Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]12[O:26][CH2:25][CH2:24][O:23]1)[CH3:2].C(=O)([O-])[O-].[Sr+2]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:23][CH2:24][CH2:25][O:26]1)[CH3:2]
Reactant: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)C1=CCC21OCCO1
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
Hydrogenate dl-13β-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (15.3 g) in benzene (300 ml) with 2% palladized strontium carbonate (5.0 g). The uptake of 1,040 ml. will require 10 minutes. Work up in the usual manner, then recrystallize from 95% ethanol (110 ml) to obtain dl-13β-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8-tetraene (11.0 g. of diamond-shaped plates; 71.8% yield), m.p. 122°-124°; ultraviolet absorption peak at 280 mμ (ε15,140).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1)#[N:2].[CH2:15]([Mg]Br)[CH3:16].FB(F)F.[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:2][C:1]1([C@@H:3]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4]2)[CH2:16][CH2:15]1
Reactant: N#C[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Product: NC1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Reaction time: 0.5 h

Procedure:
(3R)-3-Cyano-1-benzylpyrrolidine (1.40 g) was dissolved in tetrahydrofuran (21.0 mL) under an argon atmosphere. Titanium(IV) tetraisopropoxide (2.40 mL) and ethylmagnesium bromide (5.00 mL, 3 mol/L solution in ether) were added to the solution at room temperature. After 0.5 h, trifluoroboron.diethyl ether complex (1.90 mL) was added dropwise to the mixture, and the resultant mixture was stirred at room temperature. After 4 h, 2 mol/L aqueous sodium hydroxide (30 mL) was added to the reaction mixture, followed by stirring for 0.25 hours. The product that precipitated was collected through filtration and then extracted. The formed aqueous layer was again extracted with ethyl acetate, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby the target compound as a crude product (1.65 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].C(OC1C=C(C=CC=1C)C=O)C>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:12][CH2:13][CH3:14]
Reactant: CCCI
Reactant: COc1ccc(C=O)cc1O
Agent: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared by reaction of isovanillin with propyl iodide in DMF using K2CO3 as base in analogy to the preparation of 3-ethoxy-4-methyl-benzaldehyde (intermediate D2).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate as a white solid (10.3 g); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56–1.69 (m, 2H), 1.93–2.04 (m, 2H), 3.20–3.31 (m, 2H), 3.60–3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H); Mass Spectrum: (M+H)30 394.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10]CC)=[O:9].B(F)(F)F.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][O:29]/[C:30](=N/[H])/[C:31](Cl)(Cl)Cl)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>C1(C)C=CC=CC=1>[CH2:4]([C@@:3]1([C:8]([OH:10])=[O:9])[CH2:2][CH2:7][CH2:6][CH2:31][C@H:30]1[O:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:5]
Reactant: [H]/N=C(/OCCc1ccc(OC)c(OC)c1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC[C@@]1(C(=O)O)CCCC[C@H]1OCCc1ccc(OC)c(OC)c1
Yield: 110.3 %

Procedure:
To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:16])[CH3:19])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: Cc1c(C=O)cccc1OCC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(OCC(=O)OC(C)(C)C)cccc1C(C)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
(3-Formyl-2-methylphenoxy)acetic acid tert-butyl ester (0.94 g, 3.75 mmol) was dissolved in freshly distilled tetrahydrofuran and cooled to −78° C. Methyl magnesium chloride (2.62 mL, 7.88 mmol) was added dropwise and the mixture was allowed to stir at −78° C. for two hours. The mixture was allowed to warm to room temperature, stirred for an additional six hours, then carefully quenched with water, and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography, eluting with hexane/acetone, gave [3-(1-hydroxyethyl)-2-methylphenoxy)acetic acid tert-butyl ester as a clear oil (594 mg, 59.5%).
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.Cl[C:23]1[N:28]=[C:27]([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])[C:26]([CH3:42])=[CH:25][C:24]=1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.CC1(C)COB([C:60]2[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=2)OC1>>[CH3:42][C:26]1[C:27]([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])=[N:28][C:23]([C:60]2[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=2)=[C:24]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[CH:25]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2ccnn2C)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1-methyl-1H-pyrazole to give the title compound as dark brown oil. MS: 498.2 (MH+).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[CH:10]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([S:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6]
Reactant: SC1CCCCC1
Reactant: O=C(Cl)CCC(F)(F)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC(F)(F)Cl)SC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
4.0 g of 4-chloro-4,4-difluorobutyryl chloride are added dropwise over the course of 30 minutes to a solution of 2.6 g of cyclohexyl mercaptan and 4.5 g of pyridine in 50 ml of toluene at 0° C. The reaction mixture is stirred at RT for 16 hours and then diluted with 150 ml of diethyl ether and subsequently washed with 50 ml each of 1N HCl, saturated NaHCO3 and saturated NaCl solution. The organic phase is then dried over MgSO4, filtered and evaporated. The resulting crude product is distilled at +90° C./5 mbar. 3.8 g of S-cyclohexyl 4-chloro-4,4-difluorothiobutyrate are obtained as an oil, nD23 : 1.4748.
Reaction SMILES: O=S1(=O)N=CC2C=C(C(C)(C)C)C=C(I)C=2O1.[O:18]=[S:19]1(=[O:34])[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:28]([Br:29])[C:21]=2[O:20]1>>[O:34]=[S:19]1(=[O:18])[NH:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH:27]=[C:28]([Br:29])[C:21]=2[O:20]1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)C=NS(=O)(=O)O2
Agent: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Product: CC(C)(C)c1cc(Br)c2c(c1)CNS(=O)(=O)O2

Procedure:
This compound is prepared by essentially the same method as described in Example 8 except that the 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine is replaced by 2,2-dioxo-6-(1,1-dimethylethyl)-8-bromo-1,2,3-benzoxathiazine. Thereby is obtained 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-bromo-1,2,3-benzoxathiazine.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:22]1[CH2:23][CH2:24][NH:19][CH2:20][C:21]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCNCC1
Reactant: CCCCc1csc2ccc(NN)cc12
Agent: Cl
Solvent: O
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CNCC4

Procedure:
The compound is formed analogously to that described in Example 15, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 20 g of 4-piperidone hydrochloride monohydrate. Melting point: 224°-225° C.
Reaction SMILES: [C:1]([OH:17])(=O)[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH2:40])[N:37]=[CH:36]1)[CH3:31]>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH:40][C:1](=[O:17])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:3])[N:37]=[CH:36]1)[CH3:31]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C(O)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 4.6 g of benzilic acid, 3.2 g of 1,1'-carbonyldiimidazole, and 150 ml of DMF were mixed and stirred for 1 hour. A solution of 5.0 g of 4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester in DMF was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, ethyl acetate was added, and the organic solution was washed sequentially with water, a 10% sodium hydroxide solution, and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by HPLC eluting with 30% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 1.4 g of the desired titled product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]([O:13][C:14](N=C(C1C=CC=CC=1)C#N)=[O:15])([CH3:12])([CH3:11])[CH3:10]>O1CCCC1>[C:9]([O:13][C:14]([N:6]1[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N=C(C#N)c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reaction time: 2 h
Yield: 161.1 %

Procedure:
cis-2,6-Dimethylpiperazine (5.08 g) was added to 2-(tert-butoxycarbonylimino)-2-phenylacetonitrile (11.35 g) in tetrahydrofuran (150 mL) at 0° C., followed by stirring for 2 hours. The reaction solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform−7N ammonia/methanol mixture), to thereby give the title compound (15.36 g, 72%).
Reaction SMILES: C(O[C:4]([C:6]1[C:14](=[O:15])[N:13]2[C:9](=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:20]([N:8]1[C:9]2=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[N:13]2[C:14](=[O:15])[C:6]([C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:5])=[CH:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O
Product: O=C(c1cn(Cc2ccccc2)c2nc3ccccc3n2c1=O)N1CCOCC1

Procedure:
By substituting 1-benzyl-1,4-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylic acid ethyl ester in part a and morpholine in part b of Example 33, 1-benzyl-3-(4-morpholinylcarbonyl)pyrimido[1,2-a]benzimidazol-4(1H)one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][C@H:21]([CH3:34])[N:20]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([N:32]([CH3:33])[C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:23]4[CH2:24][C@H:19]([CH3:18])[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:21]([CH3:34])[CH2:22]4)=[CH:31][CH:30]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Reactant: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)N(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (3 mL) and added to a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D9) (0.23 g, 0.693 mmol) in DCM (2 mL). Triethylamine (0.193 mL, 1.386 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% EtOAc/petroleum yielded the title compound as a white foam (0.331 g). δH (CDCl3, 400 MHz) 7.89 (2H, m), 7.36 (1H, m), 7.26 (1H, m), 7.19 (2H, m), 7.10 (2H, t), 6.99 (2H, m), 4.00 (2H, m), 3.53 (3H, s), 3.34 (2H, s), 2.58 (3H, s), 2.44 (2H, d), 2.05 (2H, m), 1.44 (9H, s), 1.18 (6H, d). MS (ES): MH+ 547.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:7][C:8]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CCCO)ccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCCBr)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Under N2, a solution of 7.33 g (40.7 mmol) of 3-(3-methoxy-4-methylphenyl)-1-propanol in 200 mL of CH2Cl2 was treated with 10.67 g (40.7 mmol) of triphenylphosphine followed in portions by 7.3 g (40.7 mmol) of recrystallized N-bromosuccinimide. The solution was stirred at room temperature for 2 hours, then filtered through flash silica gel. Removal of the solvent under reduced pressure left 8.68 g (87.9% yield) of the product as a clear oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][CH2:16][C:17](OCC)=[O:18]>C(O)C(F)(F)F>[F:15][CH2:16][C:17]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC(=O)CF
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CF)CC1
Yield: 53.1 %

Procedure:
A solution of 500 mg of tert-butyl piperidin-4-ylcarbamate and 345 mg of ethyl fluoroacetate in 1 ml of trifluoroethanol was heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added to the resulting residue. Then, this was extracted with EtOAc, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and brine. This was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform to chloroform/methanol=30/1) to obtain 345 mg of tert-butyl [1-(fluoroacetyl)piperidin-4-yl]carbamate.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:13]1[CH:12]=[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:10]=[C:9]([N+:18]([O-:20])=[O:19])[C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Br)c(NC2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
A room temperature solution of Example 3A (1.81 g, 6.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (950 mg, 3.3 mmol) in dichloromethane was treated with trifluoracetic acid (796 uL, 9.0 mmol), stirred in darkness for 18 hours, treated with saturated NaHCO3, and extracted with diethyl ether. The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 376 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4](=O)[NH:5][N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.P(Br)(Br)([Br:24])=O.CN(C=O)C>>[Br:24][C:4]1[N:5]=[N:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:8][C:3]=1[C:2]([F:21])([F:20])[F:1]
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-2H-pyridazin-3-one (example C.26 step 6) (9.61 g, 31 mmol), POBr3 (26.8 g, 94 mmol) and DMF (0.72 mL, 9 mmol) was stirred for 3 h at 105° C. under nitrogen atmosphere. The reaction mixture was poured (the mixture was nearly solid) onto water (300 mL) and stirred for 2 h at 23° C., the precipitated solid was filtered off and applied onto silica gel for silica gel column chromatography with heptane/EtOAc 4:1->2:1 to give the title compound as a light brown solid (11.22 g, 97%). MS (ISP) 371 [(M+H)+], 373 [(M+2+H)+]; mp 123-125° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1
Reactant: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (3.72 g, 9.70 mmol) in dichloromethane (25 mL). Add cold trifluoroacetic acid (30 mL, 44.2 g, 388 mmol, 40 eq.). Stir for 1 hr. Partition the crude reaction mixture between aq. 5N NaOH and dichloromethane. Separate the layers (pH aqueous layer=14). Extract the aqueous layer with dichloromethane (2×50 mL). Combine organic layers, dry over anhydrous Na2SO4, filter and concentrate to obtain the title preparation (2.76 g, 100% yield). LC MS (ES): m/z=285.0 [M+H].
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:12]2[CH2:18][CH:17]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])=[CH:6][CH:5]=1.O[Li].O.O[NH:38][C:39](=[NH:41])[CH3:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:11]([CH:12]2[CH2:18][CH:17]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(CN(C2CC(C(C)C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=N)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(CN(C3CC(C(C)C)CCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(5-isopropyl-2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester (0.30 g, 0.60 mmol) was saponified to the acid using LiOH.H2O (0.04 g, 0.90 mmol). The acid (0.10 g, 0.21 mmol) was dissolved in THF (3 ml) and added dropwise to a solution of 1,1-carbonyl diimidazole (CDI, 0.04 g, 0.23 mmol) in THF (0.5 ml). After 30 min, N-hydroxy-acetamidine (0.04 g, 0.23 mmol) was added. A further two equivalents each of CDI and N-hydroxy-acetamidine were added during a further 48 h stirring at r.t. The reaction mixture was concentrated and crude, coupled amidine was purified over silica gel (gradient ethyl acetate to ethyl acetate/methanol 15%): white solid 0.09 g (73%); MS: m/e=535.5 (MH+). Purified amidine (0.08 g, 0.15 mmol) cyclised in the presence of tetrabutylammonium fluoride (1 M, THF 5 ml) over 36 h at r.t. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organice extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The concentrated, crude product was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=517.4 (MH+).