Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].CON(C)[C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:13]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:12]=1)=[O:10].Cl>C1COCC1>[C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:13]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:12]=1)(=[O:10])[CH:1]([CH3:3])[CH3:2]
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Reactant: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)C(C)C)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 0.76M solution of isopropyl magnesium bromide in THF (8.5 ml) was added dropwise to a solution of tert-butyl {4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]benzyl}carbamate (1 g) in THF (10 ml) at 10–15° C. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of 1M HCl and ice. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=20%, 25%, then 10% MeOH/CHCl3. The combined pure fraction was concentrated in vacuo to give tert-butyl {4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate (318 mg) as an amorphous powder.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[C:18]([CH2:26][CH3:27])=[N:19][C:20]([CH3:25])=[N:21][C:22]=3[CH2:23][CH3:24])[N:12]([CH2:28][CH2:29][CH2:30]O)[C:11]=2[C:10]([C:32]([O:34][CH3:35])=[O:33])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:32]([O:34][CH3:35])=[O:33])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[C:22]([CH2:23][CH3:24])=[N:21][C:20]([CH3:25])=[N:19][C:18]=3[CH2:26][CH3:27])[CH2:30][CH2:29][CH2:28][N:12]21
Reactant: CCc1nc(C)nc(CC)c1Nc1nc2c(Cl)ccc(C(=O)OC)c2n1CCCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1N1CCCn2c1nc1c(Cl)ccc(C(=O)OC)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
Methanesulfonyl chloride (1.10 mL, 13.4 mmol) was added to a stirred solution of methyl 4-chloro-2-[(4,6-diethyl-2-methylpyrimidin-5-yl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 125, 2.90 g, 6.71 mmol) and triethylamine (2.8 mL) in tetrahydrofuran (35 mL) at 0° C. The mixture was stirred at 0° C. for 90 min, and concentrated in vacuo. A mixture of the resulting mesylate and potassium carbonate (2.78 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 70° C. for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (2.21 g, 5.34 mmol, 80% in 2 steps).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OCCC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl 4-(2-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[CH:21]>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[CH:21])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Yield: 88.1 %

Procedure:
In a similar manner as described in Example 7 from 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (5.49 g, 20.0 mmol) and ethynylmagnesium bromide (100 mL, 0.5 M in tetrahydrofuran, 50.0 mmol) at 0° C., recrystallized from dichloromethane, was obtained 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (5.3 g, 88%) as a pale yellow crystalline solid. 1H NMR (CDCl3): δ 8.04 (d, 1H), 7.79 (m, 2H), 7.20 (m, 3H), 7.01 (d, 1H), 5.77 (m, 1H), 2.69 (d, 1H), 2.32 (d, 1H); MS m/z 301 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:22])=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH:42]=1)#[N:26]
Reactant: CN(CCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.33 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=629 ([M+H]+, 5), 229 (84), 109 (100); IR (KBr): 2166 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from ethanol/acetonitrile/isopropanol; m.p. 84°-86° C. (ethanol/acetonitrile/isopropanol).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[CH:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2)[CH3:2].[CH3:22][C:23](=[O:26])[C:24]#[CH:25].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:23]([C:24]1[CH:25]=[C:5]2[N:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=13)[C:3]([CH2:1][CH3:2])=[C:4]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:26])[CH3:22]
Reactant: C#CC(C)=O
Reactant: CCc1c(-c2ccc(OC)cc2)cn2ccc(OC)cc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OC)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Yield: 62.3 %

Procedure:
A solution of 1-ethyl-7-methoxy-2-(4-methoxyphenyl)indolizine (Compound 3) (2.0 g, 7.11 mmol) in 65 ml of toluene was stirred in an ice bath, while 3-butyn-2-one (0.64 ml, 8.17 mmol) was added dropwise. The cooling source was removed and stirring was continued for twenty hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.73 g, 7.61 mmol) was added in portions and stirring was continued for twenty hours. The solvent was evaporated and the residue chromatographed over aluminium oxide with heptane/tetrahydrofuran (1:1) as eluent to afford 1.54 g (63%) of the title compound. M.p. 137-39° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.39 (t, 3H), 2.64 (s, 3H), 3.15 (q, 2H), 3.87 (s, 3H), 4.09 (s, 3H), 7.19 (d, 2H), 7.80 (d, 2H), 7.82 (d, 1H), 7.89 (d, 1H), 8.15 (s, 1H). (Compound 6).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:43]=3)=[O:37])[CH:23]=2)=[CH:18][CH:17]=1)=O)(C)(C)C>>[CH3:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:43]=3)=[O:37])[CH:23]=2)=[CH:20][CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2ccc(C(=O)O)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.16 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration, and ethanol and water were added to the obtained solid substance. After adjusting the pH to 5.5 with a 1 mol/L aqueous solution of sodium hydroxide, the solid substance was collected by filtration to obtain 0.11 g of 4-(4-(methylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:54]>O1CCOCC1>[ClH:54].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)[CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCNCC5)c4)cnc32)cc1
Yield: 72.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-33, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (compound of step-i of example-33) (130 mg, 0.184 mmol) was deprotected using methanol/HCl in dioxane (5/5 mL) to give 86 mg, (72.8%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH:16][C:25](=[O:26])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCC(c1ccccc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To 4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (201) (0.75 g, 2.21 mmol) in pyridine (5 mL) was added Ac2O (5 mL). The reaction was allowed to stir at 60° C. for 1 h and then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL)), H2O (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 0.85 g (99%) product.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][C:5]2[C:6]([C:19]([NH2:21])=O)=[N:7][N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[C:4]=2[CH2:3]1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[O:1]=[C:2]1[CH2:22][C:5]2[C:6]([C:19]#[N:21])=[N:7][N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[C:4]=2[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(N)=O)c3c2CC(=O)C3)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2nc(C#N)c3c2CC(=O)C3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step E above (0.91 mmol) in anhydrous DMF (5 mL) was added cyanuric chloride (334 mg, 2.0 mmol) in two portions. After stirring at room temperature for 15 minutes, the reaction was quenched by pouring into water (10 mL). The resulting mixture was extracted with ethyl acetate, washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 25% ethyl acetate-hexaries. A white solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCOCCCN
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CCOCCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-ethoxypropan-1-amine to afford 2-chloro-N-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hu). LC-MS (M+H)+=350.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[C:18]2[C:14]([CH2:15][CH2:16][NH:17]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[C:19]([Cl:20])=[C:18]2[C:14]([CH2:15][CH2:16][N:17]2[C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Clc1ccc2c(c1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2ccc(Cl)c(Cl)c21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 6,7-dichloroindoline (D34) to give (E17) (0.84 g, 46%) m.p. 178°-180° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][CH:19]=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][C@H:19]2[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: O=CCCc1cc(Cl)cc(Cl)c1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CO[C@H](CCc2cc(Cl)cc(Cl)c2)OC1
Yield: 72.1 %

Procedure:
A solution comprising 18.3 g (155.1 mmol) of 2-propyl-1,3-propanediol, 30.0 g (147.7 mmol) of 3-(3,5-dichlorophenyl)-propionaldehyde, 1.5 g of p-toluenesulfonic acid, and 300 ml of toluene was heated to reflux while taking out the distilled water for 3 hours. After termination of the reaction, the organic layer was washed with a diluted aqueous sodium bicarbonate solution once and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 32.3 g of a crude trans-2-(2-(3,5-dichlorophenyl)ethyl)-5-propyl-1,3-dioxane. (Yield: 72.1%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][C@@H:15]([OH:27])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:30]([N:17]([CH2:16][C@H:15]([OH:27])[CH2:14][O:13][C:12]1[CH:28]=[CH:29][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(CCNC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(CCN(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (S)-1-(4-benzyloxyphenoxy)-3-[N-2-(4-hydroxyphenyl)ethylamino]propan-2-ol (1.9 g, 4.8 mMol) and benzyl bromide (0.57 ml, 4.8 mMol) in dimethylformamide (10 ml) containing sodium carbonate (770 mg, 7.2 mMol) was stirred at room temperature for 18 hours. The mixture was filtered and the residue was washed with ethyl acetate. The filtrates were combined, washed with water and brine, dried and evaporated. Purification of the residue by flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the title compound.
Reaction SMILES: N([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=C=O.[NH2:43][CH2:44][C:45]1([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46]1>C1COCC1>[C:51]([O:50][C:49]([NH:48][C:45]1([CH2:44][NH:43][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:46][CH2:47]1)=[O:55])([CH3:52])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)NC1(CN)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCC3(NC(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 1.053 mmol) and N,N-diisopropyethyllamine (0.734 mL, 4.21 mmol) in THF (6 mL) was added tert-butyl 1-(aminomethyl)cyclopropylcarbamate (294 mg, 1.579 mmol). The resulting mixture was stirred at rt. After 16 h, the solvent was concentrated. The crude material was dissolved in THF (1 mL) and MeOH (2 mL), filtered and purified by reverse phase preparative HPLC (method 1) to give the title compound (499.5 mg, 58% yield) as a white solid. LCMS: m/e 756.7 (M+H)+, 2.75 min (method 7). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.5 Hz), 5.3-5.3 (1H, m), 5.1 (1H, br. s.), 4.8 (1H, s), 4.7 (1H, s), 3.9 (3H, s), 3.5-3.5 (1H, m), 3.4 (1H, d, J=14.3 Hz), 2.8 (1H, br. s.), 2.6 (1H, d, J=12.8 Hz), 2.4 (1H, dd, J=12.2, 8.2 Hz), 2.1 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.8 (1H, d, J=13.4 Hz), 1.7-1.8 (1H, m), 1.7 (3H, s), 1.7-1.7 (2H, m), 1.5-1.7 (3H, m), 1.5 (9H, s), 1.4-1.5 (5H, m), 1.2-1.3 (1H, m), 1.1-1.2 (2H, m), 1.1 (3H, s), 1.0 (3H, s), 1.0 (3H, s), 0.9 (6H, s), 0.8-0.9 (3H, m). 13C NMR (CHLOROFORM-d) δ ppm 14.1, 15.4, 16.1, 19.0, 19.5, 20.7, 20.8, 24.8, 27.0, 28.1, 29.1, 29.2, 29.4, 31.4, 33.2, 35.1, 36.0, 36.6, 37.2, 40.4, 41.4, 41.6, 46.0, 49.1, 49.6, 51.7, 52.5, 77.3, 80.1, 109.9, 123.7, 127.6, 128.2, 129.8, 146.0, 148.4, 149.2, 167.0.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=C.C(Cl)Cl>>[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:1]
Reactant: C=Cc1ccc(C2(C#N)CC2)cc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: N#CC1(c2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
Ozone was bubbled through a solution of 1-(4-vinylphenyl)cyclopropanecarbonitrile (1.8 g, 0.011 mol) in methylene chloride (40 mL, 0.6 mol) at −78° C. until a blue color appeared and then nitrogen was bubbled through the solution for 10 minutes. Methyl sulfide was added and the mixture was stirred overnight. The mixture was washed with water and brine successively, dried, and concentrated to give the desired product.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH:67]1([CH2:70][O:71][C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH2:69][CH2:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:74]4[CH:73]=[C:72]([O:71][CH2:70][CH:67]5[CH2:68][CH2:69]5)[CH:77]=[CH:76][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OCC2CC2)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(OCC4CC4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-cyclopropylmethoxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=446.
Reaction SMILES: [CH:1]1([C:6]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]([O:17]C)[CH:10]=2)([CH3:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)C>[CH:1]1([C:6]([C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:17])[CH:10]=2)([CH3:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCC2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(c1cc(O)cc(O)c1)C1CCCC1

Procedure:
Compound 20 was prepared from Compound 13 using the same procedure as described above for Compound 16. Yield 1.29 g (72.9%) as a viscous oil. Rf=0.28 (hexane:diethyl ether 6:4); 1H NMR δ 6.44 (d, J=2.1 Hz, 2H), 6.20 (t, J=2.1 Hz, 1H), 5.70 (br s, 2H), 2.02–1.98 (m, 1H), 1.57–1.35 (m, 6H), 1.18 (s, 6H); 13C NMR δ 156.22, 154.66, 105.10, 99.83, 53.24, 50.33, 36.21, 24.99, 24.75; MS: (ESI, Neg.) m/z 219 ([M−H]−).
Reaction SMILES: C1N2CCN(CC2)C1.[CH3:9][N:10]=[C:11]=[O:12].[CH3:13][NH:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>O1CCOCC1>[CH3:13][NH:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:11]([NH:10][CH3:9])=[O:12])[CH:18]=1
Reactant: CN=C=O
Reactant: CNC(=O)Cc1cccc(N)c1
Agent: C1CN2CCN1CC2
Solvent: C1COCCO1
Product: CNC(=O)Cc1cccc(NC(=O)NC)c1
Reaction time: 3 h

Procedure:
0.1 g of triethylenediamine, followed by 5.7 g (0.1 mol) of methyl isocyanate, was added to a solution of 16.4 g (0.1 mol) of 3-amino-phenylacetic acid methylamide in 100 ml of dioxane at room temperature. The mixture was stirred for a further 3 hours at 40° to 50° C. After cooling, the crystalline precipitate which had separated out was filtered off and dried. After recrystallization from ethanol, 19.5 g (88% of theory) of 3-(N'-methylureido)-phenylacetic acid methylamide of melting point 175°-177° C were obtained.