Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)CC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(4-methyl-1-pentenyl)pyridine (Example 28) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H), 4.33 (d, J=5 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.22 (sept, J=6.6 Hz, 1 H), 2.23 (m, 2 H), 1.38 (m, 1 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.27 (m, 1 H), 1.17 (m, 1 H), 1.00 (m, 3 H), 0.76 (d, J=6.6 Hz, 6 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.63; H, 9.39; N, 3.58. mp 101-103° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:27](OC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH2:23][C:24]([NH2:26])=[O:25])=[O:20])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH:21]([C:19]([O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)=[O:20])[C@H:22]([C:27]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])[CH2:23][C:24](=[O:25])[NH2:26]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 19 h

Procedure:
16.7 g of H-Leu-OMe and 46.0 g of Z-Asn-ONP are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is allowed to stand for 19 hours at 25° C. Thereafter 1.2 liters of water are added and the crystalline precipitate is filtered off. The dipeptide derivative is dried at 40° C. in vacuo and is then twice recrystallised from methanol-water. Melting point 180°-181° C.; [α]D20 = +9° (c = 2.05 in chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([OH:9])=[CH:6][C:7]=1[F:8].[C:11]1([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(Cl)Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:10][C:4]=2[CH:3]=1
Reactant: Oc1cc(F)c(Br)cc1O
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Solvent: CO
Product: Fc1cc2c(cc1Br)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-5-fluoro-benzene-1,2-diol (12 g, 58.0 mmol) and diphenyldichloromethane (1.2 eq., 16.50 g) was stirred at room temperature until gaseous evolution ceased. The mixture was heated with stirring at 180° C. for 20 min. The reaction mixture was allowed to cool to room temperature, diluted with methanol (50 ml) and vigorously stirred. The precipitated product was collected by filtration and dissolved in toluene (50 ml). Methanol (100 ml) was added and the mixture stirred 30 min at room temperature. The precipitated product was collected by filtration (yield 10.3 g, 48%), a further batch (6.4 g, 30%) was recovered from the mother liquors.
Reaction SMILES: [H][H].[ClH:3].[C:4]([CH2:6][CH:7]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)#[N:5]>C(O)C>[ClH:3].[C:4]([CH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)#[N:5]
Reactant: N#CCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Product: N#CCC1CCNC1
Yield: 95 %

Procedure:
Catalytic debenzylation, in the presence of hydrogen and palladised carbon, of 3-cyanomethyl-1-benzylpyrrolidine hydrochloride, in ethanol, makes it possible to obtain the desired compound.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:27]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Product: COc1ccc(Cn2c(C)cc3c2C(C)CN(Cc2ccccc2)C3)cc1

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl 5-methyl-4-piperidone may be reacted with p-methoxybenzylamine to give thetitle compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)=[O:12]>>[Br:19][C:15]1[CH:14]=[C:13]([C:11]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)([OH:12])[CH3:10])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CC(=O)c1cccc(Br)c1
Product: Cc1cccc(C(C)(O)c2cccc(Br)c2)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the reaction of 3-methyl phenylmagnesium bromide with 3-bromoacetophenone yielded the 1-(3-bromo-phenyl)-1-m-tolyl-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 66% of theory) as a colourless oil. TLC: Rf: 0.83 (silica gel; heptane:ethyl acetate=4:1, UV, 254 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28]Br)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH3:32][NH:33][CH3:34]>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][N:33]([CH3:34])[CH3:32])[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: CNC
Reactant: COc1cc(C2=C(c3cn(CCCBr)c4ccccc34)C(=O)NC2=O)c2occc2c1
Solvent: CN1CCCC1=O
Product: COc1cc(C2=C(c3cn(CCCN(C)C)c4ccccc34)C(=O)NC2=O)c2occc2c1
Temperature: 60 °C

Procedure:
Dissolve 3-(5-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.058 g, 0.118 mmol) in 10 mL dichloromethane. Add carbon tetrabromide (0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent). Stir for 10 min, add another equivalent of both reagents. Stir 10 min then dilute with dichloromethane and wash with water followed by brine. Dry over magnesium sulfate then filter and concentrate. Purification by column chromatography (2% methanol:dichloromethane) affords the 3-(5-methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl)pyrrole-2,5-dione. 3-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dione is dissolved in 1.5 mL 1-methyl-2-pyrrolidinone and add dimethylamine (2M solution in tetrahydrofuran, 0.3 mL, 5 equivalents). Heat to 60° C. for 16 hrs. Extract with ethyl acetate versus water, concentrate organic layer. Redissolve in a minimal amount of methanol and load onto an SCX™ Varian column (pretreated with a 5% acetic acid: methanol solution). Wash with methanol and ethyl acetate to remove impurities, flush with 2M ammonia methanol to recover product. ES(M++H)444.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1>ClCCl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccc2cc[nH]c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a dissolved solution of (1H-Indol-6-yl)-methanol (100 mg, 0.68 mmole) in dichloromethane (31 ml), manganese (IV) oxide (1.9 g, 21.9 mmol) is added. The reaction mixture stirred at room temperature for 8 hours and then passed through celite. The reaction mixture is then concentrated to give a yellow oil (80 mg, 0.55 mmole). MS (ESI) m/z 146.2 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1.[OH-].[Na+].[CH2:18]([N:20]([CH2:44][CH3:45])[CH2:21][CH2:22][N:23]([CH2:41][CH:42]=O)[C:24](=[O:40])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br>CN1C(=O)CCC1.CO.C(Cl)Cl.C(O)C.O>[CH2:44]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][N:23]([CH2:41][CH2:42][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)[C:24](=[O:40])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:45]
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: CCN(CC)CCN(CC=O)C(=O)CCOCCc1ccc2ccccc2c1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCN(CC)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 34.2 %

Procedure:
7-(2-Aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (176 mg) was dissolved in NMP (2 ml) to give a clear, yellow solution. Sodium hydroxide (27 mg) was dissolved in methanol (0.6 ml), and added in one portion to the yellow solution which turned bright orange. N-[2-(diethylamino)ethyl]-3-[2-(2-naphthyl)ethoxy]-N-(2-oxoethyl)propanamide (Example 32d) (458 mg) was dissolved in DCM (1 ml) and added drop-wise. The mixture was allowed to stir for 1 hour. Sodium triacetoxyborohydride (303 mg) was added portion-wise, and mixture stirred for 45 mins. Water (10 ml) was added followed by DCM, and the layers separated. The aqueous layer was extracted with DCM (×3). The remaining aqueous layer was found to contain desired material, so this was mixed with ethanol, then evaporated to dryness re-dissolved in methanol water mix, and loaded onto a pre-washed SCX cartridge. The cartridge was washed with 1:1 methanol:water, then methanol, then eluted with 0.07N methanolic ammonia to give a yellow film (178 mg). This was dissolved in ethanol, aqueous HBr (100 ul) added and the solution left to stand for 30 mins. The solvents were removed in vacuo to give a yellow solid, which was azeotroped with ethanol (×3). Ethanol was added and mixture sonicated to give a pale yellow suspension. Solid collected by filtration, and washed with ethanol to give the title compound (141 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[CH3:26][C:27]1[C:31]([S:32]([NH2:35])(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1>>[CH3:26][C:27]1[C:31]([S:32]([NH:35][C:17]([C:14]2[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]3[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:19])(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1
Reactant: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)O)nn1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Product: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)NS(=O)(=O)c2c(C)noc2C)nn1

Procedure:
The title compound was prepared from 6-[5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridine-3-carboxylic acid (example 9) and 3,5-dimethylisoxazol-4-ylsulphonamide using a similar method to that of example 14.
Reaction SMILES: [CH:1]([I:4])(I)I.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH:15]=O)=[CH:8][CH:7]=1>C1COCC1.[Cr](Cl)(Cl)=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[C:14]([CH3:17])([CH3:15])/[CH:18]=[CH:1]/[I:4])=[CH:10][CH:11]=1
Reactant: IC(I)I
Reactant: CC(C)(C=O)C(=O)Nc1ccc(Cl)cc1
Agent: O=[Cr](Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(/C=C/I)C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
To a stirred suspension of chromous chloride (3.3 g) in 75 mL of dry THF was added a solution of iodoform (3.5 g) and N-(4-chlorophenyl)-2,2-dimethyl-3-oxopropanamide (1 g) in 25 mL of THF, dropwise over 10 minutes. The solution was allowed to stir an additional 1.5 hour, then poured into 100 g of ice water and extracted into ether. The organic phase was dried, filtered and evaporated, and the residue was filtered through a small silica gel column, eluting with ether, to remove chromium residues. The title product (0.55 g) was isolated as a solid, m.p. 145°-146° C.
Reaction SMILES: [N:1]1([C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@H:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17]3)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.B.C1COCC1.[ClH:34].CCOCC>C1COCC1.C(Cl)Cl>[ClH:34].[N:1]1([C:10]2[CH:27]=[CH:26][C:13]([CH2:14][N:16]3[CH2:20][CH2:19][C@H:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17]3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@H](N2CCCC2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc2c(c1)ncn2-c1ccc(CN2CC[C@H](N3CCCC3)C2)cc1
Reaction time: 12 h
Yield: 65 %

Procedure:
A solution of (3′S)-1′-[4-(1H-benzimidazol-1-yl)benzoyl]-1,3′-bipyrrolidine (0.041 g, 0.113 mmol) in THF is treated with 1.0 M Borane-THF (0.098 g, 1.13 mmol) at room temperature, stirred for 12 hours and concentrated under vacuum. The resultant residue is dissolved in methanol, and treated with 1.0 M HCl-Et2O (0.004 g, 0.113 mmol), heated at reflux temperature for 3 hours and concentrated under vacuum to afford an oil residue. The residue is dissolved in CH2Cl2, washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the concentrate by flash column chromatography (silica, 2% NH4OH:MeOH:CH2Cl2 5:3:95), followed by treatment with ethereal HCl, provides the title product as a yellow solid, 0.036 g (65% yield), identified by NMR and mass spectral analyses. MS [347.2 m/e (M+H)].
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:22].[OH-].[Na+].Cl>C(O)C.O>[C:1]1([CH2:7][CH:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][SH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C(NC(CCl)Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC(CS)Cc1ccccc1)c1ccccc1

Procedure:
80.4 millimole (mm) of 3-phenyl-2-benzamido-1-chloropropane and 80.4 mm of thiourea are dissolved in 300 ml of ethanol. The resulting solution is refluxed for three hours. 6.7 g of sodium hydroxide is dissolved in 40 ml of water and is added under an inert atmosphere to the solution which is thereafter refluxed for an additional 21/2 hours. The solution is then cooled and acidified to pH 1 with 1 N HCl. The resulting mixture is then poured over ice to yield a precipitate which is collected by filtration and then dissolved in chloroform. The chloroform is dried with magnesium sulfate and then evaporated to yield the solid 3-phenyl-2-benzamido-1-propanethiol.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10])=[O:5])[CH3:2].[C:16]1([C:22]([O:24][OH:25])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.O>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:25][O:24][C:22](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])=[O:5])[CH3:2]
Reactant: O=C(OO)c1ccccc1
Reactant: CCOC(=O)Oc1ccccc1C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: -18 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
8.6 g (67 mmol) of 2-(ethoxycarbonyloxy)benzoyl chloride (obtained in Example 1.2) and 10.2 g (44 mmol) of benzenecarboperoxoic acid are dissolved in 43 ml of chloroform. The mixture is cooled to −18° C. and then 2.2 ml (38 mmol) of pyridine in 5 ml of dichloromethane are added dropwise. After stirring at −18° C. for 2 hours, water is added and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and then concentrated. The residue is purified by chromatography on silica gel eluted with a pentane/dichloromethane 5/5 mixture. 11 g of (2-(ethoxycarbonyloxy)benzoyl)benzoyl peroxide are obtained in the form of a beige solid with a yield of 75%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([SH:11])=[N:8][C:9]=1[CH3:10].C[O-].[Na+].[I-].[CH3:17][CH3:18]>CO>[CH2:17]([S:11][C:7]1[NH:6][C:5](=[O:12])[C:4]([CH2:3][CH2:2][OH:1])=[C:9]([CH3:10])[N:8]=1)[CH3:18]
Reactant: Cc1nc(S)[nH]c(=O)c1CCO
Reactant: CC
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nc(C)c(CCO)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of intermediate 1 (37.2 g) and sodium methylate (36 g) in methanol (250 ml) was stirred for 30 min. Ethane iodide (31.2 g) was added dropwise. The reaction mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was stirred in water, filtered and recrystallized from CH3CN. The precipitate was filtered off and dried, yielding 26 g (60%) of 2-(ethylthio)-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone (intermediate 2).
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[OH:10][CH2:9][C:8]1[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc(CO)n1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
11.4 g (0.3 mol) of sodium borohydride was added in one portion to a stirred solution of 111.5 g (0.5 mol) of diethyl 2,6-pyridinedicarboxylate in 1 litre of ethanol and stirred for 6 hours when a further 2.85 g (0.075 mol) of sodium borohydride were added and the mixture stirred overnight before being evaporated. The residue was dissolved in 800 ml dichloromethane and washed with water. The aqueous was extracted with 4×50 ml of dichloromethane. The combined organics were dried, evaporated and combined with the product from reaction 1 (13.1 g). The combined material was washed through a pad of silica on a large sinter with ethyl acetate (2 litres) which was evaporated and triturated with ether and filtered off to give 72.6 g of a white solid. The MLS (mother liquors) were evaporated and biotaged (chromatographed) [ethyl acetate/hexane (3:1)] to give a further 2.9 g of product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([O:34]C(C)(C)C)=[O:33]>Cl.O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([OH:34])=[O:33]
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Yield: 41 %

Procedure:
A solution of (R)-tert-butyl 2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (257 mg, 0.453 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The purified mixture was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as a cream powder (100 mg, 28%); 1H NMR (400 MHz, DMSO-d6): δ 1.94 (m, 2H); 2.07 (m, 2H); 2.85 (m, 2H); 3.14 (m, 2H); 3.49-3.52 (m, 4H); 3.76 (t, 2H, J=6.8 Hz); 4.17 (d, 1H, J=5.2 Hz); 4.87 (d, 1H, J=4.8 Hz); 5.79 (s, 1H); 6.85 (m, 1H); 6.97-7.04 (m, 3H); 7.12 (d, 1H, J=7.6 Hz); 7.21 (t, 1H, J=7.6 and 8.4 Hz); 7.28 (dd, 2H, J=5.6 and 6 Hz); 7.42-7.45 (m, 6H) 10.6 (bs, 1H); 13.4 (bs, 1H); MS for C32H34N4O4 m/z 539 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.Br.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:15].[CH3:12][C:10]1[CH:11]=[C:2]([N:1]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: BrCCNCCBr
Reactant: Cc1cc(N)cc2c1NC(=O)CC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N2CCNCC2)cc2c1NC(=O)CC2
Temperature: 64 °C
Reaction time: 13 h
Yield: 60.1 %

Procedure:
A mixture of 6-amino-8-methyl-3,4-dihydro-2(1H)-quinolinone (19.4 g), bis(2-bromoethyl)amine hydrobromide (41 g) and methanol (140 ml) was stirred for 13 hours at 64° C. After cooling, sodium carbonate (5.83 g) was added thereto and the mixture was stirred for 9 hours at 70° C. After cooling, the resulting precipitate was collected by filtration and the residue was washed with methanol to give 3,4-dihydro-8-methyl-6-(1-piperazinyl)-2(1H)-quinolinone hydrobromide (21.6 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[N:4][CH:5]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1nncc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nncc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 66.9 %

Procedure:
Using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid (99 mg, 0.78 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (135 μL, 1.55 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 119, the title compound (182 mg, 67%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:21][CH3:22])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=3)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:21]([N:10]1[C:9]2[CH:8]=[CH:7][C:6]([CH2:4][OH:3])=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH3:22]
Reactant: CCOC(=O)c1ccc2c(c1)c1cc(OC)ccc1n2CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccc(CO)cc2c2cc(OC)ccc21
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 9-ethyl-6-methoxycarbazole-3-carboxylic acid ethyl ester (1.36 g, 4.58 mmol) in anhydrous THF was added to a solution of lithium aluminum hydride in THF (25 mL) at 0° C. The reaction was stirred for 1 hour then water (1 mL) was added followed by 2M NaOH (1 mL) and finally water (1 mL). The reaction was then filtered on diatomaceous earth and the filtrate was dried and solvent removed in vacuo to afford 0.79 g of the crude alcohol.