Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}1,2,5-thiadiazolidine-3-one-1,1-dioxide (67 mg, 0.1 mmol) was treated as described in general procedure R using excess 1-methylpiperazine (100 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4′-(4-methyl-piperazin-1-yl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:13]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)[CH2:8][NH2:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3,5-di-tert-butylbenzonitrile (863 mg, 4.02 mmol) in dry THF (10 mL) at 0° C. was added lithium aluminum hydride (304 mg, 8.0 mmol) in one portion. The reaction mixture was allowed to warm to rt for 2 h, whereupon the reaction was quenched (0.2 mL water, followed by 0.2 mL 15% potassium hydroxide solution and 0.6 mL water). The reaction mixture was stirred at rt for 1 h, then filtered through diatomaceous earth (CH2Cl2 elution). The filtrate was then concentrated and used in the next reaction without further purification: 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 7.16 (d, J=1.8 Hz, 2H), 3.86 (s, 2H), 1.33 (s, 18H); mass spec (CI): 203.2 (M−NH2).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3]C1.[F:28]C1C=C(C2C(C(C3C=C(C(=O)C(Cl)(Cl)Cl)NC=3)=O)=C(C)ON=2)C=CC=1F.C(N)C#C>>[CH2:4]([NH:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[O:14])[CH:12]=1)=[O:7])[C:1]#[CH:3]
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Agent: C#CCN
Product: C#CCNC(=O)c1cc(C(=O)c2c(-c3ccc(F)c(F)c3)noc2C)c[nH]1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and prop-2-ynylamine (commercially available) in 28.1 yield. (m/e): 370.0 (MH+; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-chloroacetophenone (M. Kihara, M. Kashimoto, and Y. Kobayashi, Tetrahedron, 1992, 48, 67-78.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5](=[O:13])[C:4]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:29][CH3:30])(=O)=O>CN(C=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5](=[O:13])[C:4](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:29][CH3:30])=[O:17])=[CH:3]1
Reactant: Cn1cc(C=CC(=O)O)c(=O)c2ccc(Cl)cc21
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(C)c2cc(Cl)ccc2c1=O

Procedure:
A solution of 1-methyl-7-chloro-4(1H)-quinolone-3-acrylic acid (3.6 g) in dry DMF (150 ml) was stirred with anhydrous sodium carbonate (4.36 g) at 70° C. for one hour. To the reaction mixture was then added diethyl sulphate (5.06 g) dropwise, and then stirring at 70° C. was continued for twelve hours.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]([C:16]1([CH3:31])[CH2:20][CH:19]2[CH:21]([CH3:30])[C:22]([N+:27]([O-])=O)=[C:23]([CH3:26])[C:24]([CH3:25])=[C:18]2[O:17]1)=[O:15].[Cl-].[Ca+2].[Cl-]>[Zn].C(O)C>[NH2:27][C:22]1[C:23]([CH3:26])=[C:24]([CH3:25])[C:18]2[O:17][C:16]([C:14]([N:2]3[CH2:3][CH2:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[NH:12][C:13]=4[CH2:1]3)=[O:15])([CH3:31])[CH2:20][C:19]=2[C:21]=1[CH3:30]
Reactant: CC1=C2OC(C)(C(=O)N3CCc4c([nH]c5ccccc45)C3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(C(=O)N1CCc3c([nH]c4ccccc34)C1)O2
Yield: 38.1 %

Procedure:
0.54 g of (±)-(1,3,4,9-tetrahydro-beta-carboline-2-yl)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)methanone, 1.86 g of zinc, 0.19 g of calcium chloride dehydrate and 30 ml of ethanol were added, followed by heating at reflux overnight. The insoluble matter was filtered through celite and the solvent was distilled off. The reaction solution was mixed with water, extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=50:1) to obtain 0.19 g of the objective product (melting point: 129-133° C.)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[N:7]=[CH:6]2.C(Cl)Cl.B(Br)(Br)Br.[Cl-].C([O-])(O)=O.[Na+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[N:7]=[CH:6]2
Reactant: COc1ccc2nc([C@]3(C)COC(=O)N3)ncc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ncc3cc(O)ccc3n2)COC(=O)N1
Temperature: -78 °C

Procedure:
(R)-4-(6-Methoxy-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (860.0 mg, 3.317 mmol) was dissolved in methylene chloride (60 mL, 900 mmol), and cooled to −78° C. A solution of 1.0 M of boron tribromide in nethylene chloride (9.95 mL, 9.95 mmol) was then added dropwise. The reaction mixture was then warmed up to at 23° C. gradually and then heated at 50° C. for 2 hours. The reaction mixture was then question with NaHCO3 (sat) to basic, and neutralized back to pH-7-8. DCM was removed under vacuum, the white solid was collected and washed with water and hexanes (560 mg, 69%). 1H NMR (MeOD) δ: 9.32 (s, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.57 (dd, J=9.0, 2.8 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 4.98 (d, J=8.5 Hz, 1H), 4.46 (d, J=8.5 Hz, 1H), 1.78 (s, 3H). MS (M+1): 246.10.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][N:31](C)[CH2:32]CO>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][N:31]([CH3:32])[CH3:30])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CN(C)CCO
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CN(C)CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 2 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 108, 2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.0060 g, 0.049 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0023 g, y. 2%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C:8]3[C:20]4[NH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12]=4[C:11]4[C:21](=[O:24])[NH:22][CH2:23][C:10]=4[C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:28][C:29](OCC)=[O:30].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CN(C=O)C.C1COCC1>[OH:30][CH2:29][CH2:28][CH:7]1[C:8]2[C:20]3[NH:19][C:18]4[C:13]([C:12]=3[C:11]3[C:21](=[O:24])[NH:22][CH2:23][C:10]=3[C:9]=2[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]1=2)=[CH:14][CH:15]=[CH:16][CH:17]=4
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccccc1-3
Reactant: CCOC(=O)CBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)C(CCO)c1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-2) (200 mg, 0.65 mmol) was added to a stirred solution of NaH (25 mg of 60% oil dispersion, 0.65 mmol) in dry DMF (10 mL) under a nitrogen atmosphere. The dark mixture was stirred at ambient temperature for 1 hour. Ethyl bromoacetate (120 mg, 0.08 mL, 0.72) was added dropwise and the mixture was stirred 12 hours. The resulting yellow solution was concentrated at reduced pressure to give a crude yellow solid. The product was dissolved in dry THF (10 mL) and lithium aluminium hydride (1 mL of 1M solution in ether) was added dropwise. The solution was stirred 6 hours at room temperature, then the reaction was quenched by the addition of H2O (1 mL). The mixture was filtered and concentrated at reduced pressure. THF was added to the residue and the product was collected to give 30 mg(17%) of Compound I-29 as a white solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ3.8-3.9 (b, 2H), 4.55 (s, 2H), 4.77 (t, 2H), 4.9 (s, 2H), 5.0 (b, 1H, D2O exchange), 7.3-7.45 (m, 3H), 7.5-7.57 (t, 1H), 7.67 (d, 1H, J=6 Hz), 7.5 (d, 1H, J=6 Hz), 8.0 (d, 1H, J=6 Hz); 8.57 (s, 1H), 9.5 (d, 1H, J=7 Hz). MS(FAB): m/e 355 (M+1)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[Br:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:18]I)([CH3:17])[CH2:14][C:13]=2[C:20]=1[CH3:21].[Cl-].[NH4+]>C(OCC)(=O)C.CN(C=O)C>[Br:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:17][N:3]3[CH:7]=[CH:6][CH:5]=[N:4]3)([CH3:18])[CH2:14][C:13]=2[C:20]=1[CH3:21]
Reactant: c1cn[nH]c1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(Cn1cccn1)O2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
60% sodium hydride (91 mg, 2.27 mmol) was added to a solution of DMF (2 mL) containing pyrazole (155 mg, 2.27 mmol) under ice-cooling condition, and the mixture was stirred at 0° C. for 20 minutes. After that, a solution of DMF (1.5 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (300 mg, 0.759 mmol) synthesized in Reference Example 133 was added thereto, and the mixture was stirred at 100° C. for 4 hours and at 120° C. for 2 hours. After cooled to room temperature, the reaction solution was distributed using a saturated ammonium chloride aqueous solution and ethyl acetate. The organic layer was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-85:15) to give 185 mg of the title compound (yield: 71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH2:19]([SH:24])[CH2:20][CH2:21][CH2:22][SH:23].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[SH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:24][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: SCCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCCS)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
40 g (0.15 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one and 109 g (0.89 mol) of 1,4-butanedithiol are dissolved in 300 ml of dimethylacetamide, and the solution is stirred at around 100° C. together with 41 g of potassium carbonate for 5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate -hexane (20:80) as an eluent. Melting point 98 ° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.36 (t, 1H), 1.76-1.90 (m, 4H), 2.53-2.62 (m, 6H), 2.98-3.04 (m, 2H), 3.69 (t, 4H), 7.25 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-phenol (46 mg, 0.12 mmol), prepared as described in Example 2, acetic anhydride (0.023 mL, 0.24 mmol), triethylamine (0.05 mL, 0.36 mmol) and CH2Cl2 (4 mL) was stirred at room temperature under N2 for 4 h. The reaction mixture was treated with saturated sodium bicarbonate, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (47 mg, 92%) as a white solid: mp 142–144° C.; 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (br s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.92 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.01 (s, 6H); APCI MS m/z 426 [(M+H)+, calcd for C22H24N3O4S, 426.1].
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=O.CCOCC.C([O-])(=O)C.[Na+]>C1COCC1.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[O:1][N:2]=[C:3]([CH:4]([OH:6])[CH3:5])[N:7]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(O)C(N)=NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
The title compound from Example 1 (6.45 g) was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g, which was directly used in the next step. The material was dissolved in ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxing over night, cooling to RT and addition of water (250 mL) the mixture was concentrated in vacuo to about half of its volume, resulting in a precipitate which was filtered off and recrystallized from EtOAc/heptane to yield 6.45 g (25%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]=[N+:14]=[N-:15]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 956 %

Procedure:
To a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.250 g, 0.104 mmol) in DMSO (3.0 mL) was added sodium azide (0.101 g, 0.156 mmol). The reaction mixture was stirred at RT for 3-4 h. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. 1HNMR (DMSO-d6): δ 4.63 (s, 2H), 7.60 (d, J=7.8 Hz, 1H), 7.70-7.80 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](Cl)(Cl)[CH2:10][C:9]2=[O:17])=[C:4]([F:18])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:9]2=[O:17])=[C:4]([F:18])[CH:3]=1
Reactant: O=C1CC(Cl)(Cl)CCCN1c1ccc(Br)cc1F
Reactant: C1COCCN1
Product: O=C1C(N2CCOCC2)=CCCCN1c1ccc(Br)cc1F

Procedure:
N-[4-bromo-2-fluorophenyl]-3,3-dichlorocaprolactam (0.49 g, 1.38 mmol) was refluxed with 10 mL of morpholine under N2 for 1 h. The solvent was then removed in vacuo. Toluene was added and the solid was filtered off. The filtrate was concentrated and dried under vacuum to give 1,5,6,7-tetrahydro-1-[4-bromo-2-fluorophenyl]-3-(morpholin-4-yl)-2H-azepin-2-one as brown oil(0.55 g). LRMS (AP+): 369.0, 371.0, (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:24])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br)=[O:13].[Cl-].[Cs+]>>[CH3:11][S:12](=[S:24])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=S)OCCOCCOCCBr
Agent: [Cl-]
Agent: [Cs+]
Product: CS(=O)(=S)OCCOCCOCCOC(=O)c1ccc(N)cc1
Yield: 70.6 %

Procedure:
In a manner analogous to that above, the reaction of p-aminobenzoic acid (473 mg; 4.90 mmol), 1-(8-bromo-3,6-dioxaoctyl) methanethiosulfonate (1.04 g, 3.39 mmol) and CsCl (1.17 g, 3.6 mmol) yielded 10-(4-aminophenyl)-10-oxo-3,6,9-trioxadecyl methanethiosulfonate (870 mg). 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d J=8.6 Hz, 2H), 6,55 (d, J=8.6 Hz, 2H), 5.94 (s, 2H), 4.25 (t, J=4.8 Hz, 2H), 3.72-3.67 (m, 4H), 3.58 (s, br., 4H). 3.51 (s, 3H), 3.35 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].O1CCCC1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].Cl>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH:1]([CH3:3])[CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccc(Br)c1

Procedure:
With cooling with ice, 150 mL of 1.0 M isopropylmagnesium chloride/tetrahydrofuran solution was added to tetrahydrofuran (200 mL) solution of 21.9 g of 3-bromobenzaldehyde. 4 N hydrochloric acid was added to the reaction liquid, extracted with diethyl ether, and washed with saturated sodium hydrogencarbonate solution and saturated saline water in that order. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=19/1 to 4/1) to obtain 4.20 g of the entitled compound as an oily substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[CH:25]=O)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](=[C:29](P(=O)(OC)OC)C(=O)C)=[N-].O>CO.C(OCC)(=O)C>[C:25]([C:17]1[N:16]([S:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:15])=[O:14])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)#[CH:29]
Reactant: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Potassium carbonate (0.97 g, 6.98 mmol) was added to a suspension of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.00 g, 3.49 mmol) in methanol (1.0 mL), followed by the addition of a solution of dimethyl 1-diazo-2-oxopropylphosphonate (0.81 g, 4.19 mmol) in methanol (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours, after which water was added, then ethyl acetate. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to afford 2-ethynyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.40 g, 41%; purity 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=O)[CH2:25][C:26](=O)[CH3:27])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.[CH:53]1([NH:57][NH2:58])[CH2:56][CH2:55][CH2:54]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:22])([F:23])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:57]([CH:53]2[CH2:56][CH2:55][CH2:54]2)[N:58]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Reactant: NNC1CCC1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 308d, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as brown oil. MS (ESI): m/z=549.8 [M+H]+.