Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][C:17]3[N:18]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:22]=3)[CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][C:17]3[N:18]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:22]=3)[CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[N:45]1[CH2:46][CH2:51][CH2:50][CH2:49]1
Reactant: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoic acid (59.1 mg, 0.126 mmol) in N,N-dimethylformamide (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (56 mg, 0.126 mmol), pyrrolidine (9.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL) at RT. The mixture was stirred at RT for 3 h, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=522.0.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:12][CH:11]3[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]3)[CH2:6]2)[CH2:3][CH2:2]1.[NH2-].[Li+].[C:18]1([CH:24](Br)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:18]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:8][CH:7]3[C:13]([CH3:15])([CH3:14])[CH:11]([CH2:12][N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6]3)[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)C2CNCC1CN(CC1CC1)C2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CC1(C)C2CN(CC3CC3)CC1CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
1 g 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane was dissolved in 25 ml absolute tetrahydrofuran, and 0.2 g lithium amide was added to the solution and stirred for 1 hour at 60° C. and then left to cool. After cooling, a solution of 3 g diphenylmethyl bromide in 25 ml absolute tetrahydrofuran was added slowly in drops, and the reaction mixture was stirred further for 90 min at a temperature of 40° C. Then the reaction mixture was acidified with aqueous citric acid solution and worked up as described in Example 1. 1.5 g 7-diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were obtained as an oleaginous base.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]([Br:17])=[C:15]([NH2:18])[N:14]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:13]3[N:12]=2)[CH2:7][NH:6]1)=[O:4].[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.[OH-].[Na+].Cl>C1COCC1.CN(C=O)C>[NH2:18][C:15]1[N:14]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][N:6]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:16]=1[Br:17]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N1CC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CCC1C(=O)O
Yield: 35 %

Procedure:
A mixture of 5-(7-amino-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-piperidine-2-carboxylic acid methyl ester (20 mg, 0.042 mmol), methoxy-acetyl chloride (13 mg, 0.071 mmol) and triethylamine (0.024 ml, 0.167 mmol) in THF:DMF (0.5 ml:0.5 ml) was stirred at room temperature for 16 h. The crude mixture was treated with 2.0 N sodium hydroxide solution (0.14 ml) at room temperature for 16 h. The reaction mixture was acidified with 1.0 N aqueous hydrogen chloride solution (0.5 ml), concentrated and purified by prep-LC to afford the title compound (7.94 mg): LC/MS RT=3.06 min. Mass calculated for, M+H 539.10, observed 539.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.C1C(=O)N(Br)C(=[O:27])C1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[C:10]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:21])[CH3:22])=[N:18][N:19]=2)[N:16]=1)=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Solvent: CS(C)=O
Product: CC(C)c1nnc2ccc(C(=O)C(=O)c3ccc(F)cc3F)nn12
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To a round bottom flask was added 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (1.50 g, 4.74 mmol, Preparation #K.1) followed by DMSO (15 mL) and NBS (0.844 g, 4.74 mmol). The reaction mixture was stirred at about ambient temperature for about 3 d. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient, 1:0 to 0:1) to give the title compound (1.14 g, 73%): LC/MS (Table 1, Method a) Rt=2.4 min; MS m/z: 331.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:18]=[CH:17][N:16]2[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[Na+].O>[C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:27]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)#[CH:22]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C#C[Si](C)(C)C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
The mixture was then poured into cold hydrochloric acid (1 M) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 2-(5-methyl-3-phenyl-isoxazol-4-yl)-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridine (86 mg, 82%) which was obtained as a yellow foam. MS: m/e=372.1 [M+H]+. Then 2-(5-methyl-3-phenyl-isoxazol-4-yl)-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridine (81 mg, 0.22 mmol) was dissolved in methanol (1 mL), a spatula tip of potassium carbonate was added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The mixture was then poured into brine and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a brown oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded the title compound (53 mg, 81%) which was obtained as a yellow foam. MS: m/e=300.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.CN(C)C=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (125 mg, 0.53 mmol) obtained in Referential Example 5 was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution were added 4-chlorobenzenethiol (115 mg, 0.80 mmol) and potassium carbonate (438 mg, 3.18 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (120 mg, 66%) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([C@@H:10]1[NH:14][C:13](=[O:15])[NH:12][C:11]1=O)[CH3:9].O.[OH-].[Na+]>C(OCC)C.C(O)C.C1COCC1>[CH3:7][CH:8]([C@H:10]1[CH2:11][NH:12][C:13](=[O:15])[NH:14]1)[CH3:9]
Reactant: CC(C)[C@@H]1NC(=O)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)[C@H]1CNC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a suspension of lithium aluminum hydride (290 mg) in diethyl ether (20 mL) was added (5S)-5-(propan-2-yl)imidazolidine-2,4-dione (540 mg) while cooling in ice, and the mixture was stirred at room temperature overnight. After cooling in ice, water (1 mL), 4M aqueous sodium hydroxide solution (1 mL), THF (15 mL) and ethanol (2 mL) were added thereto, and the resulting mixture was stirred at room temperature for 10 min. After filtration through Celite (registered trademark), the filtrate was concentrated under reduced pressure to afford (4S)-4-(propan-2-yl)imidazolidin-2-one (160 mg).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2ccccn2)cc1

Procedure:
A solution of 7.05 g (102 mmol) of sodium nitrite in 16 ml of water is added dropwise at 5° C. in the course of 30 min to a suspension of 11.8 g (0.10 mol) of 4-amino-benzonitrile in 40 ml of water and 36.2 ml of conc. HCl. The turbid yellow reaction solution is then added dropwise at 35-40° C. over a period of 100 min to 121 ml of pyridine. After 45 minutes' stirring at 90° C. the excess pyridine is evaporated off (RV; 60° C.), and the residue is taken up in ethyl acetate and washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate 4:1→3:2→1:1→ethyl acetate) yields 4-(pyridin-2-yl)-benzonitrile, followed by 4-(pyrid-3-yl)-benzonitrile [1H-NMR (CDCl3) 8.86 (dd, J=2, 1, 1H), 8.68 (dd, J=5, 2, 1H), 7.89 (m, 1H), 7.79 (d, J=9, 2H), 7.69 (d, J=9, 2H), 7.43 (dd, J=8, 5, 1H)] and finally 4-(pyridin-4-yl)-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([N:23]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1CNCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 198 mg, 0.50 mmol), 1,4-diazepane (60.2 mg, 0.60 mmol), iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 2.0 mmol) were subjected to MW irradiation 140° C. for 80 min. The vial was cooled to RT and the RM was poured into water (40 mL) to give a suspension. The supernatant was decanted off and the residue was dried under vacuum to afford the title compound. UPLC-MS (Condition 8) tR=1.15 min, m/z=459.1/461.1 [M+H]+, m/z=457.1/459.1 [M−H]−.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[S:26][C:27]3[C:28](=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=3)[N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[OH:34][C:30]1[C:28]2[N:29]=[C:25]([N:19]3[CH2:24][CH2:23][N:22]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:21][CH2:20]3)[S:26][C:27]=2[CH:33]=[CH:32][CH:31]=1
Reactant: Oc1cccc2sc(N3CCNCC3)nc12
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3c(O)cccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-Piperazin-1-yl-benzothiazol-4-ol hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:41])=[C:22]([CH2:24][S:25]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)(=[O:27])=[O:26])[N:23]=3)=[CH:15][CH:14]=2)=[O:12])[CH:3]=1.[OH-].[Na+].O>ClCCl>[CH3:41][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:11]([NH:10][CH2:9][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[O:12])=[CH:18][CH:17]=2)=[N:23][C:22]=1[CH2:24][S:25]([CH:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Excess hydrogen chloride gas was bubbled into a solution of tert-butyl 4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate (840 mg, 1.48 mmol, 1.00 equiv) in dichloromethane (20 mL) maintained at 0° C. in a water/ice bath. The reaction mixture was stirred at 0° C. for another 2 h. The pH value of the solution was adjusted to 10 with 1M sodium hydroxide solution. Water (400 mL) was then added and the resulting solution was extracted with 5×200 mL of dichloromethane. The combined organic layers was washed with 2×600 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 420 mg (61%) of 4-(5-methyl-4-((piperidin-4-ylsulfonyl)methyl)oxazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)benzamide as a white solid. LC-MS: (ES, m/z): 469 [M+H]+, 320, 235. 1HNMR (400 MHz, CD3OD, ppm) δ 8.47 (s, 1H), 8.42-8.40 (d, 1H), 8.09-8.07 (d, 2H), 7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (t, 1H), 4.45 (s, 2H), 3.70-3.66 (t, 2H), 3.43-3.39 (m, 3H), 3.03-2.99 (t, 2H), 2.88-2.82 (m, 2H), 2.50 (s, 3H), 2.34-2.31 (d, 2H), 1.91-1.88 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:10]1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>C(Cl)Cl>[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH:44][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCC1CC1CCCCCCCC(=O)O
Reactant: Cc1ccccc1NN
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)NNc1ccccc1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g of dihydrosterculic acid* in 75 ml methylene chloride cooled to -20°, is added dropwise 1.1 g triethyl amine and then dropwise 1.1 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 1.0 g triethylamine followed by 1.6 g o-methylphenyl hydrazine hydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness to obtain a residue. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions** are combined and evaporated i.v. to dryness to yield the title product as a waxy solid, NMR; b +0.65(3), b -0.3(1), d 8.0(1), d 6.1(1), s 2.1(3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:22]1([CH2:28]C#N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]4[C:15]([CH:14]=3)=[C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][N:19]=4)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5ccccc5)c4c3)OCCO2)cc1
Yield: 16.3 %

Procedure:
2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (prepared as described in WO 97/21701) (0.0373 mol) was added to a vigorously stirring mixture of benzene acetonitrile (0.041 mol) and NaOH (0.186 mol) in methanol (37.3 ml) (an exothermic effect was observed and the temperature rose to 45° C.) and the mixture was stirred vigorously for 20 h. The mixture was diluted with water and filtered off. The precipitate was washed with water and a few methanol and dried. A part (3.5 g) of the residue (10.59 g, 75%) was purified by column chromatography over silica gel (eluent: DCM). The pure fractions were collected and evaporated. The residue (2.94 g) was crystallized from DIPE, yielding 2.3 g of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-phenyl-2,1-benzisoxazole, mp. 143.4° C. (intermediate 23).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cc(I)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 8-Iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0016 mol) in N-methyl 2-pyrolidone (5 mL) was added powdered potassium hydroxide (0.9 g, 0.016 mol) and allowed to stir for 10 min at RT. 2-Methyl-5-vinyl-pyridine (0.969 g, 0.0048 mol) was added and stirred for further 24 hours at 100° C., after completion (TLC), reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (6% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), then further purified by preparative HPLC to get the desired compound as brown solid (0.105 g, 15.2% yield). 8-Iodo-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.095 g, 0.00022 mol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.0277 g, 0.00022 mol) in THF (2.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.09 g, 79% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:13]([O:20][C:21]1[CH:48]=[CH:47][C:46](Br)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:31]([O:30][C:28](=[O:29])[C:27]1[CH:35]=[CH:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:38][C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:45]=[C:46]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:47]=[CH:48][C:21]=1[O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Morpholine (0.014 mL), cesium carbonate (0.070 g), tris(dibenzylideneacetone)dipalladium(0) (1.0 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.6 mg), and palladium(II) acetate (0.5 mg) were added to a toluene (0.90 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.060 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then morpholine (4.7 μL), cesium carbonate (0.035 g), tris(dibenzylideneacetone)dipalladium(0) (1.0 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2.6 mg), and palladium(II) acetate (0.5 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-60% hexane/ethyl acetate] to obtain 0.060 g of tert-butyl-2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate as a light yellow solid.