Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH2:33][CH2:34][CH3:35].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CCCC=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 25 mg (0.061 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 1 mL chloroform was treated with 0.011 mL (0.12 mmol) butyraldehyde and 26 mg (0.12 mmol) NaBH3(CN) before 1 mL methanol was consequently added. The mixture was stirred at ambient temperature for 15 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 20 mL DCM, washed with 20 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 468 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([NH:8][CH:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[ClH:1].[C:2]1([NH:8][CH:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
2-(Phenylamino)-2-(thiophen-2-yl)acetic acid hydrochloride (I89) (359 mg, 1.33 mmol), DCC (330 mg, 1.60 mmol) and HOBT (245 mg, 1.60 mmol) are dissolved in THF (15 mL). (R)-quinuclidin-3-ol (339 mg, 2.66 mmol) is added and the reaction mixture is stirred at RT for 16 hours. HOBT (20.4 mg, 0.13 mmol) and DCC (33.0 mg, 0.16 mmol) are added again and the mixture is stirred for additional 8 hours. HOBT (20.4 mg, 0.13 mmol), DCC (33.0 mg, 0.16 mmol), (R)-quinuclidin-3-ol (16.9 mg, 0.13 mmol) are added and the mixture is stirred for additional 16 hours. THF is evaporated and the resulting crude oil is dissolved in EtOAc and washed with water and brine. The organic phase is recovered, dried over Na2SO4, filtered and evaporated. The crude is first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The pure fractions are collected and evaporated. The resulting TFA salt is dissolved in THF and passed through a PL-HCO3 cartridge (Varian, 200 mg, 1.8 mmol/g HCO3−). THF is evaporated, the product is dissolved in dioxane (2 mL) and 4M HCl in dioxane (2 mL) is added. The solvent is evaporated and the residue is dried under vacuum for 24 h to obtain the title compound as a brown solid (33 mg, 7% yield, mixture of disateroisomers).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH2:5][CH3:6].[CH3:21][O:22]N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC>>[CH3:21][O:22][C:19]1[CH:20]=[C:15]([C:2](=[O:1])[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH2:4][CH2:5][CH3:6])[CH:16]=[CH:17][CH:18]=1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91c) from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96 mmol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10]2)=[CH:6][CH:5]=1.IC.[CH2:20](O)C>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]2[CH3:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1.8 g (45 mmol) of 60% sodium hydride (washed beforehand with petroleum ether) and of 8.0 g (35.8 mmol) of ethyl 6-chloro-1H-indole-2-carboxylate in 80 ml of N,N-dimethylformamide is stirred for 2 h at room temperature, 2.8 ml (45 mmol) of iodomethane are subsequently added and the mixture is stirred at room temperature for 4 h. 5 ml of absolute ethanol are added and the solvent is evaporated under reduced pressure. The residue is taken up in water and the mixture is extracted with dichloromethane, the organic phase is dried and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 8.5 g (35.7 mmol) of a white crystalline compound are isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1)=[O:25]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3-fluoro-phenyl)boronic acid (0.7698 g, 0.005502 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform (18×125 mL), 1.221 g of 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 99-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16](=O)[CH2:17]Br)[C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][NH:21][C:22]([NH2:24])=[S:23]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[N:24]=[C:22]([NH:21][CH3:20])[S:23][CH:17]=3)[C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(N)=S
Reactant: COC(=O)c1ccc2cc(C(=O)CBr)c(=O)[nH]c2c1
Solvent: CO
Product: CNc1nc(-c2cc3ccc(C(=O)OC)cc3[nH]c2=O)cs1

Procedure:
This compound was made analogous to Example 8733, step G. 3-(2-Bromo-acetyl)-2-oxo-1,2-dihydro-quinoline-7-carboxylic acid methyl ester (497 mg, 1.5 mmol) and 1-methyl-2-thiourea (130 mg, 1.4 mmol) in MeOH were heated to 150° C. for 400 seconds in the microwave. MS m/z: 316 (M+1), 314 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25].Cl.[NH:27]1[CH2:32][CH:31]=[CH:30][CH2:29][CH:28]1C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:27]4[CH:32]([CH2:31][CH:30]=[CH:29][CH2:28]4)[CH:21]4[C:20](=[O:25])[N:19]([CH3:18])[C:23](=[O:24])[CH:22]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Reactant: O=C(O)C1CC=CCN1
Agent: Cl
Product: CN1C(=O)C2C(C1=O)C1CC=CCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
The title compound is prepared analogously from 100 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 49 mg of N-methylmaleimide and 58 mg of 1,2,3,6-tetrahydropyridine-2-carboxylic acid hydrochloride. The crude product is purified by column chromatography (silica gel, MeOH:DCM=2:98). In this manner, 3 pure fractions are isolated as racemic mixtures.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][N:5]=1.[BH4-].[Na+].O>CO>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1ccnc(Br)c1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-bromo-pyridine-4-carbaldehyde (904 mg, 4.86 mmol) was dissolved in MeOH (10 mL). NaBH4 (236 mg, 5.99 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3×20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. TLC: rf (1:1 hept-EA)=0.22. LC-MS-conditions 02: tR=0.63 min; [M+H]+=188.33.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: N
Solvent: ClCCl
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid* (0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.24 g, 1.47 mmol) in dichloromethane was stirred for 45 minutes before the addition of ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reaction mixture was stirred for 2 hours, solvent removed under reduced pressure and residue was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford the title compound (0.091 g, 36% yield). LC/MS: (PS-A2) Rt 3.08 [M+H]+ 339.93. *This starting material can be made by the method described in Example 8A through to 8C.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=O)[CH2:8][C:9]([CH3:21])([CH3:20])[O:10]2.[BH4-].[Na+]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:20])([CH3:21])[O:10]2
Reactant: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)C=C2
Reaction time: 2 h
Yield: 85 %

Procedure:
In a mixture of 60 ml of tetrahydrofuran and 40 ml of methanol 5.6 g (20 millimoles) of 5-methoxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 1.5 g (40 millimoles) of sodium tetrahydroborate are added in small portions and the reaction mixture is heated to boiling for 2 hours. The reaction mixture is worked up according to Example 31. The product is purified by column chromatography. Thus 4.4 g of the desired compound are obtained in the form of a light yellow oil, yield 85%.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].C([Li])CCC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C(OCC)C.O1CCCC1.CCCCCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc([Si](C)(C)C)cc(C)c1Br
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromo-1,3-dimethylbenzene (500 mg) in diethylether (3 mL) and tetrahydrofuran (2.5 mL) is cooled to −78° C. and treated dropwise with n-butyllithium (200 μL of a 10 M solution in n-hexane). The mixture is stirred for 1 hour and treated dropwise with chloro-trimethyl-silane (275 μL). After stirring for 2 hours the reaction is quenched by addition of saturated aqueous NH4Cl solution. The mixture is extracted with diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→90:10) to give the title compound. Yield: 260 mg; Mass spectrum (ESI+): m/z=279 [M+Na]+.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C(N(CC)CC)C.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[C:23]=1[CH2:32][O:33][CH3:34])(=[O:21])=[O:20]>C(Cl)Cl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:23]([CH2:32][O:33][CH3:34])[C:24]=2[CH3:31])=[CH:3]1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 0 °C
Yield: 101.6 %

Procedure:
0.8 g (5.8 mmols) of bicyclo[3.2.1]octan-2,4-dione (the preparation thereof is described for example in U.S. Pat. No. 5,608,101 and in the references cited therein) are dissolved in 15 ml of methylene chloride at 20° C. The solution is mixed with 0.97 ml of triethylamine and cooled to a temperature of 0° C. Then, a solution of 1.6 g (5.8 mmols) of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid chloride in 10 ml of methylene chloride is added dropwise. The reaction mixture is stirred for half an hour at a temperature of 0° C. and is subsequently diluted with methylene chloride. After washing and drying, the organic phase is concentrated by evaporation. 2.23 g of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl-ester is obtained in amorphous form. This can be used for the next step without purification.
Reaction SMILES: CSC.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([O:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[CH3:20][CH:7]1[CH:8]=[CH:9][N:4]([C:17]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH:5]=[CH:6]1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CSC
Product: CC1C=CN(C(=O)Oc2ccccc2)C=C1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
In a dry 500 ml three neck flask under nitrogen, a solution of cuprous iodide (0.28 g, 1.5 mmol) and dimethyl sulfide (8 ml) in 30 ml of dry THF was stirred at room temperature for 10 minutes. Pyridine (2.43 ml, 30 mmol) in 120 ml of dry THF was added to the reaction, then cooled to -25° C. Phenylchloroformate (3.9 ml, 30 mmol) in 10 ml dry THF was added to the reaction via an addition funnel (a thick brown precipitate formed immediately upon addition). The mixture was stirred for 15 minutes. Methyl magnesium chloride (10 ml, 30 mmol) was added to the mixture via syringe whereupon the brown precipitate dissolved. The reaction was stirred at -25° C. for 20 minutes then stirred at room temperature for 20 minutes. 20% NH4Cl(aq) (70 ml) was added to the reaction. The mixture was then extracted with 150 ml diethyl ether. The organic extract was then washed with 40 ml portions of 20% NH4Cl(aq) /NH4OH (1:1), water, 10% HCl(aq), water, and brine. The organic layer was then dried over NaCl/Na2SO4, filtered, and concentrated to yield 5.9 g of a yellow oil. Kugelrohr distillation (bp. 150°-170° C., 1 mmHg) to yield 4.9 g (77%) of the desired compound (A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH3:22][C:23]([CH3:30])([CH3:29])[C:24](=O)[CH2:25][C:26]#[N:27]>Cl.O.CCO>[NH2:27][C:26]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][NH:6][C:5]3=[O:12])[N:13]=[C:24]([C:23]([CH3:30])([CH3:29])[CH3:22])[CH:25]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2nc[nH]c(=O)c2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3nc[nH]c(=O)c3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a suspension of 6-aminoquinazolin-4(3H)-one (3.07 g, 19.0 mmol, 1.0 eq) in conc. HCl (30.0 ml) at 0° C. was added dropwise NaNO2 (1.51 g, 21.9 mmol, 1.15 eq) as a solution in H2O (20.0 ml). The resulting mixture was stirred at 0° C. for 1 h, and then treated with a solution of SnCl2.2H2O (18.5 g, 81.9 mmol, 4.30 eq) in conc. HCl (20.0 ml). The reaction was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction was diluted with EtOH (200 ml), treated with 4,4-dimethyl-3-oxopentanenitrile (3.10 g, 24.8 mmol, 1.30 eq), heated at reflux overnight, then cooled to RT and concentrated. The residue was diluted with EtOAc (100 mL), then stirred in an ice/H2O bath and made basic (pH 8) with solid NaOH. The mixture was filtered through Celite®, washed with H2O (50 mL) and then EtOAc (100 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated to yield a yellow solid, which was triturated from Et2O (100 ml) to yield 6-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (1.2 g, 22% yield). MS (ESI) m/e (M+H+) 284.2
Reaction SMILES: [C:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)#[CH:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C-:14]1([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2]>>[C-:3]1([C:1]#[C:2][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C-:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:13]
Reactant: C#C[c-]1cccc1
Reactant: Ic1cccc(C#C[c-]2cccc2)c1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: C(#C[c-]1cccc1)c1cccc(C#C[c-]2cccc2)c1

Procedure:
Example 11 describes the procedure for producing 1,3-bis(ferrocenylethynyl)benzene 516. Ethynylferrocene 500 was reacted with 1,3-diiodobenzene 502 to form 1-(ferrocenylethynyl)-3-iodobenzene 504. Sufficient ethynylferrocene 500 was present such that the second step of the reaction immediately proceeded. 1-(Ferrocenylethynyl)-3-iodobenzene 504 reacted with ethynylferrocene 514 to form 1,3-bis(ferrocenylethynyl)benzene 516. The reaction procedure is shown in FIG. 5.
Reaction SMILES: [CH3:1][CH:2]([C:7](OC)=O)[C:3]([O:5]C)=[O:4].[Na].[C:12]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2CBr)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O>[C:12]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:7][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)C(=O)OC
Reactant: BrCc1ccccc1-c1cccc2ccccc12
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1cccc2ccccc12)C(=O)O
Temperature: 130 °C

Procedure:
75 g (0.43 mmol) of dimethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH are added dropwise at room temperature to 10 g (0.43 mmol) of sodium in 100 cm3 of H2O-free EtOH. Subsequently, 140 g (0.43 mmol) of 7 in 200 cm3 of H2O-free EtOH were added dropwise and the mixture was heated under reflux for 3 hours. 85 g (1.3 mol) of KOH dissolved in 100 cm3 of H2O were added at room temperature and the mixture was heated under reflux for a further 4 hours. The solvents were removed under reduced pressure, the residue was admixed with H2O until completely dissolved and acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated at 130° C. for 1 hour. This gave 96 g (77%) of 8 as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2ncccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc2ncccc2n1

Procedure:
The title compound (0.48 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.59 g) and 2-chloro-1,5-naphthyridine Rapoport, et al J. Org. Chem (1971), 36(3), 450-4 (0.40 g) according to the method of D30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61].N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:59]([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:31])[N:10]1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[OH:38]
Reactant: O=C(NCCc1cccc(O)c1)C1c2ccccc2C(=O)N(C2CCCCC2O)C1c1ccc(Cl)cc1Cl
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 121 %

Procedure:
To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl (2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethyl azodicarboxylate at room temperature, followed by stifling for 12 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 1460 mg of tert-butyl (2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(F)c(Cl)c2)CCNC1
Reaction time: 5 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3-chloro-4-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (0.87 g, 2.77 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 5 h. Yield: 0.31 g. MS m/z (rel. intensity, 70 eV) 215 (M+, 72), 157 (bp), 133 (53), 130 (62), 129 (98).