Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:8])[O:3]1.Cl.O1CCOCC1>C(Cl)Cl.CO>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:8])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2c[nH]c(=O)o2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCC1CCNCC1)c1c[nH]c(=O)o1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate (step 2) (257.8 mg, 0.760 mmol) was solubilised in DCM (1.5 ml). 4M HCl in dioxane (1.9 ml, 7.60 mmol) was added and the reaction mixture stirred at RT. After all gas had ceased to be evolved, the reaction mixture was solubilised with in MeOH and evaporated under reduced pressure to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:15]O)[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:15][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=NO)c1ccc(Br)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(Br)cc2)N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a suspension of methyl 4-(4-bromophenyl)-4-(hydroxyimino)butanoate (5.0 g, 17 mmol) in acetic acid (60 mL) was added Zn (2.3 g, 35 mmol). The resulting mixture was stirred at 80° C. overnight under N2 atmosphere. The reaction was cooled to room temperature and filtered. The filtrate was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (30 mL×3). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The solid was washed with ether to afford 5-(4-bromophenyl)-pyrrolidin-2-one (0.82 g, 20%). 1H NMR (CDCl3, 400 MHz) δ 7.50 (d, J=8.4, 1H), 7.18 (d, J=8.4, 2H), 5.87 (br s, 1H), 4.72 (t, J=6.8, 2H), 2.63-2.50 (m, 1H), 2.48-2.38 (m, 2H), 1.98-1.89 (m, 1H). MS (ESI) m/z 240.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].CO.[C:16](=O)([O-])[O-:17].[K+].[K+]>>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:4]([CH3:13])=[N:3][C:2]=1[O:17][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1C
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nc(Cl)c(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate (6.17 g, 27.9 mmol) in anhydrous methanol (100 ml, 2.47 mol) at 0° C. was added potassium carbonate (4.30 g, 31.1 mmol) slowly. The suspension was stirred at 0° C. for 30 minutes and warmed to ambient temperature in 1 h. The solid was filtered and the filtrate was concentrated to give crude methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (6.2 g, 103% yield) which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Yield: 100.3 %

Procedure:
2-Chloro-5-nitropyridine (500.0 mg), methyl 4-hydroxybenzenecarboxylate (958.6 mg) and potassium carbonate (1.31 g) were suspended in acetonitrile (5 mL), and heated under reflux for 16 hours. Water (50 mL) was added to the reaction liquid, extracted with ethyl acetate (50 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (50 mL), water (50 mL) and saturated saline water (50 mL) in that order. The organic layer was dried with magnesium sulfate, and evaporated under reduced pressure to obtain the entitled compound (867.7 mg) as a brown solid.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]Br.[Mg].[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]1([CH3:36])[O:35][CH2:34]1.[Cl-].[NH4+]>C(OCC)C.[Cu+]>[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]([CH3:36])([OH:35])[CH2:34][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Reactant: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Agent: [Cu+]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Reaction time: 8 h

Procedure:
5.8 mmol of (3R,7R)-3,7,11-trimethyl-dodecyl bromide were heated at reflux in 20 ml of ethyl ether for 0.25 hour with calcinated magnesium. 1 g of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane and 0.9 g of copper (I) 2-propylacetylide [or 1.2 g of copper (I) bromide-dimethyl sulphide complex] were then added at 0° C. The temperature of the mixture was subsequently left to rise to room temperature and the mixture was stirred overnight. 10 ml of ammonium chloride were then added and the mixture was extracted with ethyl ether. The extract was dried, concentrated and distilled in a bulb-tube (b.p.0.01 =140° C.). There were obtained 1.28 g (72%) [or 1.41 g (79%)] of (3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecan-3-ol as a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](O)=O.C=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:19])[OH:20])[P:14]([OH:15])(=[O:17])[OH:16])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(O)(O)C(O)(CCNCCCc1ccccc1)P(=O)(O)O
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN(CCCc1ccccc1)CCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
9.3 g (26.3 mmol) of 3-(3-phenylpropylamino)-1-hydroxypropane-1,1-diphosphonic acid are refluxed for 36 hours with 6.1 ml of formic acid and 4.2 ml of a 38% formaldehyde solution in water. The reaction solution is concentrated by evaporation under reduced pressure and the residue is diluted with acetone, yielding 3-[N-(3-phenylpropyl)-N-methyl-amino]-1-hydroxy-propane-1,1-diphosphonic acid in the form of colourless crystals of m.p. 219° (decomp.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:9][C:7]1([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3](=[O:18])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH2:8]1
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: COCC(=O)Cl
Product: COCC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and Methoxyacetyl chloride in an analogous manner to Example 1271d (338 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=1
Reactant: Cc1csc(C(=O)C2C(=O)Nc3ccc(Cl)nc32)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)nc32)c1

Procedure:
The title compound was prepared from 5-chloro-3-(4-methyl-2-thenoyl)-4-azaoxindole (Example 30) according to the procedure of Example 2C, using 5-chloro-3-(4-methyl-2-thenoyl)-4-azaoxindole (0.90 g, 3.07 mmol), N-chlorosulfonyl isocyanate (0.40 mL, 4.60 mmol), and acetonitrile (15 mL). The crude N-chlorosulfonyl isocyanate was hydrolyzed by stirring in DMSO in a flask open to the air. The product was isolated by dilution with water and filtration, and was recrystallized from acetic acid. Yield: 190 mg (18%). M.P. 227°-228° C.
Reaction SMILES: O1C=CC(NC[C@@H:8]2[O:12][C:11](=[O:13])N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:56])[Cl:55])=[O:51])[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.ClC(OC)=O>>[CH3:8][O:12][C:11]([NH:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:55])[Cl:56])=[O:51])[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:13]
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: COC(=O)Cl
Agent: Cl
Product: COC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(R)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (1.61 g, 2.81 mM) and methyl chloroformate gave the desired product (1.61 g). NMR (DMSO-d6) δ: 1.82 (hextet, 1H); 2.11 (hextet, 1H); 3.13 (m, 1H); 3.28 (dd, 1H); 3.39 (dd, 1H); 3.52 (s overlapping m, 4H); 3.82 (dd, 1H); 4.14 (overlapping m, 3H); 4.36 (dd, 1H); 4.97 (d, 1H); 5.03 (m, 1H); 5.08 (d, 1H); 6.72 (t, 1H); 6.89 (d, 1H); 7.08 (dd, 1H); 7.35 (dd, 1H); 7.41 (br, 1H); 8.89 (d, 1H). MS (ESP): 594 (MH+) for C22H23Cl3FN5O7
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:27][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)c1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methoxybenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(3-methoxyphenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Br>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
2-Pyridin-2-yl-1H-benzoimidazole (1.95 g, 0.01 mol) was dissolved in DMF (50 mL) under an atmosphere of nitrogen. Sodium hydride (60% dispersion in oil, 0.48 g, 0.012 mol) was then added. The reaction mixture was stirred at ambient temperature for 0.5 hour. 3,4-Dichlorobenzyl bromide (2.4 g, 0.01 mol) was then added. The mixture was stirred at 80° C. for a period of 4 hours. The mixture was cooled and diluted with water. The mixture was then extracted with ethyl acetate. The organic extract was washed with water twice then evaporated. The residue was triturated with a small amount of ethyl acetate/hexane. The solid was collected and crystallized from ethanolic hydrogen chloride. The solid was collected to give the title compound (1.3 g, 36.7% yield) as a mono-hydrochloride, light brown solid, m.p. 227°-229° C. Anal. Calcd. for C19H13Cl2N3.HCl: C, 58.41; H, 3.61; N, 10.76. Found: C, 58.21; H, 3.54; N, 10.80. Mass spectrum (+FAB; [M+H]+) 354/356/358. 1H-NMR (DMSO-d6 ; 400 MHz) δ 8.78 (d, 1H), 8.52 (d, 1H), 8.15 (t, 1H), 7.9 (d, 1H), 7.77 (d, 1H), 7.65 (d, 2H), 7.54 (d, 1H), 7.48-7.52 (m, 2H), 7.23 (d, 1H), and 6.22 ppm (s, 2H).
Reaction SMILES: C1([C@H]2OC(=O)N[C@@H]2C2C=CN=C(C#CC3C=CC=CN=3)C=2)C=CC=CC=1.Br[C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:38]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=3)[O:37][C:36](=[O:46])[NH:35]2)[CH:31]=[N:32][CH:33]=1.C[Si]([C:51]#[C:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1)(C)C>>[F:45][C:41]1[CH:40]=[C:39]([C@H:38]2[O:37][C:36](=[O:46])[NH:35][C@@H:34]2[C:30]2[CH:31]=[N:32][CH:33]=[C:28]([C:51]#[C:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH:29]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cccc(F)c2)O1
Agent: O=C1N[C@H](c2ccnc(C#Cc3ccccn3)c2)[C@@H](c2ccccc2)O1
Product: O=C1N[C@H](c2cncc(C#Cc3cccnc3)c2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-5-phenyl-4-(2-(pyridin-2-ylethynyl)pyridin-4-yl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromopyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one and 3-((trimethylsilyl)ethynyl)pyridine. 1H-NMR (CDCl3, 500 MHz) δ 8.10-9.50 (bm, 3H), 7.94 (s, 1H), 7.88 (d, J=7.9, 1H), 7.42 (m, 2H), 7.10 (m, 3H), 6.81 (bs, 1H), 5.31 (d, J=7.3, 1H), 4.85 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 164.2, 162.2, 158.4, 152.9, 147.4, 139.1 (d, J=6.7), 138.7, 136.5, 132.1 (d, J=11), 131.13, 131.06, 128.6 (d, J=12), 121.5 (d, J=3.8), 116.7 (d, J=21), 113.0 (d, J=23), 90.8, 88.5, 84.8, 62.5. Mass spec.: 360.0 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([CH2:22][C:23]3[N:24]=[CH:25][NH:26][C:27]=3[CH3:28])[C:17](=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C(N(CC)CC)C.CCCCCC>ClCCl>[CH3:1][N:2]([CH3:7])[S:3]([N:26]1[C:27]([CH3:28])=[C:23]([CH2:22][CH:18]2[C:17](=[O:29])[C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH3:8])[C:21]=3[CH2:20][CH2:19]2)[N:24]=[CH:25]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C

Procedure:
A solution of dimethylsulphamoyl chloride (0.16 ml) in dry dichloromethane was added to a stirred solution of 1,2,3,9-tetrahydro-9-methyl -3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one (438 mg) and triethylamine (0.25 ml) in dry dichloromethane (30 ml) and the mixture was heated at reflux for 18 h. After cooling the reaction mixture was adsorbed onto FCC silica which was then applied to a column and FCC eluting with System A (150:8:1) gave an oil, which solidified to a powder on trituration with dry hexane (30 ml). This powder was then further purified by dissolution in dry dichloromethane (30 ml) and crystallisation by addition of dry hexane (10 ml) to give the title compound (518 mg), m.p. 122°-124°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[NH:38]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>O1CCCC1>[NH2:38][CH2:21][C:20]1[CH:19]=[N:18][C:17]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:24]=[CH:25][C:16]=2[C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CO)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Yield: 24.2 %

Procedure:
{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol (212 mg, 0.454 mmol), phthalimide (134 mg, 0.909 mmol) and triphenylphosphine (238 mg, 0.909 mmol) in tetrahydrofuran was stirred at room temperature for 30 minutes and with diisopropyl azodicarboxylate (184 mg, 0.909 mmol) for one day. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1/(v/v)) to remove triphenylphosphine oxide. The residue was dissolved in ethanol (10 mL) and stirred with hydrazine monohydrate (1.00 mL, 11.6 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (51.1 mg, yield 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[Br:17]
Reactant: BrBr
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2nc3ccccc3s2)cc1Br
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 79 %

Procedure:
To a solution of 2-(4'-aminophenyl) benzothiazole (0.45 g, 1.99 mmol) in CH2Cl2 (50 ml) was added a solution of bromine (0.32 g, 1.99 mmol) in CH2Cl2 (10 ml) at -5° C. After the reaction mixture had been stirred still at -5° C. for 2 minutes, it was poured into ice-water (400 ml). The resulting mixture was stirred for 40 minutes at room temperature. The organic layer was separated, washed with 10% aqueous sodium thiosulfate (50 ml×2) and water (60 ml×2), dried (MgSO4) and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate-hexane (1:3), to give pale yellow crystals (0.48 g, 79.1%), m.p. 160.0-161.4° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: Nc1cccnc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 850 mg of 3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in 40 ml of ethyl acetate was admixed with 2.3 g of tin(II) chloride and stirred at room temperature for 3 hours. The mixture was then extracted with 50 ml of water, the aqueous phase was adjusted to pH=6 using sodium dihydrogenphosphate and the product was extracted with ethyl acetate. After drying the organic phase over sodium sulfate, it was concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:10]([NH:9][C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])=[O:11])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=C=Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 90 °C
Yield: 18.9 %

Procedure:
2,6-Difluorophenyl isocyanate (36.1 mg, 0.233 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (50 mg, 0.15 mol) in pyridine (3 mL). The resulting solution was heated to 90° C. for 3 h. The reaction was quenched with water and concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a yellow solid (21 mg, 28%). MS: 477.2/322.2 (MH+); HPLC Rf: 5.66 min. (HPLC method
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23](CC3C=CC=CC=3)[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23]([C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:46])[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 99.6 %

Procedure:
1.52 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.24 g of benzyloxycarbonyl chloride and 18 ml of benzene are treated in the same manner as described in Example 4-(2), whereby 1.64 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)O1.I[C:22]1[C:23]2[N:24]([N:28]=[C:29]([NH2:31])[N:30]=2)[CH:25]=[CH:26][N:27]=1>>[NH2:31][C:29]1[N:30]=[C:23]2[C:22]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)=[N:27][CH:26]=[CH:25][N:24]2[N:28]=1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Nc1nc2c(I)nccn2n1
Product: CS(=O)(=O)Nc1ccc(-c2nccn3nc(N)nc23)cc1

Procedure:
Reaction of N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide with 8-iodo-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine analogously to general procedure 1 gives N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-phenyl]-methanesulfonamide which is reacted with 4-(4-chloro-phenyl)-morpholine to give the title compound as a solid.