove triethylamine hydrochloride and the possible hydrophilic side-product, the benzene solution is dried over anhydrous sodium sulfate after distillation of the solvent and the residue is evaporated to dry under reduced pressure to give 27.9 g. (93%) of the named product as a pale yellow oil which is of 96% purity according to analysis by gas chromatography and is directly useful for practical purposes without any purification; nD25 =1.4649.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7]Br.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:17][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Product: CCCCNCCOc1cc(Cl)cc(Cl)c1
Product: Cl
Yield: 51.5 %

Procedure:
A solution of 33.76 g (0.126 mole) of 2-(3,5-dichlorophenoxy)-1-bromoethane in 200 ml of n-butylamine was stirred at 25° C. for 20 hr. The excess n-butylamine was evaporated in vacuo, and the residue was suspended in a mixture of dilute sodium hydroxide and shaken with methylene chloride. The methylene chloride layer was extracted in sequence with two additional portions of dilute sodium hydroxide, one of dilute sulfuric acid and once more with dilute sodium hydroxide. The volume of the methylene chloride layer was reduced to about 150 ml and excess ethereal hydrogen chloride was added. Addition of anhydrous ether gave a white precipitate which was collected and dried under high vacuum (78° C.) to give 19.35 g (51.5%) white crystals, m.p. 195°-196° C.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)N(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 7.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isopropyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.Br.CCOC(C)=O>CC(O)=O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2ccccc2)c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cccc(O)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
1458 g (6.9 mol) of (3-methoxyphenyl)(phenyl)methanone was dissolved in 2090 mL of AcOH. To the solution, 2320 ml (20.6 mol) of 48% HBr was added and the mixture was stirred at 90° C. for 18 hours. The reaction was monitored by TLC (AcOEt:hex 1:9). After reaction was completed the mixture was cooled down to RT and poured into ice with stirring. The precipitated solid was filtered, washed with water and dried yielding the title compound as a white solid (1234 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CI
Solvent: CCOCC
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3 M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:3]1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.N1CCCCC1.[CH2:34]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35]#[CH:36].C1C=CC=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:36]#[C:35][CH2:34][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:9][CH:8]=2)[CH2:3]1
Reactant: C#CCOCc1ccccc1
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Yield: 86 %

Procedure:
A round bottomed flask was charged with (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (30 g, 80 mmol), copper(I) iodide (0.153 g, 0.804 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.82 g, 4.02 mmol) and THF (200 mL). The reaction mixture was purged with nitrogen. After about 15 minutes piperidine (35.8 mL, 362 mmol) and ((prop-2-ynyloxy)methyl)benzene (11.75 g, 80 mmol) were added and the reaction mixture was heated to about 65°. After about 2 hours additional (prop-2-ynyloxy)methyl)benzene (11.75 g, 80 mmol) was added. After about 8 hours the crude reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried (Na2SO4) filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with EtOAC/Heptane followed by EtOAc/MeOH) to provide (1R,3R)-methyl 1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentanecarboxylate (25 g, 68.8 mmol, 86% yield) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].O.[C:9]1(C)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1.O>>[F:1][C:2]([F:7])([F:6])[C:3]([NH:5][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1[CH:24]=[CH:20][CH:21]=[C:22]([OH:23])[CH:14]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Reactant: NC(=O)C(F)(F)F
Solvent: O
Product: O=C(NCCCCc1cccc(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 107 (0.72 g, 2.08 mmol) and p-toluenesulfonic acid monohydrate (0.366 g) in THF: H2O (3:1, 20 mL) was stirred at room temperature for 3.5 hr. The reaction mixture was partitioned between aqueous NaHCO3-brine solution and EtOAc. Aqueous layer was aextracted with EtOAc. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc-hexanes gradient) gave 2,2,2-trifluoro-N-(4-(3-hydroxyphenyl)butyl)acetamide as a colorless oil. Yield (0.438 g, 96%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: Cn1c(N2CCCNCC2)nc2ccccc21
Product: Cn1c(N2CCCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-1-methyl-1H-benzimidazole.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][N:10]2[CH:14]([C:35](=[CH2:38])[CH2:36][CH3:37])[C:15]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:17][C:9]2=[N:8]1)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C:15]3([CH:14]([C:35](=[CH2:38])[CH2:36][CH3:37])[N:10]4[C:9](=[N:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[CH2:11]4)[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:32]2=[CH:31][CH:30]=1
Reactant: C=C(CC)C1N2CC(=O)N(CCOC(C)=O)N=C2CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(CC)C1N2CC(=O)N(CCO)N=C2CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of racemic (6′R, 3R, 8′S)-2′-(2-acetoxyethyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione (0.3 g, 0.54 mmol) prepared in example 7b in tetrahydrofuran (25 mL) and methanol (15 mL) was added sodium hydroxide aqueous solution (1N, 10 mL). the reaction mixture was stirred at room temperature for 2 h, then neutralized to “pH” 7 by aqueous HCl. The mixture was then extracted with ethyl acetate. The organic layer was separated, died over MgSO4, concentrated, and dried in vacuo to give racemic racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-hydroxyethyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione as a white solid (0.22 g, 79%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=2)[N:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([C:28]([C:31]([F:32])([F:34])[F:33])=[N:29][N:30]=4)[N:27]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(6-bromonaphthalen-2-yl)sulfonylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(6-bromonaphthalen-2-yl)sulfonylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.O>FC(C1C=CC=CC=1)(F)F.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:16])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(C)c(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: CC(=O)Oc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 4-methyl-3-(trifluoromethyl)phenyl acetate (6.04 g) and 75% benzoyl peroxide (0.45 g) in (trifluoromethyl)benzene (60 mL) was added N-bromosuccinimide (5.42 g), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.6 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([OH:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C([O-])([O-])=O.[K+].[K+].C(OCCO)C.Cl>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:14][C:13]1[C:12](=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:20])=[O:19])([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chlorobenzoic acid (100 g), anthranilic acid (90 g), anhydrous powered K2CO3 (135 g), Cu/CuO (2 g) and 2-ethoxyethanol (200 ml) was heated with swirling on the steam bath until gas evolution ceased and then stirred at 145° for a further 21/2 hours. The thick reaction mixture was diluted with water, acidified (HCl) and then the crude product was collected and washed well with hot water. This was dissolved in hot dilute aqueous Na2CO3 treated liberally with charcoal-celite and filtered through a celite pad. The hot filtrate was diluted with half the volume of EtOH and then slowly acidified (HCl). The pale yellow product which separated was collected when still warm, washed well with hot water, benzene and dried, providing material (84% yield) of sufficient purity for use in the next step (lit, m.p. 295° dec.).