Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:8]1([CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOCC>[CH:8]1([CH2:14][CH:15]([O:18][C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:16]=[CH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)CC(=O)Cl
Reactant: C=CC(O)CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(CC1CCCCC1)OC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.4 ml (19.5 mmol) of isovaleric acid chloride are added dropwise at 0° C. to a solution of 2.75 g (17.76 mmol) of 1-cyclohexyl-3-buten-2-ol, 3 ml (21.3 mmol) of triethylamine and 430 mg (3.5 mmol) of 4-dimethylaminopyridine in 20 ml of methylene chloride. When the addition is complete, the mixture is stirred for a further 3 hours at room temperature. After diluting with ether, the mixture is washed twice with 2N HCl, twice with saturated NaHCO3 solution and twice with brine and dried over MgSO4. After concentration by evaporation, the residue is distilled in a bulb tube at 150°/0.007 mbar.
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:45]=[C:46]=[O:47])[CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42].[NH2:48][C:49]1[CH:50]=[N:51][C:52]2[C:57]([C:58]=1[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[Cl:65])=[CH:56][C:55]([CH3:66])=[CH:54][C:53]=2[CH3:67]>O1CCOCC1.C(N(CC)CC)C>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[C:58]1[C:57]2[C:52](=[C:53]([CH3:67])[CH:54]=[C:55]([CH3:66])[CH:56]=2)[N:51]=[CH:50][C:49]=1[NH:48][C:46]([NH:45][C:37]1[CH:36]=[C:35]([O:34][CH3:33])[C:40]([O:41][CH3:42])=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:47]
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(NC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc(OC)c1OC
Reaction time: 0.67 h

Procedure:
Triethylamine (0.37 ml) was added dropwise to a mixture of 3,4,5-trimethoxybenzoic acid (563 mg), diphenylphosphoryl azide (730 mg) and dioxane (10 ml) under stirring. The mixture was further stirred for 30 mins. at room temperature and then for 40 mins. under reflux to prepare a solution of 3,4,5-trimethoxyphenyl isocyanate. After cooling, to the resultant solution was added 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (500 mg), and the whole was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by a column chromatography on silica gel and recrystallized from dichloromethane to give 4-(2-chlorophenyl)-6,8-dimethyl-3-[3-(3,4,5-trimethoxyphenyl)ureido]-quinoline as colorless needles. Yield 490 mg (56.3%). m.p. 204°-206° C.
Reaction SMILES: C[Al](C)C.[C:5](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C.[CH3:22][C@:23]12[CH2:40][CH2:39][C@H:38]3[C@@H:28]([CH2:29][CH2:30][C:31]4[C@:36]3([CH3:37])[CH:35]=[CH:34][C:33](=[O:41])[CH:32]=4)[C@@H:27]1[CH2:26][CH2:25][C:24]2=[O:42]>CCCCCC.C(OC)(=O)C.[Ni+2].C/C(/[O-])=C/C(C)=O.O>[CH3:5][C:35]1[C@@:36]2([CH3:37])[C:31]([CH2:30][CH2:29][C@@H:28]3[C@@H:38]2[CH2:39][CH2:40][C@@:23]2([CH3:22])[C@H:27]3[CH2:26][CH2:25][C:24]2=[O:42])=[CH:32][C:33](=[O:41])[CH:34]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: COC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Temperature: 50 °C
Yield: 183.1 %

Procedure:
86.4 ml (80 mmol) of a 10% solution of trimethylaluminum in hexane is introduced at room temperature under nitrogen atmosphere. With stirring, 17.4 g (80 mmol) of 2,6-di-tert-butyl-4-methylphenol is added in portions. The solution is stirred for 30 more minutes and subsequently stirred until the end of the methane generation. 28.4 g (100 mmol) of androsta-1,4-diene-3,17-dione (ADD) in 200 ml of methyl acetate is added at 25° C. The solution is heated to 50° C. 1.43 g (5 mmol) of nickel(II)-acetylacetonate is added at 50° C. The solution is stirred for 50 more minutes at a temperature of 50° C. For hydrolysis, 15 ml of water is added with cooling, for completion, it is stirred for 15 more minutes. The inorganic solid is filtered off and rewashed twice with 50 ml of methyl acetate. After concentration by evaporation Of the methyl acetate phases, 43.71 g of crude product is obtained, which is chromatographed on silica gel with hexane/ethyl acetate as eluent with increasing ethyl acetate portion. After concentration by evaporation of the fractions, 6.5 g of 1-methyl-androsta-1,4-diene-3,17-dione (23% of theory) of melting point 168° C. is obtained.
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[C:6]([NH:25][C@H:26]([CH2:29][CH3:30])[C@@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CSC
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a stirred suspension of CuBr.SMe2 (2.74 g, 13.33 mmol) in Et2O (100 mL) under Ar e at −70° C., was added methyl lithium (1.6 M in Et2O; 16.6 mL, 26.56 mmol) dropwise and the solution allowed to warm to RT. The mixture was re-cooled to −70° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (2 g, 6.05 mmol) in. Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h, when TLC (8:2 hexane:Et2O) indicated that the reaction had gone to completion. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to RT over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane/Et2O (8:2) to afford the title compounds as a light yellow oil (1.91 g, 91%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.44-0.58 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5H, —NHCH (CH2CH3)CH(CH3)OH+—NHCH(CH2CH3)CH(CH3)OH), 2.03 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.32-3.51 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.40 (d, 1H, J=3.79 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.14-7.51 (m, 15H, 3×Bz).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:29]([N:25]1[CH2:26][CH2:27][CH:22]([C:20]2[CH:19]=[CH:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)[CH2:23][CH2:24]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: c1ccc(-c2cc(-c3cnc4cc(C5CCNCC5)ccn34)ccn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-phenyl-pyridin-4-yl)-7-piperidin-4-yl-imidazo[1,2-a]pyridine (Ex. 1.198) (1.0 eq, 0.16 mmol, 80 mg) in MeOH (2 ml) is added acetone (10 eq, 1.6 mmol, 0.12 ml) and acetic acid (2 eq, 0.33 mmol, 0.19 ml) and the reaction mixture is stirred at room temperature for 30min. After this time sodium triacetoxyborohydride (5 eq, 0.82 mmol, 183 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2C12 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-(1-Isopropyl-piperidin-4-yl)-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a light yellow solid; [M+H]+=397
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[CH2:7][NH:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]2[N:13]3[CH2:12][CH2:11][NH:10][C:9]3=[N:8][CH2:7]2)=[CH:4][CH:3]=1
Reactant: OC(CNC1=NCCN1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: Clc1ccc(C2CN=C3NCCN32)cc1

Procedure:
3.4 parts of p-chloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol are added to 30 parts of sulfuric acid 80% while stirring and cooling in an ice-bath. Upon completion, the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto crushed ice, alkalized with a concentrated sodium hydroxide solution and the product in base form is extracted with methylene chloride. The extract is dried, filtered and evaporated. The residue is dissolved in 2-propanol. The solution is filtered over diatomaceous silica and the filtrate is acidified with an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off, washed with acetone and dried, yielding 5-(p-chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole hydrochloride, m.p. 266.1°C.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C[N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=O.C(N(C(C)C)CC)(C)C.[C:27]1(C)[CH:32]=CC=[CH:29][CH:28]=1>>[Cl:1][C:2]1[N:7]([CH2:13][C:14]2[CH:29]=[CH:28][CH:27]=[CH:32][C:15]=2[C:16]#[N:12])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: CN1CCCC1=O
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)cc(Cl)n(Cc2ccccc2C#N)c1=O
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-chloro-3-methyluracil (1 equiv., 1 wt.), N-methylpyrrolidone (NMP; 4 vol.) and diisopropylethylamine (Hünig's base, 1.5 equiv., 1.21 wt.), was added a solution of α-bromotoluoylnitrile (1.1 equiv., 1.35 wt.) and toluene (4 vol.). The mixture was heated at 60-70° C. and agitated for 2-3 hrs, or until completion. The solution was then cooled to 20-30° C., quenched with deionized water (5 vol.) at less than 35° C., agitated for 30 min, cooled to 0-5° C., and then agitated for at least one hour. The resultant slurry was filtered, reslurried in isopropanol, displacement washed with isopropanol, and dried under vacuum at 55-60° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:21][C:18]4[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=4)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
After adding 2.97 of potassium carbonate and 30 ml of dimethylformamide to 3.09 g of 4-nitrophenol and stirring the mixture at 130° C. for 10 minutes, 2.49 g of 6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine was added and the mixture was further stirred at 130° C. for 5 hours and at 135° C. overnight. After returning the mixture to room temperature, water was added, the precipitated solid was filtered out and subjected to NH silica gel column chromatography (ethyl acetate) and silica gel column chromatography (ethyl acetate), and then ether and ethyl acetate were added prior to sonication. The solid was filtered out to obtain 1.2 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methyl 4-t-butylphenylacetate (20 mmol) was dissolved in MeOH (160 mL) and treated with water (40 mL) and LiOH monohydrate (30 mmol). The reaction was allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the remaining residue was diluted with water and neutralized to pH 4 with 1 N sulfuric acid. The resulting solids were filtered, washed with water and dried to leave 4-t-butylphenylacetic acid as an off-white solid (3.8 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[O:16][C:15](=[O:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[OH-:19].[K+]>CO>[OH:16][C:17]1[C:9]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:15]([OH:18])=[O:19]
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2O1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: O=C(O)Cc1cccc(Sc2ccccc2Cl)c1O

Procedure:
7-(2-Chlorophenylthio)-2,3-dihydrobenzofuran-2-one (0.2 g) was added to a solution of potassium hydroxide in methanol, and the mixture was stirred under warming to give 2-[2-hydroxy-3-(2-chlorophenylthio)phenyl]acetic acid (0.2 g), mp. 91°-93° C.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C:13]1[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=1>C(O)(=O)C.[Fe]>[NH2:10][C:6]1[C:7]([Cl:9])=[CH:8][C:3]([Cl:2])=[C:4]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Then, 0.59 g of iron powder was added to a mixture of 5.3 ml of acetic acid and 3.2 ml of water, to which a solution of 0.65 g of 3-(2,4-dichloro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-333) in 1.6 ml of acetic acid was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 0.49 g (yield, 82%) of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334; m.p., 188.7° C.).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>O1CCCC1>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)=[CH:24][CH:25]=1)#[N:30]
Reactant: N#Cc1ccc(CCCC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(C#N)cc3)CC2)CC1

Procedure:
50 ml (0.18 moles) of a tetrahydrofuran (hereinafter referred to simply as THF) solution of 2.5M of propylmagnesium chloride was dropped in a mixed solution of 37.4 g (0.1 mol) of 1-chloro-4-(trans-4-(4-(4-cyanophenyl)butyl)cyclohexyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of the solvent and salts, followed by isolation through chromatography to obtain 30.2 g (yield: 79%) of the intended trans isomer product.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH2:14])[CH2:7][CH2:6]2.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O1CCCC1>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH:14][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CCc2cc(I)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CCc2cc(I)ccc2O1)OCc1ccccc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of (R)-6-iodo-chroman-2-methylamine hydrochloride of Example 10 (3.3 g, 10 mmol) and benzylchloroformate (1.57 mL, 11 mmol) in tetrahydrofuran (30 mL) cooled in an ice-water bath was added slowly 1N aqueous sodium hydroxide in 20 minutes. The resulting mixture was stirred for 1 hour. The organic layer was separated and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined ethyl acetate layer was combined with the above residue and washed with water (50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude product as a white solid (4.2 g, 99%). 1H nmr (DMSO d6) δ 1.5-1.6 (m, 2H), 1.9 2.0 (m, 1H), 2.7 (m, 2H), 3.3 (m, 2H), 4.0 (m, 1H), 5.0 (s, 2H), 6.5 (d, 1H), 7.3 (m, 7H), 7.5 (t, 1H).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1/[CH:14]=[CH:34]/[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)oc2C)cc1

Procedure:
(5-Methyl-2-phenyl-4-oxazolylmethyl)triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless prisms having a melting point of 164°-165° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[C:5]2[CH:9]=[CH:10][NH:11][C:4]=2[CH:3]=1.P(Br)(Br)([Br:14])=O.C([O-])(O)=O.[Na+]>>[Br:14][C:6]1[C:5]2[CH:9]=[CH:10][NH:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc2[nH]ccc2c(O)n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2[nH]ccc2c(Br)n1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
A mixture of 6-methyl-1H-pyrrolo[3,2-c]pyridin-4-ol (J. Het. Chem., 1996, 303) (161 mg, 1.09 mmol) and phosphorus oxybromide (1.87 g, excess) was heated in a sealed tube at 120° C. for 50 minutes. The reaction mixture was poured onto water (10 mL), basified with aqueous NaHCO3 to pH 8 and the organic product extracted into DCM. The organic layer was dried (phase separator), evaporated and the residue purified by column chromatography (Si—PCC, cyclohexane:ethyl acetate, gradient 100:0 to 70:30) to give 4-bromo-6-methyl-1H-pyrrolo[3,2-c]pyridine (20 mg, 12%) as a white solid. LCMS RT=2.00 min, [M+H]+ 211
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C(O)=O)CC=CCC1.C(Cl)(Cl)Cl.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>O>[OH:19][CH2:18][CH2:17][C:16]1[C:4]2[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Agent: O=C(O)C1CC=CCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1oc2c(CCO)cccc2c1-c1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 28.6 g. (0.0904 mole) of 2-bromo-7-(2-hydroxyethyl)-3-phenylbenzofuran (the product of step A, Example 5) and 15.1 g. of 4-cyclohexenecarboxylic acid in 250 ml. of chloroform is added dropwise 10.8 g. (0.118 mole) of dinitrogen tetraoxide in 30 ml. of chloroform. After 16 hours, 7 g. of dinitrogen tetraoxide and 5 g. of 4-cyclohexenecarboxylic acid in 30 ml. of chloroform are added, and the mixture is heated at 45° C. for four hours. Water is added to the mixture, the chloroform layer is separated and washed with water, then thrice with sodium bicarbonate solution, thrice with water, once with saturated sodium chloride solution and dried. Evaporation provides a yellow residue. Thin layer chromatographic analysis shows two main products. This residue is recrystallized from 50/50 ethanol/water, then again from carbon tetrachloride to yield 7-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran as a yellow solid, m.p. 133.5°-136° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1Cl
Yield: 63.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 2-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 118 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([CH3:19])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:18])[C:15]=1[CH2:16]O)=[O:7].O=S(Cl)[Cl:23].ClC1C=NC=C(Cl)C=1CCl>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([CH3:19])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:18])[C:15]=1[CH2:16][Cl:23])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CC(C)C(=O)NCc1cncc(Cl)c1CO
Agent: ClCc1c(Cl)cncc1Cl
Product: COC(=O)CC(C)C(=O)NCc1cncc(Cl)c1CCl

Procedure:
N-(5-Chloro-4-hydroxymethyl-pyridin-3-ylmethyl)-3-methyl-succinamic acid methyl ester (1.39 mg, 0.0046 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 318.9 [M+H+].