Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:6]=1.C1CCN2C(=NCCC2)CC1.[C:34](=O)([O-])[O-:35].[K+].[K+]>ClCCl>[CH3:1][C:2]1[N:6]2[C:34](=[O:35])[N:8]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]3)[CH2:7][C:5]2=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1nc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(C)n2c1CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Yield: 97 %

Procedure:
tert-Butyl 4-(((2,5-dimethyl-1H-imidazol-4-yl)methyl)amino)-1-piperidinecarboxylate (8.0 g) obtained in Example 88a) was dissolved in dichloromethane (100 ml), DBU (3.6 ml) and N,N′-carbonyldiimidazole (3.9 g) were added thereto. The reaction solution was mixed for 15 hours, and then the reaction solution was poured into an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified with silica gel column to obtain a pale yellow oily title compound (7.8 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCCCCC.C1COCC1>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[CH:1][O:2][CH3:3])[C:31]=1[Cl:30]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=Cc1cccc(Cl)c1Cl
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
Into a flask under argon containing 700 ml of dry THF was placed 159 g (0.47 mole) of methyl(triphenylphosphoranylidene)acetate. To the stirred suspension cooled in an ice/water bath was added dropwise 320 ml (0.47 mole) of 1.45M n-butyllithium in hexane. After stirring for 20 min, 74 g (0.42 mole) of 2,3-dichlorobenzaldehyde in 700 ml of dry THF was added. After 2 hr the reaction mixture was washed with an ammonium chloride solution, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was taken up in ether, the undissolved solid was filtered off, and the solvent was evaporated in vacuo. The residue was distilled in a Kugelrohr apparatus at 0.005 mm Hg and the fraction distilling between 80°-100° C. collected. The distillate was distilled at 0.005 mm Hg using a Vigro column and the product collected between 101°-116° C. A preparative hplc on silica gel using hexane as the elutant gave 28.02 g of the title compound as an oil (33%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1C(CO)=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1C(CO)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 55.3 %

Procedure:
A suspension of 10% palladium carbon (16 g) in acetic acid (50 ml) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (9.0 g) in ethanol (300 ml.), and the mixture was subjected to catalytic reduction at 65° C. in the presence of hydrogen at 20 atm. for 9 hours. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (150 ml.) and adjusted to pH 7.5 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with petroleum ether and collected by filtration to give t-butyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (5.0 g.).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH2:17][N:18]2[N:22]=[CH:21][N:20]=[CH:19]2)[CH:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1)([C:4]#[N:5])[CH3:3].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CO.C(#N)C>[CH3:3][C:2]([C:6]1[CH:7]=[C:8]([CH2:17][N:18]2[N:22]=[CH:21][N:20]=[CH:19]2)[CH:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:13])[CH3:14])[CH:11]=1)([C:4]#[N:5])[CH3:1].[C:23]([O-:28])(=[O:27])[C:24]([O-:26])=[O:25]
Reactant: O=C(O)C(=O)O
Agent: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Solvent: CC#N
Solvent: CO
Product: O=C([O-])C(=O)[O-]

Procedure:
Anastrozole (28.3 mg, 0.096 mmol) and oxalic acid (8.9 mg, 0.099 mmol) were dissolved in 1 mL methanol:acetonitrile (1:1 v/v) solution. Crystals of anastrozole oxalate were obtained from slow evaporation at room temperature in an ambient atmosphere. Crystals of anastrozole oxalate were also obtained via crystallization of anastrozole (38.3 mg, 0.131 mmol) and oxalic acid (10.7 mg, 0.119 mmol) in 1.5 mL methanol:ethyl acetate (1:0.5 v/v) solution. The crystalline form of anastrozole oxalate was characterized by single crystal x-ray diffraction and melting point. (See FIGS. 14 and 15)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:18].O>C1COCC1>[CH3:18][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc2nccnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a solution of N-(quinoxalin-6-yl)acetamide (8.0 g, 0.043 mol) in THF (120 mL) was added sodium hydride (60% wt in mineral oil, 3.42 g, 0.086 mol). The mixture was stirred at room temperature for 10 min. Then iodomethane (7.28 g, 0.051 mol) was added. The mixture was stirred at room temperature for 2 h. Water (60 mL) was added carefully. The mixture was extracted with EtOAc (3×150 mL). The extracts were dried over sodium sulfate, concentrated to give N-methyl-N-(quinoxalin-6-yl)acetamide as a brown solid (8.04 g, yield 93%). ESI MS: m/z 202.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO[Si](C)(C)C(C)(C)C)cc2)CC1
Yield: 83.4 %

Procedure:
To a 1,2-dichloroethane (15 mL) solution of 4-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethyl)benzaldehyde (0.70 g) and tert-butyl piperazine-1-carboxylate (0.52 g) was added NaBH(OAc)3 (0.83 g) at 0° C. The resultant mixture was stirred at room temperature for 66 hours. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 2/1) to afford tert-butyl 4-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzyl]piperazine-1-carboxylate (0.96 g) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)#[N:2].Cl.[F:22][C:23]([F:28])([F:27])[CH2:24][NH:25][NH2:26].C(N(CC)CC)C>C(O)C>[CH2:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4]1[CH:3]=[C:1]([NH2:2])[N:25]([CH2:24][C:23]([F:28])([F:27])[F:22])[N:26]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNCC(F)(F)F
Reactant: N#CCC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc([C@H]2CCCN2C(=O)OCc2ccccc2)nn1CC(F)(F)F

Procedure:
To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10 mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11 mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated and the residue was separated by flash chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI): m/z 369 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[NH2:22][C:23]1[N:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=1>>[NH2:22][C:23]1[N:28]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[C:7]3[CH2:17][CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:8]=3[N:9]=[C:10]([NH2:12])[N:11]=2)[CH:26]=[CH:25][N:24]=1
Reactant: NCCCNc1nc(N)nc2c1CCCc1ccccc1-2
Reactant: Nc1nccc(Cl)n1
Product: Nc1nccc(NCCCNc2nc(N)nc3c2CCCc2ccccc2-3)n1

Procedure:
The product of Example 3B (45 mg, 0.126 mmol) and 2-amino-6-chloropyrimidine (21 mg, 0.164 mmol) were treated under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.86 (d, J=5.16 Hz, 1H) 7.64-7.70 (m, 1H) 7.28-7.40 (m, 2H) 7.17-7.23 (m, 1H) 5.77 (d, J=5.95 Hz, 1H) 5.30 (s, 1H) 5.02 (t, J=5.55 Hz, 1H) 4.63 (s, 2H) 3.59 (q, J=6.35 Hz, 2H) 3.32 (d, J=5.16 Hz, 2H) 2.58 (t, J=6.54 Hz, 2H) 2.05-2.24 (m, 4H) 1.83-1.96 (m, 2H); MS (ESI+) m/z 377.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][N:26]=[N+]=[N-])=[N:12][C:11]=2[N:10]([CH3:29])[C:8]1=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][NH2:26])=[N:12][C:11]=2[N:10]([CH3:29])[C:8]1=[O:9]
Reactant: [H][H]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CN=[N+]=[N-])n2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O
Yield: 251.6 %

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine (1.7 g, 1.65 mmol) in ethanol (100 ml) was added 10% palladium on carbon catalyst (0.6 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provided (S)-1-(5-hydroxyhexyl)-7-benzyl-8-aminomethyl-3-methylxanthine (1.6 g, 100% yield).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C.Cl[C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16].C(Cl)Cl.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C#CCOC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Agent: CN(C)C
Solvent: ClCCl
Solvent: O
Product: C#CCOC(=O)OCCOC(=O)C(=C)C
Yield: 73.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 13.0 g of 2-hydroxyethyl methacrylate and 11.5 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 13.0 g of propargyl chloroformate dropwise over one hour. The mixture was allowed to react for 6 hours at 30° C. After the reaction, the mixture was treated with methylene chloride-water mixture. The organic phase was separated and dried over magnesium sulfate. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting residue was applied on a 200 mesh silica gel column and developed with ethyl acetate-hexane mixture. The title compound was obtained as colorless liquid. Yield was 73.6% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 717.3 [(M+H)+]
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(F)cc2)c2ccc(C(C)=O)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)c(=O)c(C(=O)O)cn2Cc1ccc(F)cc1
Yield: 81.6 %

Procedure:
A solution of compound 9 (0.46 g, 1.3 mmol) and 20% aqueous NaOH (4.3 mL) in ethanol (3 mL) was stirred for 18 hours at room temperature, then was poured into water (100 mL) and treated with 1N HCl until pH 3. The precipitate was filtered, washed with dry ethanol and light petroleum ether to give compound 12 (0.36 g, 88%); mp 206-208° C. (washed with dry ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)O)=[CH:4][CH:3]=1.[N:26]1[CH:31]=CC=C[CH:27]=1.CS(Cl)(=O)=O.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[N:26]([CH3:31])[CH3:27])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (141 mg, 0.382 mmol) (synthesized in an analogous way as described in Example 3) in methylene chloride (2.8 mL) was added pyridine (6.0 mL, 74 mmol) and methanesulfonyl chloride (0.148 mL, 1.91 mmol) at 0° C. After the addition, the mixture was warmed to rt and stirred for 30 min and then heated at 60° C. for 20 min. The mixture was cooled in an ice bath and dimethylamine (0.553 mL, 11.5 mmol) in THF was added to the mixture. After the addition, the ice bath was removed and the mixture was stirred at rt for 30 min and then heated at 55° C. for 2 h. The mixture was cooled, concentrated, and the residue was purified by HPLC to afford 1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamine as white powder (115 mg, 76%). LCMS: (AA) ES+ 396.3, 398.1; 1H NMR (400 MHz, d6-DMSO) δ: 14.48-14.27 (m, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.55, 1.62 Hz, 2H), 7.95 (s, 1H), 7.73-7.63 (m, 4H), 7.39-7.30 (m, 2H), 5.53 (s, 1H), 2.13 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:35]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(-n5cccn5)c4)cc23)CC1
Yield: 10 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1H-pyrazol-1-yl)phenyl]boronic acid (36 mg, 0.193 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2 mL). To this mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160° C. then concentrated under a stream of nitrogen (greenhouse) at 80° C. The crude product was partitioned between water (2 mL) and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous layer was extracted with CH2CL2 (2×2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80° C. Dimethyl sulfoxide (0.8 mL) was added to residue, which was sonicated for 10 sec. filtered through a cotton plug, and then filtered through a 0.2 μm filter. The crude product was purified on an Agilent MDAP using a Zorbax Eclipse XDB 610 21.2×50 mm column to afford 2.3 mg of the title compound (10%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: CC(C)OCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)OCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
In a similar manner as Example I, 27.7 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene and 4.9 grams of dichloroacetyl chloride was added 4.1 grams of triethylamine. After the appropriate work up procedure, there was obtained a yield of 8.9 grams, nD30 1.4564. Analytical data supports the structure.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(=O)CCCCCCCCCCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: CCCCCCCCCCCC(C)=O
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(cccc3c1)NCN2

Procedure:
1,8-Diaminonaphthalene of 26.05 g, 32.66 g of 2-tridecanone, 55 mg of p-toluenesulfonic acid monohydrate, and 250 ml of toluene were mixed with stirring. The reaction mixture was refluxed with heating under a nitrogen atmosphere and was allowed to react for 5 hrs. using Dean-Stark trap to remove water from the reaction mixture Thereafter, the mixture was washed with aqueous saturated sodium hydrogen carbonate solution, dried using potassium carbonate anhydride, filtered and solvent was removed under reduced pressure. The product was distilled to obtain 46.50 g of dihydroperimidine intermediate, exhibiting a boiling point of 192 to 213° C./0.3 to 0.4 Torr. The thus prepared dihydroperimidine intermediate of 8.00 g, 1.48 g of squaric acid, 64 ml of n-butanol and 64 ml of toluene were mixed with stirring. The reaction mixture was refluxed with heating under a nitrogen atmosphere and was allowed to react for 3 hrs. using Dean-Stark trap to remove water from the reaction mixture Thereafter, the mixture was filtered, run into petroleum ether and allowed to stand at a temperature of 5° C. for 18 hrs. The product was filtered out, washed with petroleum ether and air-dried to obtain 6.00 g of squarylium dye SS-1. The dye was recrystalized from the mixture of tetrahydrofuran and petroleum ether to refine the product. exhibiting an maximum absorption wavelength (?max) of 802 nm (e=1.8×105) in ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].[C]=O.[OH-:10].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)CCl
Agent: [C]=O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)OCC
Yield: 94 %

Procedure:
In a pressure vessel with a capacity of 7.5 liters, there are combined 20 g of Co2 (CO)8 in 2.5 liters of ethanol, and 612.5 g (5 moles) of chloroacetic acid ethyl ester, in a nitrogen atmosphere. Then the apparatus is scavenged three times with carbon monoxide, and a CO pressure of 7 bars is established. After the reaction temperature of 55° C. is reached, an 11.8% ethanolic solution of NaOH is pumped in by a proportioning pump at a CO pressure of 8 bars, in such a manner that a pH value of about 7.0 is sustained during the reaction. The reaction solution is constantly agitated during the reaction by means of a circulation pump. After 5 hours of reaction time a transformation of 79.2% is achieved. The reaction solution is separated from the NaCl on a rotary evaporator and distilled. 596 grams of malonic acid diethyl ester (94% yield) are obtained, and 20 g of acetic acid ethyl ester (5.7% yield) plus 127 g of chloroacetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[CH2:37][NH:38][CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][C:28]=2[CH2:37][N:38]([C:8](=[O:9])[C:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:12])[CH3:11])[CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-chloro-phenoxy)-2-methyl-propionyl chloride (0.58 mmol) in CH2Cl2 was added (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.200 g, 0.52 mmol) in triethylamine (0.17 mL, 1.23 mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.