Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)cc(CN3CCN(C)CC3)c2[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a solution of 0.125 g (0.30 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in THF (1 ml) at RT, 55 mg of 1-methyl-piperazine was added. The reaction mixture was stirred at 40° C. for one hour and concentrated under vacuo. The crude was dissolved in CH2Cl2 (1 m) and at RT 0.2 ml of TFA was added and stirring was continued over night. Preparative HPLC (30% CH3CN/H2O) afforded 30 mg (29%) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OCCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCO)CCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (10.5 g, 47.6 mmol) in anhydrous methylene chloride (25 mL) was added dropwise with stirring to a 0° C. solution of diethanolamine (5.00 g, 47.6 mmol) and triethylamine (4.92 g, 47.6 mmol) in anhydrous methylene chloride (50 mL). Reaction stirred three hours at 0° C. and then overnight at room temperature. Reaction mixture concentrated under reduced pressure. Residue dissolved in ethyl acetate, washed with 1 N NaOH, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with ethyl acetate to afford the title compound. MS (ESI) m/z 291 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:7][C:8]=1[CH:14]=[O:15]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(CC(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(F)(F)F)cc1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a stirred solution of Compound 45 (760 mg, 4.00 mmol) in dry CH2Cl2 (15 ml) was added TiCl4 (1.67 g, 8.80 mmol) via a syringe with ice-cooling. After 15 min, to this was added a solution of dichloromethyl methyl ether (920 mg, 8.00 mmol) in dry CH2Cl2 (5 ml) at same temperature. The reaction mixture was stirred at 0° C. for 15 min, and then for 1.5 h at room temperature. The mixture was diluted with water (20 ml) with ice-cooling and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried MgSO4), and concentrated in vacuo to give crude product as a yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (40:1-20:1) to give Compound 46 (500 mg, 57%) as a colorless solid(needle).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][N:9]1C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CO
Product: CC[C@@H]1CN[C@H]1C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
To a stirred solution of (+)trans-1-benzhydryl-3-ethylazetidine-2-carboxylic acid tert-butyl ester (2.85 mmol, 1 eq.) in dry MeOH (50 mL) was added 1 M acetyl chloride (3.1 mL, 3.13 mmol, 1.1 eq.) in MeOH and sonicated the mixture to obtain clear solution. To this was added palladium hydroxide on carbon (20% Pd(OH)/C, 200 mg) and the mixture was hydrogenated at 60 psi for 5 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford (+)-trans-3-ethylazetidine-2-carboxylic acid tert-butyl ester in quantitative yield. This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=O)[CH:28]=[CH:29][CH:30]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:32]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: COc1cccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)c1

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 610 mg (3.81 mmol) of 3-methoxyphenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 160 mg (28%) of the diastereomer which elutes more rapidly, M.p.: 92° C., and 145 mg (25%) of the diastereomer which elutes more slowly, M.p.: 54° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2([S:11][CH3:12])[CH2:10][CH2:9]2)[CH2:5][C:4](=[O:13])[C:3]=1[C:14](=O)[CH2:15][CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][O:29][NH2:30])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][O:29][N:30]=[C:14]([C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3([S:11][CH3:12])[CH2:10][CH2:9]3)[CH2:7][C:2]=2[OH:1])[CH2:15][CH3:16])=[CH:23][CH:24]=1
Reactant: CCC(=O)C1=C(O)CC(C2(SC)CC2)CC1=O
Reactant: NOCC/C=C/c1ccc(Cl)cc1
Solvent: CO
Product: CCC(=NOCC/C=C/c1ccc(Cl)cc1)C1=C(O)CC(C2(SC)CC2)CC1=O
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 2.0 g (7.9 mmol) of 3-hydroxy-5-(1-methylthiocyclopropyl)-2-propionyl-2-cyclohexen-1-one, 1.8 g (9.0 mmol) of O-[4-trans-(4-chlorophenyl)-but-3-enyl]-hydroxylamine and 100 ml of methanol was stirred for 24 hours and then evaporated down under reduced pressure. Yield: 100%
Reaction SMILES: Br[C:2]([CH3:29])([CH3:28])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:19]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH3:21])=[O:18])[N:6]=1)=[O:4].[P:30]([O:35]C)([O:33][CH3:34])[O:31][CH3:32]>>[P:30]([O:33][CH3:34])([O:31][CH3:32])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:19]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH3:21])=[O:18])[N:6]=1)=[C:2]([CH3:29])[CH3:28])=[O:35]
Reactant: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(=O)C(C)(C)Br)c2ccc(OC)cc21
Reactant: COP(OC)OC
Product: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C(C)C)c2ccc(OC)cc21

Procedure:
Reaction of 2-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-N-(3,3-dimethylbutyl)-N-ethylacetamide from the above with trimethyl phosphite using the procedure as described in Method I Step B Example 1 provided the title compound following RP-HPLC using 50-100% MeCN gradient without TFA. 1H NMR (CDCl3, 500 MHz) showed two amide rotomers in about 1.3:1 ratio:o Major rotomer: 7.65 (d, 8.7 Hz, 1H), 6.83 (dd, 9.0 & 2.1 Hz, 1H), 6.805 (d, 1.9 Hz, 1H), 5.15 (s, 2H), 3.88 (s, 3H), 3.55 (d, 11.2 Hz, 6H), 3.48 (q, 7.1 Hz, 2H), 3.32˜3.35 (m, 2H), 2.01 (d, 2.5 Hz, 3H), 1.83 (d, 3.5 Hz, 3H), 1.40˜1.44 (m, 2H), 1.14 (t, 7.1 Hz, 3H), 0.91 (s, 9H). Minor rotomer: 7.66 (d, 8.7 Hz, 1H), 6.83 (dd, 9.0 & 2.1 Hz, 1H), 6.77 (d, 1.8 Hz, 1H), 5.12 (s, 2H), 3.88 (s, 3H), 3.54 (d, 11.4 HZ, 6H), 3.41˜3.44 (m, 2H), 3.38 (q, 7.2 Hz, 2H), 2.01 (d, 2.5 Hz, 3H), 1.84 (d, 3.5 Hz, 3H), 1.56˜1.60 (m, 2H), 1.12 (t, 7.1 Hz, 3H), 1.00 (s, 9H). 13C NMR (CDCl3, 125 MHz): Major rotomer: 165.85, 160.95, 142.34, 140.22, 133.82 (d, JC-P=9.6 Hz), 125.87 (d, JC-P=6.7 Hz), 122.56, 118.22, 113.71, 90.89, 55.74, 54.685 (d, JC-P=5.8 Hz), 51.96, 42.99, 42.51, 41.05, 29.99, 29.46, 20.13, 18.75, 14.51; Minor rotomer: 165.71, 159.96, 142.45, 140.22, 133.88 (d, JC-P=9.6 Hz), 125.79 (d, JC-P=7.7 Hz), 122.60, 118.27, 113.51, 90.94, 55.74, 54.685 (d, JC-P=5.8 Hz), 51.18, 44.03, 42.82, 41.50, 29.96, 29.46, 20.18, 18.75, 13.21. LC-MS: 3.67 min. (m/Z=518.3, 496.3, 370.4).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][CH:33]1[O:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[N:19]=1
Reactant: ClCC1COc2ccccc2O1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(-c2nn(CC3COc4ccccc4O3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 2-chloromethyl-2,3-dihydro-benzo[1,4]dioxine using the procedure described in example 14. MS: ESI (negative): 514, 516 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.1 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (0.36 g, 2.93 mmol), 3,3,3-trifluoropropanol (0.5 g, 4.39 mmol) and triphenylphosphine (1.15 g, 4.39 mmol) in dry THF (10 ml) at 0° C. under an atmosphere of argon was added dropwise diisopropylazodicarboxylate (0.89 g, 4.39 mmol). On completion of the addition, the reaction mixture was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (4:1 Hexane/EtOAc) to give the title compound (0.25 g, 46%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:11]=3[CH:10]=2)[O:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.C(OCC)(=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:18][C:16]2[CH:15]=[CH:14][C:12]3[S:13][C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]4)=[CH:10][C:11]=3[CH:17]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine (825 mg, 3 mmol, 1 eq) in anhydrous tetrahydrofuran (15 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (678.3 mg, 1 eq) and the reaction solution was stirred at room temperature under nitrogen atmosphere overnight. The reaction was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure. 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)urea was obtained as slightly brown colored foam in vacuo in the amount of 1.5 g which was used directly without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[S:10][C:9]([S:11]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:13])=[O:12])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: C1CNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
Azetidine (0.258 mL, 3.82 mmol) was added to a solution of 5-bromo-2-thiophenesulfonyl chloride (500 mg, 1.912 mmol) in DCM (4.8 mL) in a 4 dram vial. The reaction was stirred at room temperature for 5 min. The reaction mixture was concentrated under a stream of nitrogen at 50° C. and dried under high vacuum. The residue was taken up in EtOAc (10 mL) and extracted with saturated NaHCO3 (2×2 mL). The organic layer was dried (Na2SO4), concentrated under a stream of nitrogen at 50° C., and dried under high vacuum, giving 501 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[CH2:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:2][C:3]#[C:4][CH3:5])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCN1CCC(Cc2ccccc2)CC1
Yield: 44 %

Procedure:
A mixture of 1-bromobut-2-yne (1.19 g, 9.00 mmol), 4-benzylpiperidine (1.58 g, 9.00 mmol) and K2CO3 (2.5 g, 18 mmol) in 25 mL of CH3CN was refluxed for 12 hr. The mixture was filtered and was washed with EtOAc (3×30 mL). The filtrate was evaporated in vacuo and was purified by flash chromatography to give the product as a colorless oil (0.9 g, 50%): 1H NMR (CDCl3) d 1.31 (m, 2 H), 1.60 (m, 1 H), 1.63 (m, 2 H), 1.81 (s, 3 H), 2.04 (m, 2 H), 2.52 (d, J=9.9 Hz, 2 H), 2.88 (m, 2 H), 3.16 (s, 2 H), 7.15-7.27 (m, 5 H); HRMS calcd for C16H21N 227.1670, found 227.1670.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:18][CH:19]1[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[CH2:25]([N:21]1[CH2:22][CH2:23][O:24][CH:19]([CH2:18][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:16])[CH2:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1[nH]c2ccccc2n1-c1ccccc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ccccc2n1-c1ccccc1

Procedure:
The condensation of 0.1 mol of 1-phenyl-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine in accordance with the procedure (a) of Example 1 gives, after evaporation of the solvent under reduced pressure, a pale pink solid which melts at about 90° C. and which is used as such for the subsequent operations.
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])[CH3:2].[S:10](F)([F:13])([F:12])[F:11]>ClC(Cl)(Cl)F>[CH2:1]([N:3]([S:10]([F:13])([F:12])[F:11])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: FS(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: CCN(CC)S(F)(F)F
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 96 g (0.66 mole) of diethylaminotrimethylsilane in 100 ml trichlorofluoromethane was added dropwise to a solution of 40 ml (measured at -78°, 0.72 mole) of sulfur tetrafluoride in 200 ml of trichlorofluoromethane at -65° to -60°. The reaction mixture was warmed to room temperature and then distilled to give 88.86 g (84% yield) of diethylaminosulfur trifluoride as a pale yellow liquid, bp 46°-47° (10 mm).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
100 mg (0.271 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 82.3 mg (0.813 mmol) of triethylamine was added to the obtained solution. A solution of 39.2 mg (0.325 mmol) of pivaloyl chloride in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 3:1).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[CH3:12][C:2]1[S:15][C:14]([NH2:16])=[N:13][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(=O)C(C)Br)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc(-c2nc(N)sc2C)cc1
Yield: 98.5 %

Procedure:
A mixture of 2-bromo-1-(p-tolyl)propan-1-one (6.88 g, 30.3 mmol) and thiourea (2.54 g, 33.4 mmol) in 95% EtOH (43 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 5-methyl-4-(p-tolyl)thiazol-2-amine (6.10 g) as white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.18 (bs, 2H), 2.37 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:22]([C:5]1[C:4]2[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:23]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2c(-c3cccs3)noc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3cccs3)noc2c1O
Temperature: 110 °C
Yield: 57.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (310 mg, 0.745 mmol) and CuCN (200 mg, 2.24 mmol) were added to 5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 136 mg of the title compound. MS: (+) m/z 316.29 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=4)[N:27]=3)=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1Oc1ccc2ncc([N+](=O)[O-])n2n1

Procedure:
In analogy to the method described in example 1, 1.25 g (4.25 mmol) of 4-[(5-chloro-2,6-dimethyl-pyrimidin-4-ylamino)methyl]-2-methoxyphenol (from example B3), 0.86 g (4.25 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine and 3.0 g (21.25 mmol) of potassium carbonate are reacted in 25 ml of dimethylformamide. After chromatography on silica gel (mobile phase: gradient toluene/dioxane 5:1 to 2:1) and crystallization from methylene chloride/methanol, 1.24 g (64%) of the title compound are isolated as a pale beige solid. m.p.: 229-232° C.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br.Br[CH2:54][C:55]1[C:60]([Cl:61])=[C:59]([Cl:62])[CH:58]=[CH:57][N:56]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:54][C:55]3[C:60]([Cl:61])=[C:59]([Cl:62])[CH:58]=[CH:57][N:56]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Clc1ccnc(CBr)c1Cl
Agent: Br
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3nccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as white solid. MS (m/e): 422.2 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][NH2:13]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: ClCCCOc1cccnc1
Solvent: CO
Product: CNCCCOc1cccnc1
Temperature: 80 °C

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (4.90 g, 28.55 mmol) was dissolved in methanol (60 mL) and added to a 40 wt % solution of methylamine (60 mL) in a heavy-walled pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 80° C. for 15 h. After cooling, the mixture was concentrated by rotary evaporation, a saturated NaCl solution (25 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The mixture was extracted with chloroform (4×30 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 3.64 g of a brown oil. The product was purified by column chromatography on silica gel (100 g) eluting with chloroform-methanol-triethylamine (70:30:2.5, v/v/v). Selected fractions containing the product (Rf 0.30) were combined and concentrated by rotary evaporation. The resulting residue was dissolved in chloroform (15 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 1.92 g (40.4%) of a brown oil. 1H NMR (CDCl3, 300 MHz): δ 8.31 (dd, 1H, J=2.39, 1.44 Hz), 8.20 (dd, 1H, J=3.88, 2.29 Hz), 7.14 (m, 2H, J=3.90, 1.11 Hz), 4.09 (t, 2H, J=6.22 Hz), 2.78 (t, 2H, J=6.80 Hz), 2.46 (s, 3H), 1.99 (p, 2H, J=6.54 Hz), 1.59 (br, s, 1H). 13C NMR (CDCl3, 75 MHz): δ 155.16, 142.08, 138.09, 123.84, 121.05, 66.59, 48.78, 36.53, 29.44. EI-MS: m/z (relative intensity) 166 (M+, 10.08%), 123 (41.85%), 95 (100.00%), 70 (45.84%), 44 (89.75%), 39 (41.62%).