Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[N:10][N:9]([CH3:12])[C:8]=2[CH:13]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CC1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:3]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cn1nnc2ccc(C(Br)c3ccc(Cl)cc3)cc21
Reactant: c1c[nH]cn1
Agent: Br
Solvent: Cc1ccccc1
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3ccnc3)cc21
Temperature: 80 °C
Yield: 29.7 %

Procedure:
A solution of 203 parts of 6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole monohydrobromide and 170 parts of 1H-imidazole in 1350 parts of methylbenzene was stirred for 28 hours at reflux temperature. The reaction mixture was allowed to cool to 80° C. and then evaporated. The oily residue was dissolved in dichloromethane. The organic layer was washed with a diluted hydrochloric acid solution. The separated aqueous layer was treated with a sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane layers were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. To the residue were added 210 parts of 1,1'-oxybisethane and the whole was allowed to stand over weekend. The solid product was filtered off and dried at 50° C., yielding 48.1 parts (29.7%) of 6-[(4-chlorophenyl)(1H-imidazol-1 -yl)methyl]-1-methyl-1H-benzotriazole; mp. 87.7° C. (compound 63).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:20][CH2:19]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[ClH:17].[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][N:31]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
(R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (442 mg) described in Preparation Example 37, 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (435 mg) described in Preparation Example 48 and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (829 mg) were dissolved in chloroform (3 mL) and methanol (3 mL), N-methylmorpholine (220 μL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate). The obtained compound was dissolved in ethyl acetate (20 mL), 4N hydrogen chloride/ethyl acetate (0.5 mL) was added, and the mixture was filtered to give the title compound (652 mg).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:16][CH2:15][CH2:14][C:6]2([CH:11]=[CH:10][CH2:9][CH2:8][C:7]2([CH3:13])[CH3:12])[CH2:5]1.Cl>C(#N)C.[Cl-].[Na+].O>[CH3:12][C:7]1([CH3:13])[C:6]2([CH2:5][CH:4]([CH:3]=[O:2])[CH2:16][CH2:15][CH2:14]2)[CH:11]=[CH:10][CH2:9][CH2:8]1
Reactant: COC=C1CCCC2(C=CCCC2(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCC=CC12CCCC(C=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 8-(1-methoxymethylidene)-5,5-dimethyl-spiro[5.5]undec-1-ene (240 mg) obtained in Step 6 in acetonitrile (6 mL) was added 1N aqueous hydrochloric acid solution (1.1 mL), followed by stirring the reaction mixture at room temperature for 3 hours. Then, after addition of saturated brine, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in a mixed solution of methanol (5.4 mL)-water (0.6 mL). To the solution was added potassium carbonate (150 mg), followed by stirring the reaction mixture at room temperature for 2 hours. Then, after addition of water, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=40:1) to give 11,11-dimethyl-spiro[5.5]undec-7-ene-2-carbaldehyde (195 mg).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([NH:22][N+:23]([O-:25])=[O:24])=[NH:21])=[CH:14][N:13]=1.CCCCCC>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([N:21]=[CH:4][N:5]([CH3:7])[CH3:6])=[N:22][N+:23]([O-:25])=[O:24])=[CH:14][N:13]=1
Reactant: CN(Cc1ccc(Cl)nc1)C(=N)N[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CN(C)C=NC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 130 °C

Procedure:
Variant a): 1.5 g of N,N-dimethylformamide-diethyl-acetal are added to 2.43 g of N-(2-chloropyrid-5-ylmethyl)-N-methyl-N'-nitroguanidine in 75 ml of dioxane. The mixture is heated at 130° C. for 45 minutes and is then freed of solvent using a rotary evaporator. The crude product is chromatographed over silica gel using first ethyl acetate and then ethyl acetate/ethanol (5:1). A viscous oil is formed which, after the addition of hexane, yields crystals of the desired product (m.p.: 85°-89° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH2:33])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19].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>CN(C=O)C>[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH:33][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:17][CH:16]=3)[CH:12]=2)=[O:15])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cnn(Cc2ccc(CO)cc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
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(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carboxylic acid (220 mg, 0.95 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (238 mg, 0.95 mmol), HATU (7206 mg, 1.90 mmol) and DIPEA (0.64 mL, 2.84 mmol) in 5 mL DMF was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, dissolved in ethylacetate and extracted with aq. NaHCO3-solution. The organic layer was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). LCMS (method A) RtA=1.243 min; [M+H]+=466.0.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:51]=[CH:50][CH:49]=[CH:48][C:28]=1[CH2:29][CH2:30][C:31]1[N:32]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[C:33]([C:36]([O:38]CC)=[O:37])=[CH:34][N:35]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:51]=[CH:50][CH:49]=[CH:48][C:28]=1[CH2:29][CH2:30][C:31]1[N:32]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[C:33]([C:36]([OH:38])=[O:37])=[CH:34][N:35]=1
Reactant: CCOC(=O)c1cnc(CCc2ccccc2F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(CCc2ccccc2F)n1-c1ccc(F)cc1

Procedure:
2-(2-Fluorophenethyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (45) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-(2-fluorophenethyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (44) (222 mg, 0.62 mmol), lithium hydroxide (60 mg, 2.5 mmol), THF (1.0 mL), methanol (1.0 mL), and water (2 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[CH:9]=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14].[Br:17]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].[NH4+].[OH-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[C:9]([Br:17])=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14]
Reactant: BrBr
Reactant: COc1c2occc2cc2ccc(=O)oc12
Agent: O=S([O-])([O-])=S
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c2occc2c(Br)c2ccc(=O)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
8-methoxypsoralen (8-MOP, Aldrich, Milwaukee, Wis., 0.75 g, 3.5 m mol) was dissolved in tetrahydrofuran (THF, 75 mL), Bromine (1.5 mL, 3.5 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for overnight. 10% Sodium thiosulfate (5 mL) was added and the solution was basified using conc. aqueous NH4OH, and then extracted twice with chloroform. The organic layer was recrystallized from chloroform to give the product 5-bromo-8-methoxypsoralen (0.75 g, 73.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1I.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1B(O)O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCSc1ccc(I)c(Cl)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Product: CCSc1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and the product from example 16 step (ii). Yield 3.64 g
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:13][CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)=[O:5]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1Cl)N1CCc2ccccc2C1

Procedure:
26.08 g of 2-chlorobenzoyl chloride were reacted with 44.33 g (0.6 mol) of 1,2,3,4-tetrahydroisoquinoline in chloroform overnight, whilst stirring. After the chloroform had been driven off, the resulting solid was recrystallised from isopropyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[C:18]([CH3:20])[CH:19]=3)=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]N2C(C)=CC(I)=N2)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[C:18]([CH3:20])[N:17]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:22][CH:23]=1
Reactant: Cc1cc(I)nn1CCc1ccc(F)cc1
Reactant: Cc1cc(-c2nc(C)c(C(=O)NCc3ccc(F)cc3)s2)[nH]n1
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-[5-methyl-2H-pyrazol-3-yl]-thiazole-5-carboxylic acid 4-fluoro-benzylamide and 1-[2-(4-fluoro-phenyl)-ethyl]-3-iodo-5-methyl-1H-pyrazole as described in Example 93 and isolated as a white solid (0.035 g, 14% yield). 1H NMR (400 MHz, CDCl3) δ 7.23-7.27 (m, 2H), 6.98 (t, J=8 Hz, 2H), 6.82-6.90 (m, 4H), 6.41 (s, 1H), 5.92-6.00 (bm, 1H), 4.50 (d, J=4 Hz, 2H), 4.15 (t, J=6 Hz, 2H), 3.05 (t, J=6, 2H), 2.68 (s, 3H), 1.84 (s, 3H); MS (M+H)+=452.9; Rt=1.56 min; HRMS (M+H)+=453.16.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13])[CH3:15]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)CN1CCC(O)C1=O

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 3.7 g of 2-(diethylamino)ethylamine are heated to 95°-100° for 3.5 hours under nitrogen. The mixture is chromatographed on 45 g of aluminum oxide (neutral, activity grade III). The crude (R/S)-N-[2-(diethylamino)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride and ethyl acetate is again chromatographed on 25 g of aluminum oxide (neutral, activity grade III). The product which is eluted with ethyl acetate and ethanol is distilled in a bulb-tube at about 250°/0.03 mmHg.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:2])[CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Reactant: NC1CC1
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CC1
Yield: 30 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (32 mg, 30%) which was obtained as a white solid. MS: m/e=403.2 [M+H]+.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Mg])=[CH:14][CH:13]=1>C1COCC1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc([Mg])cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A 1-litre reactor is charged under nitrogen with cyanuric chloride (36.9 g, 0.2 mol) and then with 50 ml of THF. The suspension is cooled to 5-10° C. With stirring, at a temperature of less than 10° C., a 0.5M solution of para-methoxyphenylmagnesium in THF (400 ml, 0.2 mol) is run in under inert gas over 45 minutes. The reaction mixture is left to stand overnight. The solvent is evaporated on a rotary evaporator. The residue is poured into acidified water. Following extraction with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. The solvent is evaporated. The crude solid obtained is triturated with isopropanol and then filtered. The solid is dissolved in hot toluene. Addition of the same volume of heptane precipitates the product. The precipitate is cooled, isolated by filtration and dried. This gives 31.7 g (yield: 62%) of 2,4-dichloro-6-(4-methoxyphenyl)[1,3,5]triazine in the form of a beige powder (m.p. 133-136° C.), which is used as it is in the following step.
Reaction SMILES: C([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[C:22]([O:29][P:30]([O:40]CC2C=CC=CC=2)([O:32]CC2C=CC=CC=2)=[O:31])[CH:21]=1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[C].[Pd].C(O)C>[P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[C:22]([O:29][P:30]([OH:32])([OH:40])=[O:31])[CH:21]=1)([OH:11])([OH:10])=[O:8]
Reactant: CC(C)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(OP(=O)(O)O)cc1OP(=O)(O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To an ethanol solution (10 ml) of 1,3-bis(dibenzylphosphonooxy)-4-isopropylbenzene (1.01 g), 5% palladium-carbon (50% water-containing product) (109 mg) was added and stirred under a hydrogen atmosphere at room temperature for 14 hours. After the removal of the catalyst by filtration, the filtrate was concentrated, to give the title compound (464 mg, yield: 100%) as a yellow paste.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:8]([CH2:22][O:23][CH3:24])=[N:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[O:6]>C1COCC1>[CH3:24][O:23][CH2:22][C:8]1[C:7]([C:5]([OH:6])=[O:4])=[C:16]([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:13][CH:14]=2)[N:9]=1
Reactant: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A 2M aq. LiOH sol. (9.3 ml) was added to a solution of 980 mg (3.1 mmol) 2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid methyl ester in THF (25 ml) and the mixture was subsequently heated to 60° C. for 16 h. The THF was removed as far as possible in a vacuum and the obtained aqueous solution was washed with ether, the pH was set to 2 with 2M hydrochloric acid and dilution was performed with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 612 mg (2.0 mmol, 66%) 2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:2]12.[I-].[Na+]>>[C:2]1(=[O:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CCCCCCCC2OC2CCCCCC1
Agent: [I-]
Agent: [Na+]
Product: O=C1CCCCCCC=CCCCCCCC1
Yield: 81 %

Procedure:
11.8 g of 1,2-epoxy-cyclohexadec-9-ene, 5 ml of N,N'-dimethyl ethylene urea and 0.5 g of sodium iodide were stirred at 200° C. for 6 hours. The result was 81% yield of cyclohexadec-8-en-1-one.
Reaction SMILES: [C@@H:1]12[NH:7][C@@H:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10]C)=[O:9])[CH:2]2[C:12]([O:14]C)=[O:13].[OH-].[Na+].[C:18](ON1C(=O)CCC1=O)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(Cl)Cl.CO>O.CC(C)=O>[CH2:21]([O:20][C:18]([N:7]1[C@H:4]2[CH2:5][CH2:6][C@@H:1]1[CH:2]([C:12]([OH:14])=[O:13])[CH:3]2[C:8]([OH:10])=[O:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1C(C(=O)OC)[C@H]2CC[C@@H]1N2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O)C1C(C(=O)O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(1R,4S)-dimethyl 7-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (LXIX) (2.46 g, 9.86 mmol) was suspended in water (50 mL) and aq. 1 M NaOH was added to adjust the suspension to pH 12. To this mixture was added a solution of CBz-OSu (2.70 g, 10.84 mmol) in acetone (50 mL) and the reaction mixture was stirred overnight at room temperature. An additional portion of aqueous 4 M NaOH was added to adjust the mixture to pH 14, and the mixture was stirred for another 4 hours at room temperature. The acetone was removed under vacuum and aqueous residue was washed with Et2O (×2). The aqueous layer was acidified to pH 3 using 6 M HCl and extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by silica gel chromatography using 100% DCM then DCM/MeOH 200/1→100/1 to give (1R,4S)-7-(benzyloxycarbonyl)-7-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (L) as a white foam (2.33 g, 7.30 mmol, 74% yield). 1H NMR (CDCl3) δ ppm 1.57 (brs, 2H), 1.75 (brs, 1H), 1.87 (brs, 1H), 3.03 (brs, 1H), 3.60 (brs, 1H), 4.67 (brs, 2H), 5.08 (brs, 2H), 7.03 (brs, 5H), 8.60 (brs, 2H); ESIMS found for C16H17NO6 m/z 342 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CS(C)=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:24][CH2:25][CH2:26][Cl:27])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Temperature: 0 °C

Procedure:
First, 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (131.5 g, 0.6 mol) is suspended in dimethylsulphoxide (900 ml) and potassium tert. butoxide (80.8 g, 0.72 mol) is added with stirring. After 10 minutes the resulting solution is added dropwise, while cooling with ice water, to 1-bromo-3-chloropropane (77 ml, 0.72 mol) in dimethylsulphoxide (300 ml).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O>[C:17]([CH:16]=[CH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:6]2[C:7](=[O:8])[C:2]([Cl:1])=[N:3][S:4][N:5]=2)=[CH:21][CH:20]=1)([OH:19])=[O:18]
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C=Cc1ccc(Oc2nsnc(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred suspension of 14.6 grams (0.08 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 350 ml of water was added dropwise a previously prepared solution of 13.1 grams (0.08 mole) of p-hydroxycinnamic acid in 80 ml of aqueous 1 N sodium hydroxide. The reaction mixture was stirred for 2 hours at ambient temperature, then acidified with aqueous 6 N hydrochloric acid. A yellow precipitate was collected by vacuum filtration and washed with water, then dried for 5 hours/50° C. The solid was triturated with hot ethanol and collected by vacuum filtration, to give 23.3 grams (93.8%) of 3-[4-(2-carboxyethenyl)phenoxy]-5-chloro-4H-1,2,6-thiadiazin-4-one; m.p. >280° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 3,3-bis(4-fluorophenyl)acrylate, prepared in the previous step, and palladium (10% weight on carbon, 2.68 g, 25.2 mmol) under a nitrogen atmosphere was added EtOH (100 mL). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was filtered through a pad of Celite and concentrated to give ethyl 3,3-bis(4-fluorophenyl)propanoate which was used in the next step without further purification.