Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH3:31])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 23A (60 mg, 0.19 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (43 mg, 0.26 mmol) to yield 17 mg (21%).
Reaction SMILES: CO[CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5].[CH:27]([NH:30][CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH:3]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:33][CH2:32][CH2:31][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:12][CH2:10][CH2:9][CH2:15]1
Reactant: CC(C)NCCN
Reactant: COCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CCCC4)sc3c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-(2-methoxyacetylamino)-benzothiazol-6-yl ester (intermediate 68) (90 mg, 0.214 mmol), N-isopropylethylenediamine (65.6 mg, 0.642 mmol) and cesium carbonate (69.7 mg, 0.214 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 26.2 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-(cyclopentanecarbonyl-amino)benzothiazol-6-yl ester (white powder) in a yield of 24%.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)Cl.Cl.[CH3:20][NH:21][O:22][CH3:23].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]([O:22][CH3:23])[CH3:20])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
1.04 g (5 mmol) of 2-fluoro-3-(trifluoromethyl)benzoic acid (compound of formula (III)) 3 ml of SOCl2 were dissolved and the mixture was refluxed for 2 hrs. Remaining SOCl2 was removed in vacuo and the residue (crude acid chloride derivative) was dissolved in 5 ml of CH2Cl2. N,O-Dimethyhydroxylamine hydrochloride (585 mg, 6 mmol) in 8 ml of CH2Cl2 was added followed by 0.5 ml of pyridine. The reaction mixture was stirred for 1.5 hrs., quenched with aq. NH4Cl solution and the product was extracted twice with CH2Cl2, and the combined organic phases were washed with brine and dried over sodium sulfate. Evaporation of solvents in vacuo gave 1.02 g of product as an oil which was pure enough to be used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCN(CC)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-diethylethane-1,2-diamine according to general procedure 1 providing the intermediate (160 mg, 80%) as a clear oil: Rf=0.22 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.52 (t, J=6.0 Hz, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.68 (quart, J=7.2 Hz, 4H), 1.12 (t, J=7.2 Hz, 6H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Yield: 95.8 %

Procedure:
A solution of 4-bromo-2,6-diethylaniline (5.48 g, 24 mmol) in dichloromethane was added and stirred under nitrogen. Pyridine (5.7 g, 72.1 mmol) was added followed by benzoyl chloride (4.39 g, 31.2 mmol). The reaction was stirred for 1 h. The reaction was diluted with dichloromethane, washed with 10% sodium hydroxide solution, 1N HCl, and dried over magnesium sulfate, filtered, and evaporated. The residue was pre-absorbed onto Celite and purified by column chromatography. The column was eluted with 40 to 100% dichloromethane/hexanes. 7.64 g (96% yield) of product was obtained after purification.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([O:21][CH3:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:19]2[C:20]([O:21][CH3:22])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (3.15 g, 17 mmol) and 4,6-dichloro-5-methoxy-pyrimidine (3.00 mg, 17 mmol) in 15 ml of THF, IM potassium-t-butoxide in THF (18.4 ml, 18.4 mmol) was added dropwise at 0° C. After 45 min, the crude mixture was extracted with CH2Cl2 and brine. Organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1→1:1 v/v) to provide 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (4.7 g, 85%). 1HNMR (CDCl3, 400 MHz) δ 1.24-1.28 (d, 6H), 1.80-1.84 (m, 2H), 2.00-2.05 (m, 2H), 3.37-3.44 (m, 2H), 3.77-3.81 (m, 2H), 3.91 (s, 3H), 4.92-4.95 (m, 1H), 5.38-5.40 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C14H20ClN3O4 329.11. found 330.1 (MH+).
Reaction SMILES: [CH3:1][O-].[Na+].[I-].C[S+](C)(C)=O.[CH3:10][C:11]([C:14]([CH2:16][N:17]1[N:21]=[CH:20][N:19]=[CH:18]1)=[O:15])([CH3:13])[CH3:12]>CS(C)=O.O1CCCC1>[C:11]([C:14]1([CH2:16][N:17]2[CH:18]=[N:19][CH:20]=[N:21]2)[CH2:1][O:15]1)([CH3:10])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: C[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(Cn2cncn2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
6 g (0.11 mol) of sodium methylate were introduced in portions into a suspension of 24 g (0.11 mol) of trimethylsulphoxonium iodide in 24 g of dimethylsulphoxide. 10 ml of tetrahydrofuran were also added, and the reaction mixture was then stirred for 5 hours at room temperature. Thereafter, a solution of 16.8 g (0.1 mol) of 1,2,4-triazol-1-yl-pinacolin in 100 ml of tetrahydrofuran was added dropwise, and the mixture was heated at 70° C. for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform, and the solution was washed with water, dried over sodium sulphate, filtered and concentrated. 13.8 g of a 69.4% pure 2-tert.-butyl-2-(1,2,4-triazol-1-yl-methyl)-oxirane of refractive index nD20 =1.4872 were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16]>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[S:16][C:8]2[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=2[CH:6]=1)=[O:17]
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: COC(=O)CS
Solvent: CC#N
Product: COC(=O)c1cc2c(F)cc(Br)cc2s1
Yield: 62.1 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25a, 4-bromo-2,6-difluoro-benzaldehyde (I-26a: 2.8 g, 12.8 mmol) was reacted with TEA (1.66 g, 16.47 mmol), mercapto-acetic acid methyl ester (1.47 g, 13.83 mmol) and acetonitrile (50 mL) to afford crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 2.3 g of the product (64% yield).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[Cl-].[NH4+]>C1COCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33])[S:15][C:14]=23)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)c2ncn3ccsc23)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)c3ccc(C)cc3)c2s1
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
A solution of: 669 mg of 7-p-toluenesulfonylimidazo[5,1-b]thiazole in 65 ml of THF was cooled to −60° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (2.5 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 20 min. A solution of 1.25 g of tri-n-butylstannyl chloride in 10 ml of THF was added thereto, and the mixture was stirred at the same temperature for 40 min. A semisaturated aqueous ammonium chloride solution (150 ml), was added thereto, followed by extraction with 250 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (590 mg) was obtained from the fraction of Rf=0.4.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:5]=[CH:6][C:7](O)=[C:8]([CH:11]=1)[CH:9]=[O:10].[I:13]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([I:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10]
Reactant: O=C1CCC(=O)N1I
Reactant: [H][H]
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cc(Cl)cc(I)c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
Scheme VI depicts a method for preparing aldehyde 15. For example, a mixture of an aldehyde of formula 14 wherein R3 and R5 are hydrogen, i.e., 5-chloro,2-hydroxy benzaldehyde (0.10 g, 0.64 mmol) and N-iodosuccinimide (0.16 g, 0.71 mmol) in acetic acid (2 mL) was heated to 95° C. for 2 h. Another portion of N-iodosuccinimide (0.020 g, 0.09 mmol) was added and heating was continued for 1 h. The mixture was diluted with ethyl acetate, washed in succession with 5% aqueous Na2S2O3, saturated NaCl, and dried (Na2SO4). The solvent was removed under reduced pressure, and 5-chloro-3-iodo-benzaldehyde was obtained as a yellow crystalline solid (0.17 g, 94%)
Reaction SMILES: [C:1]([C@H:5]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49](=[O:66])[NH:50][C@:51]2([C:56](=[O:65])[NH:57][S:58]([C:61]3([CH3:64])[CH2:63][CH2:62]3)(=[O:60])=[O:59])[CH2:53][C@H:52]2[CH:54]=[CH2:55])[O:41][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][C@@H:28]3[O:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:67][C@H:9]2[O:8][C:7](=[O:68])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C@H:5]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49]([NH:50][C@:51]2([C:56](=[O:65])[NH:57][S:58]([C:61]3([CH3:64])[CH2:62][CH2:63]3)(=[O:59])=[O:60])[CH2:53][C@H:52]2[CH:54]=[CH2:55])=[O:66])[O:41][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][C@@H:28]3[O:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:67][C@H:9]2[O:8][C:7](=[O:68])[NH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CN(C(=O)OC(C)(C)C)CCO1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CNCCO1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of the product from step 1 (92 mg) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) The resulting solution was stirred for 3 hours at room temperature until disappearance of the starting material. The solvent was removed in vacuo. The reaction mixture was dissolved in ethyl acetate and a saturated solution of sodium bicarbonate was added slowly. After extracting 3× with ethyl acetate, the combined organics were dried with sodium sulfate, filtered and concentrated to afford the desired product (77.9 mg). LRMS (ES+) m/z 865.45 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]#[N:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.O[Li].O>C1COCC1.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]#[N:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CC#N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#CCn1c(C(=O)O)cc2cc(Cl)ccc21
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 1.0 eq. of 5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (prepared according to Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1989), 28B(12), 1065-8) in a mixture of THF/H2O ((9/1) was added LiOH.H2O (1.0 eq.) and the reaction mixture stirred 6 h at R/T, acidified to pH2 and then partially concentrated until precipitation of the crude product which was filtered off and washed with Et2O and then dried to give the desired product as a light yellow solid (84%).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])[CH3:32])=[O:29])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:12][C:11]=1[CH3:27])=O)C.[ClH:46].O1CCOCC1>C(O)(=O)C>[ClH:46].[CH3:16][C:15]1[CH:14]=[C:13]([O:17][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:12]=[C:11]([CH3:27])[C:10]=1[CH2:9][C@@H:8]([C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])[CH3:32])=[O:29])[NH2:7]
Reactant: Cc1cc(OC(=O)Oc2ccccc2)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(OC(=O)Oc2ccccc2)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
The product of Example 13 is dissolved in glacial acetic acid and reacted with 6.8N HCl-dioxane according to the method of Example 3 to produce the titled hydrochloride compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-chloro-2-methyl-5-nitrophenol (18.8 g, 100 mmol) in DMF (200 ml) was added potassium carbonate (13.8 g, 100 mmol) and methyl iodide (21.3 g, 150 mmol). The mixture was stirred for about two hours at room temperature. 5% Citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated under reduced pressure which gave the title compound (20 G, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: OCCC#Cc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C(#Cc1ccccn1)CCn1nnc(-c2ccccc2)n1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
A mixture of 5-phenyl-2H-tetrazole (330 mg, 2.2 mmol), 4-(pyridin-2-yl)but-3-yn-1-ol (220 mg, 1.49 mmol) and triphenylphosphine polymer supported (750 mg, 2.2 mmol, loading 3 mmol/g) were dissolved DCM (3 mL) and stirred at 0° C. Diisoprpylazodicarboxylate (452 mg, 2.2 mmol) was added dropwise, at 0° C. over a period of 30 min The reaction mixture was then warmed to room temperature and stirred over night. The reaction mixture was filtered through celite and the cake was washed with DCM. The combined organic layers were washed with aqueous ammoniac, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 209 mg of 2-(4-(5-phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine (Yield: 51%) as a pink powder (M.P.=71-73° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[Na+].Br[CH2:21][CH2:22][OH:23].O.CCOC(C)=O>CN(C=O)C>[OH:23][CH2:22][CH2:21][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: OCCBr
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)[O-])cc2)cs1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)CCO)cc2)cs1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Sodium 4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (600 mg) was dissolved in DMF (2 ml) under N2 atmosphere. Then 2-bromoethanol (0.168 ml) was added to the solution at 0° C. The reaction mixture was stirred at 100° C. for 7 hours. After cooled to r.t., water and AcOEt were added to the mixture. The precipitate was filtered in vacuo to give N-(4-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide (80.2 mg) as an off-white solid.
Reaction SMILES: [C:1]([S-:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:1]([S:9][S:9][C:1](=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C([S-])c1ccccc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: S=C(SSC(=S)c1ccccc1)c1ccccc1

Procedure:
Potassium ferricyanide (III) (32.93 g) was dissolved in deionized water (500.0 mL). Sodium dithiobenzoate solution (350.0 mL) was transferred to a 1 L conical flask equipped with a magnetic stir bar. Potassium ferricyanide solution was added drop wise to the sodium dithiobenzoate via an addition funnel over a period of one hour under vigorous stirring. The red precipitate was filtered and washed with deionized water until the washings become colorless. The solid was dried in vacuum at room temperature overnight; the product was recrystallized from ethanol.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)#[N:5].[Cl-:12].[NH4+:13].C(OC)(C)(C)C>CO>[ClH:12].[N:7]1[CH:8]=[CH:9][N:10]=[CH:11][C:6]=1[C:4]([NH2:13])=[NH:5]
Reactant: [NH4+]
Reactant: N#Cc1cnccn1
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: Cl
Product: N=C(N)c1cnccn1
Temperature: 30 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a solution of sodium methoxide (NaOCH3) (51.4 g, 0.952 mol) in methanol (3800 ml) there is added cyanopyrazine (1.00 KG, 9.53 mol) slowly at room temperature. The mixture is heated to 30° C. and stirred for 6 h. The mixture is cooled to 25° C. followed by the addition of ammonium chloride (NH4Cl) (572 g, 10.5 mol). The reaction mixture is stirred for 22 h and methyl t-butyl ether (4000 mL) is added and the mixture is stirred for 15 min forming a solid. The solid is filtered and washed with methyl t-butyl ether (2×1000 mL) then dried at 40° C./0-10 mmHg for 17 h to give white solid product (1435 g) in 95% yield with 95% HPLC purity. 1H NMR (DMSO-D6): δ 9.7 (bs, 3H), 9.49 (d, 1H, J=1.5 Hz), 9.04 (m, 1H), 8.93 (t, 1H, J=1.5 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.C([C:14]1C=CC=C[N:15]=1)=C.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:11][C:2]1([CH3:1])[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][CH:10]1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:14][N:15]=1
Reactant: c1ccccc1
Reactant: C=Cc1ccccn1
Reactant: CC1(C)N=C1c1ccccc1
Product: CC1(C)N=C(c2ccccc2)CC1c1ccccn1
Reaction time: 48 h

Procedure:
9.5 G. of 2,2-dimethyl-3-phenyl-2H-azirine and 12 g. of freshly distilled 2-vinylpyridine are irradiated in 2 l. of benzene for 7 hours under the conditions given in Example 11. After evaporation of the solvent under reduced pressure, the resulting residue is taken up in 400 ml. of n-pentane and decolorized with active carbon. After 48 hours at -18° C., the crude product which crystallizes is recrystallized from n-pentane/small amount of benzene to yield 2-(5,5-dimethyl-2-phenyl-1-pyrrolin-4-yl)-pyridine (melting point 101°-102° C.).
Reaction SMILES: O[C:2]1[C:7]2=[C:8]([CH3:15])[C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[CH3:16][C:17](O)=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:7]2=[C:8]([CH3:15])[C:9]([C:11]3[O:12][C:16]([CH3:17])=[N:14][N:13]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C(=O)NN)cn2ncnc(O)c12
Product: Cc1nnc(-c2cn3ncnc(Cl)c3c2C)o1
Temperature: 80 °C

Procedure:
To a suspension of 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbohydrazide (100 mg, 0.48 mmol) in POCl3 (5 mL) was added AcOH (50 mg, 0.83 mmol). The reaction mixture was heated at 80° C. for 3 d, cooled to rt, and concentrated in vacuo. The resulting residue was dissolved in EtOAc and treated with sat. aq. NaHCO3 solution, brine, and dried over MgSO4. Filtration, followed by concentration, provide the title compound, which was used directly in next step. MS (ESI) m/z 250.1/252.1 (M+H)+.