Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@H:39]1[NH:47][C:48]([C:50]1[NH:54][C:53]2[C:55]([Cl:59])=[C:56]([Cl:58])[S:57][C:52]=2[CH:51]=1)=[O:49]>C(Cl)Cl>[Cl:58][C:56]1[S:57][C:52]2[CH:51]=[C:50]([C:48]([NH:47][C@@H:39]3[CH2:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C@H:38]3[NH:37][C:23](=[O:25])[CH2:22][O:21][CH3:20])=[O:49])[NH:54][C:53]=2[C:55]=1[Cl:59]
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), methoxyacetic acid (0.5 mmol, 38 μL) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 8, 240 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue was purified by flash column chromatography on SiO2 (1:1 EtOAc:isohexane); the solvent removed by evaporation under reduced presssure and dried to give the title compound (44 mg, 20%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[C:7]([CH:20]=[O:23])=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a stirred suspension of 71 (411 mg, 1.31 mmol) in toluene (12.8 mL) under N2 were sequentially added saturated NaHCO3 (aq. 0.5 mL), a solution of 99 (303 mg, 2.02 mmol) in EtOH (8.9 mL), and PdCl2(Ph3P)3 (52 mg, 0.07 mmol). The reaction was heated at 80° C. for 41 hours before it was allowed to cool to room temperature and extracted with ethyl acetate (50 mL). The ethyl acetate extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 100 as a yellow solid (166 mg, 37.4%).
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].[CH2:8](N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:19][N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]1[C:27](=[O:28])OC(C)(C)[O:24]1>CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:19][N:20]([CH3:32])[C:21]([C:22]1[CH2:8][N:5]([CH2:4][C:3]([F:7])([F:6])[F:2])[C:27](=[O:28])[C:23]=1[OH:24])=[O:31]
Reactant: CCN(CC)CC
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(F)(F)F)C1
Reaction time: 24 h
Yield: 20.5 %

Procedure:
To a stirred warm (60° C.) solution of 2,2,2-trifluoroethylamine hydrochloride (100 mg, 1.0 mmol) paraformaldehyde (32 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) in methanol (5 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (344 mg, 1.0 mmol). After 24 h, the reaction mixture was cooled and purified by preparative HPLC using a C18 column and water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (81.4 mg, 21% yield). 1HNMR (500 MHz, CDCl3) δ: 10.05 (1H, br s), 7.42 (1H, d, J=8.2 Hz), 7.36 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.60 (2H, s), 4.32 (2H, s), 4.10 (2H, q, 8.9 Hz), 3.04 (3H, s). HRMS calcd for C15H12Cl2F3N2O3 (M−H): 395.0177. found: 395.0192.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.O>ClC1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Into a 1-L jacketed reactor equipped with a retreat curve stir blade, overhead stirring, a thermocouple, a condenser, and a nitrogen bubbler was charged 1-aminopropan-2-ol (110 mL, 1430 mmol), which was then heated to 85 and 90° C. 1-Chloro-4-(2-chloroethyl)benzene (50.054 g, 286 mmol) was charged via addition funnel over 1 h with a maximum reaction temperature of 93° C. Stirring was then continued at 90 to 95° C. for 2.5 h. Chlorobenzene (100 mL) and water (50 mL) were added and the mixture was stirred at 70 to 75° C. for 15 min. The phases were allowed to separate and the aqueous phase was extracted with chlorobenzene (2×50 mL) at 70 to 75° C. The combined organic phases were then washed with water (2×50 mL) at 70 to 75° C. and concentrated by distillation under reduced pressure. The residue was dissolved in chlorobenzene to a total weight of 503 g and allowed to stand at room temperature overnight. A solid precipitate formed which was redissolved by adding chlorobenzene (50 mL) and heating the mixture at 30 to 35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][N:33]=[CH:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[CH2:39][CH2:40]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: c1cn(CCN2CCNCC2)cn1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCN(CCn2ccnc2)CC1
Temperature: 105 °C
Yield: 70 %

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 290 mg (1.6 mmol) of 1-(2-imidazole-1-yl-ethyl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 95:5methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-{4-[2-(1H-imidazole-1-yl)ethyl]piperazin-1-yl}-6-methoxyquinoline-3-carbonitrile as a beige solid, mp 251-253° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>O>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([S:2][CH3:1])[N:10]=1
Reactant: C[S-]
Reactant: Cc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1nc(C)nc(Cl)n1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Sodium methanethiolate (0.49 g, 7.0 mmol) was added portionwise at 0° C. to a stirred cloudy solution of 2,4-dichloro-6-methyl-1,3,5-triazine (7) (1.04 g, 6.3 mmol) in toluene (10 mL, 94 mmol) over 15 min. After addition, the pale yellow mixture was stirred at the same temperature for another 1 h, and water (10 mL) was added. The separated aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (hexanes to 70% DCM in hexanes) to give 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.87 g, 78% yield) as a white solid. MS (API-ES) m/z 176 (M+H)+; 1H NMR (d6-DMSO, 400 MHz) δ 2.55 (s, 3H) 2.51 (br. s., 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[C:5]2=[O:13].[H-].[Na+].[H][H].I[CH3:19]>CN(C=O)C.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:19])[C:6](=[O:12])[C:5]2=[O:13]
Reactant: [H][H]
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(=O)c2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
To a solution of 5,6-dichloroisatin (0,15 g; 0.7 mmol) in anhydrous DMF (5 ml) was added sodium hydride (40 mg, 60% dispersion in mineral oil). When the evolution of hydrogen had ceased iodomethane (0.1 ml) was added and the mixture was stirred for 20 min. at ambient temperature. Water (15 ml) and glacial acetic acid (0.1 ml) were added and the product was filtered off, washed with water and dried to yield 5,6-dichloro-1-methylisatin (0.13 g, 81%). The following compounds were prepared analogously: 4,5-dichloro-1-methylisatin (2b) from 4,5-dichloroisatin, and 6,7-dichloro-1-methylisatin from 6,7-dichloroisatin.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>C(OC(=O)C)(=O)C>[CH:19]([N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])=[O:20]
Reactant: O=CO
Reactant: CC(C)CC(CNOCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC(CN(C=O)OCc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
1.0 g of N-benzyloxy 2(RS)-isobutyl-3-amino-propionic acid in 10 ml of formic acid and 1 ml of acetic anhydride was stirred at room temperature for 2 hours and then evaporated. The residue was taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to yield 1.2 g (100%) of N-formyl-N-benzyloxy 2(RS)-isobutyl-3-aminopropionic acid as a gum. Rf (toluene/acetic acid 4:1) 0.39.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][CH2:13][OH:14].CC1(C)C(C)(C)OB([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:15])[C:5]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:4][N:3]=1
Reactant: OCCCCO
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: OCCCCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 4b and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 1,4-butandiol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Cl:28])(=O)C>CO>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reactant: CC(=O)Cl
Solvent: CO
Product: Brc1cnc2ccc(NC[C@@H]3CCCN3)nn12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (13.4 g, 33.8 mmol) in MeOH (100 mL) was cooled to 0° C. and added acetyl chloride (24 mL, 338 mL) dropwise. The reaction was warmed to rt and stirred for overnight, and concentrated to give (S)-3-bromo-N-(pyrrolidin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine as HCl salt (11 g, 100% yield). LRMS (ESI) m/e 298.0 [(M+H)+, calcd for C11H15BrN5 298.2].
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O.CN(C)C=O>C(Cl)Cl>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Cl)cc1
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 6-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-nicotinic acid (49 mg, 0.15 mmol) and TBTU (53 mg, 0.17 mmol) in DMF (0.8 mL) was added DIPEA (129 μL, 0.76 mmol). Then isopropylamine (14 μL, 0.17 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (45 mg, 82%) as a light yellow solid after recrystallisation from methanol/water. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]OS(C)(=O)=O>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: CS(=O)(=O)OCCc1ccccc1Cl
Reactant: Ic1c[nH]cn1
Product: Clc1ccccc1CCn1cnc(I)c1

Procedure:
The compound is synthesized using the method described in example 4C starting from 4-iodo-1H-imidazole and methanesulfonic acid 2-(2-chlorophenyl)-ethyl ester (example 78D).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:17])[N:15]=O.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]1[N:22]=[N:15][N:14]([CH3:17])[CH:13]=1
Reactant: CN(C)N=O
Reactant: N#Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1cc(-c2ccccc2F)nn1
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a pre cooled (−78° C., internal temp. −70° C.) solution of diisopropyl amine (193.13 g, 1899.04 mmol) in THF (1500 ml) under nitrogen atmosphere was added n-Butyllithium (759.617 ml, 1899.04 mmol, 2.5 M solution in hexane) and stirred for 90 min. Then N,N-dimethyl nitrous amide 2 (134.57 g, 1816.48 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min. and stirred for 1 h. Then a solution of 2-Fluorobenzonitrile 1 (100.0 g, 825.671 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min and stirred at −78° C. (internal temp. −70° C.) for 1 h. Then cooling bath was removed and stirred at room temperature for 2 h. The reaction was monitored by TLC and UPLC. The above reaction mass was slowly quenched with saturated solution of ammonium chloride (2000 ml) at room temperature and the aqueous layer was extracted with dichloromethane (5×2000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (170.0 g, 116.21% mass balance). It was purified by gravity column using 30% ethyl acetate in pet ether as an eluent to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (64.52 g, 44.10% mass balance) as reddish gum. Then it was triturated with methyl tert-butyl ether (1000 ml) and hexane (500 ml), the supernant layer was decanted and the solid was dried to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (32.9 g, 22.49%) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:10][OH:11].[S:21](Cl)([CH3:24])(=[O:23])=[O:22].N1C=C[CH:29]=[CH:28][CH:27]=1>>[CH:28]([O:22][CH:18]([CH3:17])[CH3:13])([CH3:29])[CH3:27].[CH3:24][S:21]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])(=[O:23])=[O:22]
Reactant: OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Product: CC(C)OC(C)C
Product: CS(=O)(=O)OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 48.2 parts of 2,3-bis(2,4-dichlorophenyl)-1-propanol in 150 parts of pyridine are added dropwise 14 parts of mesyl chloride at room temperature. Upon completion, stirring at room temperature is continued overnight. The reaction mixture is poured onto water and the product is extracted twice with diisopropylether. The combined extracts are washed successively three times with a dilute hydrochloride acid solution and once with water, dried, filtered and evaporated. The residue is crystallized first from methanol and then from diisopropylether, yielding 25.8 parts of 2,3-bis(2,4-dichlorophenyl)-1-propanol methanesulfonate; mp. 84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19](Br)[CH3:20])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]21[O:18]CCO2.[Mg].[C:23](=[O:25])=[O:24].Cl>O1CCCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]([CH3:20])[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:18]
Reactant: O=C=O
Reactant: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reaction time: 4 h
Yield: 61 %

Procedure:
5.6 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethyl bromide were dissolved in 50 ml of tetrahydrofuran and added dropwise over one hour to 0.55 g of magnesium suspended in 10 ml of tetrahydrofuran, after which the whole was refluxed under agitation for three hours and cooled to produce a Grignard's reagent. The Grignard's reagent so produced was poured onto an excessive amount of solid carbon dioxide and allowed to stand still for 4 hours, after which the whole was acidified with diluted hydrochloric acid and extracted with 100 ml of ether. The extract obtained was concentrated to obtain a residue which was then incorporated with 25 ml of acetic acid and 10 ml of water and refluxed under agitation for two hours. After the end of the reaction, the reaction mixture was incorporated with 100 ml of water and extracted with 50 ml of ether. The extract obtained was washed with water, dried and freed of the solvent to obtain a residue which was then recrystallized from isopropyl ether thereby to obtain 2.7 g (yield 61%) of 2-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl] propionic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[BrH:11].[NH+]1C=CC=CC=1.Br>C(O)(=O)C>[Br:11][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxyacetophenone (10 g) and pyridinium hydrobromide perbromide (23.5 g) in acetic acid (80 ml) was added hydrogenbromide (30% in acetic acid solution) (40 ml) and the mixture was stirred overnight at ambient temperature. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to afford 2-bromo-1-(4-hydroxyphenyl)ethanone (1.72 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:23]3[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])=[CH:25][C:24]=3[F:26])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 81.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.113 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (26 mg, 0.113 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 82%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:8]1[CH2:13]CCC[CH2:9]1)=O.CN(C)[CH:16]=[O:17]>>[CH3:16][O:17][C:3]1[CH:2]=[CH:13][N:8]=[CH:9][C:4]=1[CH:5]=[O:1]
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: O=CN1CCCCC1
Product: COc1ccncc1C=O
Yield: 60 %

Procedure:
A reaction scheme according to embodiments of the present invention is illustrated in FIG. 1. As illustrated in FIG. 1, methoxypyridine is deprotonated using the alkylmetal reagent (trimethylsilylmethyl)lithium. According to embodiments of the present invention, 4-methoxypyridine may be reacted with (trimethylsilylmethyl)lithium then N-formylpiperidine to produce 4-methoxy-3-pyridinecarboxaldehyde (MPC). The reaction is carried out at a temperature of about −20° C. or less in the presence of tetrahydrofuran (THF). HCONR2 is also added to the reaction mixture, wherein R is an alkyl group, for example, dimethylformamide or 1-formylpiperidine. The resulting 4-methoxy-3-pyridinecarboxaldehyde is crystallized directly from the reaction mixture with yields between about 60 percent to about 100 percent MPC, depending on temperature used. For example, in the reaction scheme of FIG. 1, a 60 percent yield was achieved at −10° C. and a 100 percent yield was achieved at −30° C. Yields may be higher at temperatures below about −20° C. but are still acceptable at higher temperatures, for example at about −12° C. or higher. The presence of directed ortho metallating groups gives typical selectivity for deprotonation on the aromatic rings. Likewise, lateral lithiation, where side chains on the aromatic ring are metallated, is possible with these bases.