Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[C:2]1=[O:1]
Reactant: Cc1ccc(C2CNC(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decane-7-carboxylate (333 mg, 0.967 mmol) in dry THF (6 ml) at −60° C. under nitrogen was added LiHMDS 1M in THF (1.26 ml, 1.257 mmol) dropwise and the mixture was left to stir at −60° C. for 1 hr. After this time a solution of iodomethane (79 ul, 1.257 mmol) in dry THF (1 ml) was added dropwise at −60° C. and the reaction mixture was allowed to warm from −60° C. to room temperature over 1 hr. After a further 3 hrs at room temperature the reaction mixture was added to sat. ammonium chloride (25 ml), extracted with EtOAc (3×25 ml) and the combined organics were washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure to give the crude product as an orange oil. The crude material was purified via silica chromatography eluting with 20-80% iso-hexane/EtOAc. The appropriate fractions were combined and concentrated to give the product as a yellow solid (270 mg).
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35].[ClH:36]>C(#N)C.[Cu](Cl)Cl>[Cl:36][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35]
Reactant: Nc1ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c(F)c1CCO
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccc(F)c2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
To a flask charged with copper(II) chloride (1.84 g, 13.7 mmol) was added a solution of tert-butylnitrite (1.46 g, 12.8 mmol, 90%, Aldrich) in acetonitrile (35 mL) under argon atmosphere. The resulting green reaction mixture was cooled in an ice-bath to 0° C., and a solution of N-[4-amino-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl) acetamide (3.58 g, 9.13 mmol), as prepared according to the procedure of the preceding step, in acetonitrile (60 mL) was added over a period of 45 minutes. After stirring for an additional 6 hours at 0° C., the resulting brown mixture was allowed to warm up to ambient temperature, then poured into 20% aqueous HCl (160 mL), and extracted with DCM (3 times). The extracts were combined, washed with 20% HCl, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 and 2.5%) to deliver the title compound (2.1 g, 56% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 8.24-8.12 (m, 3H), 7.84 (dd, J=8.2, 5.3 Hz, 1H). 7.68-7.60 (m, 2H), 7.22-7.20 (m, 2H), 3.87 (dd, J=12.6, 6.5 Hz, 2H), 3.09 (dt, J=6.7, 2.2 Hz, 2H), 1.47 (t, J=5.6 Hz, 2H). Mass spectrum (LCMS, ESI) calc'd for C20H15ClF4NO2 (M+H): 412.1. Found: 412.6.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])=[C:9](Cl)[N:8]=1)=[O:6].[CH:21]1([CH2:24][OH:25])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][O:25][C:9]2[N:8]=[C:7]([C:5]([OH:4])=[O:6])[CH:12]=[CH:11][C:10]=2[N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Sodium hydride (0.029 g, 0.86 mmol) was added in portions to a solution of cyclopropanemethanol (CAN 2516-33-8, 20 mL) and the reaction mixture was stirred for 30 min at room temperature. 6-Chloro-5-(1,1-dioxido-isothiazolidin-2-yl)-pyridine-2-carboxylic acid methyl ester (0.050 g, 0.17 mmol) was added and the mixture was heated to 100° C. overnight, quenched with water and concentrated under reduced pressure. The residue was dissolved in water, extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and subsequently extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 4 g, 33% ethyl acetate in petroleum ether) to yield the title compound (25 mg, 0.08 mmol, 46%) as yellow solid; MS (EI): m/e=313.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]1[N:29]2[C@H:23]([CH2:24][O:25][CH2:26][C:27]3[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=32)[CH2:22][CH2:21]1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:34][C:32]2[CH:31]=[CH:30][C:28]3[N:29]4[C@H:23]([CH2:24][O:25][CH2:26][C:27]=3[CH:33]=2)[CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)COC[C@@H]1CCCN21
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)COC[C@@H]2CCCN32)ncc1Cl

Procedure:
As per the procedure described in Example 1, the reaction of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and (S)-(2,3,3a,4-Tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amin gave 2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzamide, upon purification by flash chromatography (Dichloromethane: MeOH 98:2) followed by trituration with Et2O: MeOH (9:1), as solid (21%); 1H NMR (400 MHz, DMSO-d6) δ11.59 (s, 1H), 9.24 (s, 1H), 8.74 (br s, 1H), 8.17 (s, 1H), 7.74 d, J=7.87 Hz, 1H), 7.48 (m, 2H), 7.36 (d, J=8.40 Hz, 1H0, 7.12 (m, 1H0, 6.83 (d, J=8.40 Hz, 1H0, 7.12 (m, 1H), 6.83 (d, J=8.71 Hz, 1H), 4.56 (d, J=13.03 Hz, 1H0, 4.30 (d, J=13.02 Hz, 1H), 3.89 (d, J=11.55 Hz, 1H), 3.31-3.2 (m, 4H), 2.90 (m, 1H), 2.81 (s, 3H), 2.12-1.45 (3m, 4H); MS (m/e) 465, 466 (M+H); mp 216-218° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:14][CH2:15]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: BrCC1CCC1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(O)COCCC12CCC(c3cccc(OCC4CCC4)c3)(CC1)OC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (7F; 15 mg, 0.041 mmol), (bromomethyl)cyclobutane (9.25 mg, 0.062 mmol) and Cs2CO3 (41 mg, 0.124 mmol) in MeCN (1.0 mL) was heated to ˜60° C. for 10 h. The reaction was then cooled to rt, filtered and the filtrates were concentrated in vacuo. The crude alkylated phenol ester product was dissolved in THF/MeOH (1 mL of a 1:1 mixture) and aq. NaOH (90 μL of a 1 N solution, 0.090 mmol) and the mixture was stirred at rt for 3 h, then was concentrated in vacuo. The residue was dissolved in EtOAc (3 mL) and washed with 1 N aq. HCl, water, brine, then dried (MgSO4), and concentrated in vacuo. The crude product was purified by preparative HPLC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% HCO2H; Mobile Phase B: 95:5 MeCN:water with 0.1% HCO2H; Gradient: 45-85% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (7.7 mg, 67% yield; 99% purity by LC/MS) as a light yellow oil. LCMS [M−H]−=373; 1H NMR (500 MHz, DMSO-d6) δ 7.18 (t, J=8.3 Hz, 1H), 6.97-6.86 (m, 2H), 6.75 (dd, J=8.1, 1.2 Hz, 1H), 3.95 (s, 2H), 3.92 (d, J=6.6 Hz, 2H), 3.77 (s, 2H), 3.53-3.48 (m, 2H), 2.74-2.65 (m, 1H), 2.14-1.98 (m, 4H), 1.97-1.74 (m, 6H), 1.72-1.58 (m, 4H), 1.41 (t, J=6.6 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:3][O:4][NH2:5].[C:12]([N:16]=[C:17]=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([NH:16][C:17]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCN(CC)CC(O)CON
Reactant: CC(C)(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CC(O)CONC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
O-(2-hydroxy-3-diethylamino-propyl)-hydroxylamine was dissolved in 40 ml abs chloroform and 3,08 ml (0,027 mol) tert-butyl isocyanate was added thereto dropwise. The mixture was stirred at room temperature for 15 hours and evaporated. The product thus obtained was purified by column chromatography. The material thus obtained is in oily form which crystallizes when storing in refrigerator. The crystals were filtered after trituration with petroleum ether. Yield: 1,44 g (20%). Mp.: 58-61° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:24][CH2:23][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: NCCO
Product: OCCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Hydroxyethylamine were converted to yield 2-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propylamino}-ethanol as white semisolid, MS: 407 (MH+,1Br).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C1C(=O)N([I:26])C(=O)C1>>[I:26][C:10]1[C:11]([NH2:16])=[N:12][C:13]([NH2:15])=[N:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1
Product: Nc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.8 g (7.1 mmol) 6-(3-trifluoromethyl-phenyl)-pyrimidine-2,4-diamine and 1.8 g (7.8 mmol) NIS. Yield: 2.0 g (74%).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][C:19]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)([CH3:29])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([C:19]([CH3:29])([CH3:18])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:35][CH:34]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 28.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.0 g, 6.4 mmol) was reacted with tert-butyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (3.6 g, 9.7 mmol) to afford the desired product (864 mg, 28%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1)=[O:4].[NH2:19][C:20]1[C:36]([O:37][CH3:38])=[CH:35][C:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:27][CH2:28][C:22]=2[CH:21]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:19][C:20]2[C:36]([O:37][CH3:38])=[CH:35][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:12]=1)=[O:4]
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl
Temperature: 120 °C
Yield: 50.7 %

Procedure:
cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide (46 mg, 0.160 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (44 mg, 0.160 mmol) and camphorsulfonic acid (56 mg, 0.240 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 90 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 43 mg (51%) of a white foam. Compound 5: mp 240° C.; MS (ES+ calculated—529; found—530 M+H). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.65 (s, 1H), 6.14 (d, J=7 Hz, 1H), 5.57 (br s, 1H), 4.61 (t, J=7 Hz, 1H), 3.88 (s, 3H), 3.29 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.89 (s, 4H), 2.71 (d, J=4 Hz, 6H), 2.17 (m, 1H), 2.08 (m, 1H), 1.98 (br s, 2H), 1.65 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCCO)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NCCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-(3-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H19FN4O3S, 402.12; m/z found, 403.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=1.2, 1H), 8.30 (s, 1H), 8.08-8.03 (m, 1H), 8.01-7.96 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.56 (m, 1H), 7.42-7.32 (m, 1H), 7.36-7.28 (m, 2H), 3.51 (t, J=6.2, 2H), 2.88 (t, J=7.0, 2H), 1.65-1.54 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>CN(C=O)C>[CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([CH2:21][Cl:35])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(cc1[Se]c1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1[Se]c1ccc(CCl)cn1)C(C)(C)CCC2(C)C

Procedure:
2 g (5 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinic acid, 20 ml of toluene, 100 μl of DMF and 450 μl of thionyl chloride are introduced into a round-bottomed flask. The reaction medium is refluxed for one hour and evaporated. 100% of the expected acid chloride are collected, this product being used for the rest of the synthesis without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].C(=O)=O.Cl>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)O
Reactant: CSc1ccc(C=O)cc1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Product: CSc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of 50.70 g (0.33 mol) 4-methylsulfanyl-benzaldehyde, 39.65 g (0.38 mol) malonic acid 3.25 g (0.04 mmol) piperidine and 150 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (5 h). The reaction mixture was poured into a solution of 750 ml ice water and 190 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried at 50° C. Yield: 60.0 g (93%) 3-(4-methylsulfanyl-phenyl)-acrylic acid as a light brown solid melting at 163-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.Cl.[NH2:14][CH2:15][CH2:16][SH:17]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:14][CH2:15][CH2:16][S:17]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: NCCS
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2NCCS2)cc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (2.19 g, 13.2 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 40 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2×25 ml), washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.77 g). The material was triturated with hexane (3×5 ml) to give 2-(3,4-dimethoxyphenyl)-1,3-thiazolane (8) as a friable white solid (0.65 g, 66%), mp 54-56°.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[C:3]([CH:2]([F:18])[F:1])[N:21]3[N:22]=[CH:23][CH:24]=[C:20]3[N:19]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CC(=O)C(F)F)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Yield: 82 %

Procedure:
A mixture of 4,4-difluoro-1-(3-trifluoromethyl-phenyl)-butane-1,3-dione (6.75 g, 25.4 mmol) and commercially available 3-aminopyrazole (2.11 g, 25.4 mmol) in acetic acid (70 mL) was refluxed for 7 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(3-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (6.52 g, 82%) as a light yellow solid. MS (EI) 313.1 [(M)+]; mp 127° C.
Reaction SMILES: [C:1]([O:4][C@:5]1([O:28][C@H:27]([C@@H:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16]1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C@:5]1([O:28][C@H:27]([C@@H:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16]1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@](OC(C)=O)(C(=O)OCc2ccccc2)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@](OC(C)=O)(C(=O)O)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A mixture of 20b (220 mg, 0.41 mmol) and Pd-C (10%, 55 mg) in ethanol (3 mL) was vigorously stirred under H2 at room temperature for 1 h. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether to give 20a (177 mg, 97%) as fine needles, mp 132-133° C.; [α]25D+374° (c 0.88, CHCl3). Its 1H NMR spectrum (C6D6) was identical with that reported previously by Unger et al. (Carbohydr. Res. 1980, 80, 191).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:22][CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1c(OCC(=O)c2cccnc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (600 mg, 2 mmol) (HBr salt) was added to a mixture of 2-amino-3-nitrophenol (300 mg, 2 mmol) and potassium carbonate (400 mg, 3 mmol) in acetone (30 mL, 400 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, was diluted with water, and was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-(2-amino-3-nitrophenoxy)-1-pyridin-3-ylethanone (0.35 g, 60%). LCMS calculated for C13H12N3O4 (M+H)+: m/z=274.1. found: 274.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C(O)(=O)C.O1CCOCC1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC1CCC(OC)O1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2cccc2)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzoic acid (2.0 g) and 2,5-dimethoxytetrahydrofuran (1.52 ml) in a mixture of acetic acid (10 ml) and 1,4-dioxane (10 ml) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane=10:90) to give crude solid. The solid was recrystallized from ethyl acetate (5.0 ml) and hexane (200 ml) to give 3-(pyrrol-1-yl)-5-(trifluoromethyl)-benzoic acid (1.72 g) as a powder.