Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C>CO.[Pd]>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[C:4]([NH:11][C@H:12]([C:14]1[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])[CH3:13])=[CH:3][CH:2]=[N:7]2
Reactant: C[C@H](Nc1cc(Cl)nn2ccnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ccnn2ccnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (S)-3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-7 (50 mg, 0.104 mmol, 1.0 eq) in MeOH (20 mL), palladium on carbon (10%, 17 mg) and triethylamine (0.1 mL, 0.72 mmol, 6.9 eq) were added. The resulting mixture was degassed and back-filled with hydrogen (three cycles), and then stirred at RT under hydrogen overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% ethyl acetate-petroether) to afford the product, (S)-3-(1-(imidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-8. ESI-MS m/z: 450.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.C(O)(C)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[S:45]([NH2:48])(=[O:47])=[O:46]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([NH:48][S:45]([C:38]3[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=3[Cl:36])(=[O:47])=[O:46])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1c(C(=O)O)nc2c(Cl)cc(C(F)(F)F)cn12
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2nc3c(Cl)cc(C(F)(F)F)cn3c2C)c1
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
To the carboxylic acid prepared in Step B (200 mg, 0.72 mmol) was added a solution of 4-(dimethylamino)pyridine (262 mg, 2.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mmol) in a 1:1 solvent mixture of t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, 2-chloro-5-methoxybenzenesulfonamide (143 mg, 0.65 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 118 mg of the title compound, a compound of the present invention, as a white solid, m.p. 222-223° C. 1H NMR (dmso-d6) δ 10.0 (br s, 1H), 8.94 (s, 1H), 7.96 (s, 1H), 7.65 (d, 1H), 7.59 (d, 1H), 7.30 (dd, 1H), 3.87 (s, 3H) 2.71 (s, 3H).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40].S>C(O)C>[C:1]1([C:7]2[S:40][C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:9][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1cc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc(OC)c1OC
Temperature: 10 °C
Reaction time: 3 h
Yield: 193 %

Procedure:
In a 1-liter stirred stainless steel autoclave were placed 40.4 g 1,2-diphenyl-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 22.2 g of phosphorus pentasulfide and 128 g of hydrogen sulfide. The reaction mixture was heated with stirring for 3 hours at 160°-168° C. (1210-1250 psig. pressure). The reactor was cooled to 10° C. and the hydrogen sulfide was released. The residue was stirred with 150 ml of ethanol to decompose unreacted phosphorus pentasulfide. Filtration and evaporation gave 38.8 g (96.4%) of 2,3-diphenyl-5-(3,4,5-trimethoxyphenyl)thiophene.
Reaction SMILES: I[CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:24]([CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1)#[N:25]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CI)c3ccccc32)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC#N)c3ccccc32)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of (5S)-5-iodomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.41 g), potassium cyanide (0.42 g), a catalytic amount of 18-crown-6 and dimethylformamide (16 ml) is heated with stirring at 85° C. for one hour. To the mixture is added potassium cyanide (0.42 g), and the mixture is further stirred at 85° C. for totally 6 hours. To the reaction solution is added ice, and the mixture is extracted with ethyl acetate--toluene. The extract is dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1), and recrystallized from ethyl acetate--n-hexane to give (5R)-5-cyanomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.41 g).
Reaction SMILES: C1(CO[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]2)[C:14]3=[O:19])C=CC=CC=1.F[C:35](F)(F)[C:36]([O-:38])=O>>[CH3:14][CH:15]([C:10]1[CH:11]=[CH:12][C:35]([CH2:36][O:38][C:18]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:19])[CH:13]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]2)[CH2:12][CH2:11]3)=[CH:18][CH:9]=1)[CH3:16]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1c2cccc(OCc3ccccc3)c2CCC1CCN1CCC(c2ccccc2)CC1
Product: CC(C)c1ccc(COc2ccc3c(c2)CCC(CCN2CCC(c4ccccc4)CC2)C3=O)cc1

Procedure:
3,4-Dihydro-5-(phenylmethoxy)-2-[2-(4-phenyl-1-piperidinyl)ethyl]-1(2H)-naphthalenone, trifluoroacetate (1:1);
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Hexanoylchloride (0.029 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.05 g.) and N-methylmorpholine (0.05 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (15 ml.). This mixture was extracted with ethyl acetate (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 4:6 v/v ethyl acetate:hexane, to give a colorless oil, which was crystallized from a mixture of toluene and hexane to give the title compound (0.05 g, 65%) as a white powder; NMR: 0.86(t, 3H, CH2.CH3), 1.28(m,4H, CH2.CH2.CH3), 1.57 (quintet, 2H, CH2.CH2.CON), 2.25(t, 2H, CH2.CH2.CON), 3.69(s,3H, NCH3), 3.82(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s, 2H, CH2.Ar), 7.05(s,1H), 7.13(d,1H), 7.27(d,1H), 7.28(d,1H), 7.40(dd,1H), 7.48(s,1H), 7.74(s,1H), 9.61(s,1H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[C:17]1([CH2:27]Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C(O)C.CCCCCC>[C:17]1([CH2:27][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(Cc1cccc2ccccc12)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
Sodium (28 mmol; 0.64 g) is introduced into 50 cm3 of absolute ethanol, under inert atmosphere. At 0° C., diethyl 2-acetamidomalonate (28 mmol; 6.08 g) dissolved in 35 cm3 of absolute ethanol is added, followed by dropwise addition, with a syringe, of (1-naphthyl)methyl chloride (28 mmol; 4.1 cm3). The mixture is maintained at reflux until the starting material has disappeared (6 h, then overnight at room temperature and then 2 h at reflux). The reaction medium is poured onto a KHSO4 (0.05M; 240 cm3)/hexane (120 cm3) mixture and stirred vigorously. A white precipitate, which is the expected malonic derivative, is recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](OC1C=C(C(C)(CCCCC)C)C=CC=1Br)C1C=CC=CC=1.C1(=O)CCCC=C1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:30])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1
Agent: O=C1C=CCCC1
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1

Procedure:
3-[2-Benzyloxy-4-(1,1-dimethylhexyl)phenyl]cyclohexanone as an oil (11.0 g., 35%) from 2-(3-benzyloxy-4-bromophenyl)-2-methylheptane (30.2 g., 0.0806 mole) and 2-cyclohexen-1-one (8.5 g., 0.0886 mole).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[CH:7]=1.[CH2:19](Br)[C:20]#[CH:21]>>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:21][C:20]#[CH:19])[C:8](=[O:13])[CH:7]=1
Reactant: C#CCBr
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)[nH]1
Product: C#CCn1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Yield: 44.9 %

Procedure:
The title compound was prepared by alkylation of 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2.5 g, 10 mmol) with propargyl bromide (1.3 ml, 11.0 mmol) as described above to give 1.3 g (44%) of the desired product. 1H-NMR (DMSOd6/300 MHz) δ 7.60 (app q, J=8.4 hz, 1H), 7.35-7.27 (m, 1H); 7.16-7.10 (m, 1H); 5.94 (d, J=2.1 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.03 (s, 2H), 4.76 (d, J=2.4, Hz, 2H), 3,31 (s, 3H), 3.24 (t, J=2.4 Hz, 1H), 2.39 (s, 3H); ES-HRMS m/z 290.0994 (M+H calcd for C16H14F2NO2=290.0993).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>O1CCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Fc1ccc(Nc2nc3ccccc3o2)cc1C(F)(F)F

Procedure:
To a solution of 17.9 g. (0.1 mole) of 4-fluoro-3-(trifluoromethyl)aniline in 200 ml. of tetrahydrofuran was added dropwise 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 150 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. Then the tetrahydrofuran solvent was removed by distillation under vacuum, and 100 ml. of water was added to the residue. The residue was an oily liquid which solidified on the addition of the water. The residue was removed by filtration and dried in vacuo. The dried residue was dissolved in a minimum amount of warm acetone, and about 200 ml. of water was added to the solution, resulting in the crystallization of the reaction product. The precipitate was filtered and dried and 24.5 g. of 2-[4-fluoro-3-(trifluoromethyl)anilino]benzoxazole having a melting point of 190°-191° C. was recovered.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuran (20 mL) under a nitrogen atmosphere was cooled to 0° C. Diisopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(NC=NCCCC)CCC.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Agent: CCCCN=CNCCCC
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 2.3 g of N,N'-dibutylformamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 97% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CCCCCCC>[CH:15]1([CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:34]([C:33]4[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=4)[CH2:20][CH2:19]3)[CH2:11][CH2:10]2)=[O:18])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CCC2CC2)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C(CCC1CC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Yield: 15.9 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(3-cyclopropyl-propionyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.1 g), dimethylaluminium chloride in heptane (0.9 molar, 0.71 ml) and 4-trifluoromethoxyanilin (0.057 g) to give the desired 8-(3-cyclopropyl-propionyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.021 g) as an off-white solid. MS (ESI): 449.17 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:34][CH2:33][NH:32][CH2:31][C:28]21[CH2:30][CH2:29]2>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:31][C:28]5([CH2:30][CH2:29]5)[N:27]([CH3:26])[CH2:34][CH2:33]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN1CCNCC12CC2
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)C5(CC5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-1.34 (m, 4 H) 2.33 (d, J=2.27 Hz, 3 H) 2.91 (s, 3 H) 3.31-3.85 (m, 6 H) 7.62 (d, J=7.83 Hz, 1 H) 7.70-7.78 (m, 1 H) 7.82-8.75 (m, 4 H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][O:17][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OC(CC=C(C)CCCC(C)CO)C(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
324 mg (1.20 mmol) of a raw product of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one and 219 μl (202 mg, 2.40 mmol) dihydropyrane was dissolved in 8.5 ml DCM. After addition of 30 mg (0.12 mmol) pyridinium paratoluene sulfonate, the reaction mixture was stirred for 18 hrs at ambient temperature. Then, 25 ml diethylether was added, the resulting organic phase was washed once with 25 ml semiconcentrated NaCl solution, and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the remaining product was purified by flash chromatography (parameters of the chromatography column: 2.0×20.0 cm, ethylacetate/petroleum ether=1:4) on silica gel.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]4[C:30](=O)[O:29][C:28](=[O:32])[C:17]=4[CH:18]=[C:19]4[C:27]=3[C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=[CH:20]4)=[CH:14][C:9]=2[O:8][CH2:7]1.O>C1(C)C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:27]4[C:19](=[CH:20][CH:21]=[C:22]5[O:26][CH2:25][O:24][C:23]5=4)[CH:18]=[C:17]4[C:28](=[O:32])[N:1]([CH2:2][CH2:3][CH2:4][OH:5])[C:30](=[O:29])[C:16]=34)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: NCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2C(=O)N1CCCO)OCO4
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
3-Amino-1-propanol (27 mg, 0.36 mmol) in toluene (5 mL) at 0° C. was added dropwise to a stirred solution of anhydride 1 (109 mg, 0.3 mmol) in toluene (40 mL). The mixture was stirred at room temperature for 1 h and then heated under Dean-Stark trap for 3 h. After water ceased to distill, the reaction mixture was cooled, washed successively with water (2×50 mL), 5% aqueous NaHCO3 solution (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed in vacuo, and the resulting product was purified by column chromatography on silica gel using CH2Cl2/acetone (3:1 to 1:1, v/v) to provide 29 (10 mg, 11%) as a pale yellow powder. mp 150-152° C.; 1H NMR (CDCl3) δ 8.27 (s, 1H, H4), 7.56 (d, 1H, H5, J=8.4 Hz), 7.26 (d, 1H, H6, J=8.4 Hz), 6.86-6.91 (m, 3H, H2′+H5′+H6′), 6.04 (s, 2H, 3′,4′-OCH2O—), 5.97 (s, 2H, 7,8-OCH2O—), 3.69-3.76 (m, 4H, NCH2CH2CH2OH), 1.83 (m, 2H, NCH2CH2CH2OH).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:21]([O-])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:24](O)=O>C(OC)(OC)OC.[Fe]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=3[N:21]=[CH:24]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1
Reactant: O=CO
Agent: [Fe]
Solvent: COC(OC)OC
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid (1.27 g, 4.04 mmol), Fe (1.77 g, 31.6 mmol, powder) in HCO2H (30 mL) and HC(OMe)3 (20 mL) was stirred under N2 at rt for 18 h. After this time, the reaction mixture was filtered through Celite, the cake washed with EtOH and the filtrate concentrated in vacuo. The resultant crude material was purified by column chromatography over silica gel eluting with 10% MeOH in DCM to afford 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.34 (s, 1H), 8.71 (s, 1H), 10.3 (s, 1H); MS (ES+): m/z 296 [MH+]
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1>C1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 45.8 %

Procedure:
600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid were added to 97 g of 2-(1,3-benzodioxol-5-yl)-2-propanol. The obtained mixture was heated under reflux for 4 hours and distilled to remove the solvent. The pH of the residue was adjusted to 10 with a 1N aqueous solution of sodium hydroxide. The resulting mixture was washed with ethyl acetate. 4N hydrochloric acid was added to the mixture under cooling with ice to acidify the aqueous layer. The resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 62.70 g of the title compound as a colorless crystal.