Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)(OC(C)(C)C)=O.CN1CCOCC1.CN(C1C=CC=CN=1)C.[NH2:30][C:31]1[NH:32][C:33]2[CH:39]=[C:38]([CH3:40])[C:37]([CH3:41])=[CH:36][C:34]=2[N:35]=1.[Na+].[Cl-]>CN(C=O)C.C(Cl)CCl>[CH3:40][C:38]1[C:37]([CH3:41])=[CH:36][C:34]2[NH:35][C:31]([NH:30][C:11](=[O:13])[CH2:10][CH2:9][NH2:8])=[N:32][C:33]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc2nc(NC(=O)CCN)[nH]c2cc1C
Reaction time: 1 h

Procedure:
Boc-β-alanine (1.89 g; 10 mmol) was dissolved in 15 ml of DMF and, after addition of 2.02 g of N-methylmorpholine, 0.122 g of dimethylaminopyridine and 1.92 g of EDC*HCl, stirred for 1 h. 1.93 g (12 mmol) of 2-amino-5,6-dimethylbenzimidazole were added to the clear solution, and the mixture was stirred at RT for 16 h and then at 60° C. for 1 h. After the reaction was complete, NaCl solution was added, followed by extraction 2× with ethyl acetate, and the organic phase was washed with 10% citric acid and 2× with water, dried and concentrated. The residue (1.3 g) was dissolved in 10 ml of CH2Cl2, and 10 ml TFA were added. After 2 h, the mixture was evaporated, the residue was taken up in diethyl ether, ethereal HCl was added. After 1 h, the crystals were filtered off with suction, washed until neutral and dried at 40° C. 0.90 g; ESI-MS [M+H+]=233.2
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[S:22]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CC(=O)c1nccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a mixture of 1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone (680 mg, 4.25 mmol) in anhydrous THF (40 mL) at 0° C. was added NaH (60% in mineral oil, 204 mg, 5.1 mmol). After the mixture was stirred at 0° C. for 30 min, 4-methylbenzene-1-sulfonyl chloride (850 mg, 4.46 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water (150 mL), extracted with EtOAc (3×50 mL) and concentrated under reduced pressure to afford 1.32 g (98.9%) of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone as yellow solid: MS (ESI) m/z: 315.2 [M+1]+.
Reaction SMILES: B(Br)(Br)[Br:2].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@H:7]([N:13]1[CH:28]=[CH:27][C:16]3[N:17]([CH3:26])[C:18]4[CH:19]=[CH:20][C:21]([O:24]C)=[CH:22][C:23]=4[C:15]=3[C:14]1=[O:29])[CH2:6]2.CO>ClCCl>[BrH:2].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@H:7]([N:13]1[CH:28]=[CH:27][C:16]3[N:17]([CH3:26])[C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][C:23]=4[C:15]=3[C:14]1=[O:29])[CH2:6]2
Reactant: COc1ccc2c(c1)c1c(=O)n([C@@H]3CN4CCC3CC4)ccc1n2C
Reactant: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Cn1c2ccc(O)cc2c2c(=O)n([C@@H]3CN4CCC3CC4)ccc21
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of BBr3 (0.5 mmol) in dichloromethane (0.5 ml) was added dropwise at -70° C. to a solution of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2-dihydro-8-methoxy-5-methyl-1-oxopyrido[4,3-b]indole (0.11 g, 0.33 mmol)in dichloromethane (1 ml), from Example 3. The reaction mixture was warmed to ambient temperature, then recooled to -70° C. Methanol (0.5 ml) was added and the reaction mixture was brought to ambient temperature. The solvent was removed under reduced pressure and the residue was recrystallized from isopropanol to afford 0.04 g (37% yield) of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2-dihydro-8-hydroxy-5-methyl-1-oxopyrido[4,3-b]indole hydrobromide, m.p. 235°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH:11][C:21](=[O:22])[CH2:20][Cl:19])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1cncc(Br)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To an ice-cold suspension of 5-bromo-3-pyridinecarbohydrazide (3.0 g, 13.88 mmol) in anhydrous CH2Cl2 (60 mL) was added 4-methyl-morpholine (2.1 g, 20.82 mmol), followed by dropwise addition of chloroacetyl chloride (1.88 g, 16.67 mmol). The cold bath was then removed and the mixture stirred at rt for 15 h. Heavy precipitation occurred and the mixture was diluted with additional CH2Cl2 (50 mL) and stirring continued for 24 h. The solids were collected by filtration and washed with CH2Cl2 to afford the title compound (3.66 g, 90% yield): MS (ES) m/z 292 and 294 (M+1 Br isotopes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:1]4[CH:29]=[CH:30][CH:31]=[C:27]4[C:25]([O:24][CH3:23])=[O:26])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[NH:5][C:6](=[O:22])[C:7]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
10 g (33 mmol) of 6-amino-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione (Example 28e), 6.9 g (36 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap. After reaction was complete, the mixture was concentrated under reduced pressure, and the residue was treated with water. The precipitate was filtered off with suction to yield 11 g (79%) of the product. Melting point 211°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C>C(OCC)C>[Br-:11].[CH2:12]([N+:10]1[CH:9]=[CH:8][N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2nccn2c1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc2n(cc[n+]2Cc2ccccc2)c1
Product: [Br-]

Procedure:
A solution of 2.3 g. of 6-chloroimidazo[1,2-a]pyridine and 3.42 g. of α-bromotoluene in 40 ml. of dry acetonitrile is heated at reflux temperatures overnight. The solution is cooled and 35 ml. of diethyl ether added. The precipitated solids are collected and twice recrystallized from isopropanoldiethyl ether, 3.8 g., m.p. 193°-195° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.C1C[O:18][CH2:17][CH2:16]1.[H][H]>[Pd].CO>[C:17]([O:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:18])[CH3:16]
Reactant: C1CCOC1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A 10 g portion of ferulic acid, 150 mL of THF, and 80 mL of methanol were placed in a Parr pressure reactor with 1.5 grams of 10% palladium on charcoal. The reaction mixture was stirred at 30° C. under 60 psi of hydrogen for 12 hours. To remove the palladium on charcoal, the solution was vacuum filtered through celite, dried over magnesium sulfate, and condensed in vacuo. The solid was dissolved in a minimum amount of warm THF and poured into ice chilled hexanes and the solid portion recrystallized from a 5:1 mixture of ethyl acetate and water and dried on the Schlenk line. The crystals of dihydroferulic acid were acetylated by reaction with 9.6 g of acetic anhydride in the presence of 7.6 mL of pyridine. The mixture was stirred at room temperature for three hours and poured over an ice/water slurry (300 mL), to form a white precipitate that was filtered and dried on a Schlenk line, giving a 78% yield.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC1C=C(Cl)C=C(Cl)C=1[C:19](C1C(Cl)=CC(Cl)=CC=1Cl)([C:23]([O-])=[O:24])[C:20]([O-])=[O:21]>COCCOCCOC>[OH:24][C:23]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:9])[NH:1][C:20](=[O:21])[CH:19]=1
Reactant: O=C([O-])C(C(=O)[O-])(c1c(Cl)cc(Cl)cc1Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: COCCOCCOC
Product: CCOC(=O)c1c(O)cc(=O)[nH]c1C

Procedure:
A solution of ethyl 3-aminocrotonate (12.6 g, 97.5 mmol) and of intermediate 11 in diglyme (400 ml) was heated at 100° C. for 3 hours during which the product separated out. After cooling, diethylether (1.5 l) was added and the desired intermediate 12 was filtered (14.2 g, 75%). m.p. 243–245° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:27]([OH:29])=O)[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C@H:16]([CH2:17][C:18]3[CH:19]=[C:20]([CH3:26])[C:21]([OH:25])=[C:22]([CH3:24])[CH:23]=3)[C:27](=[O:29])[N:74]3[CH2:73][CH2:72][N:71]([CH:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)[CH2:76][CH2:75]3)=[O:14])[CH2:11][CH2:12]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 100 mg (0.21 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate, 74 mg (0.23 mmol) TBTU and 35 μL (0.26 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 35 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction mixture was stirred for a further 5 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN([C:38]([O:42]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.N1CCC(N2CCC[C@H]2CO)CC1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][CH2:21][C@H:22]4[CH2:38][OH:42])[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: OC[C@@H]1CCCN1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 9) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 505.3 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:47][CH:48]1[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)=[O:11])=[CH:20][CH:19]=3)=[O:23])[CH2:50][CH2:49]1
Reactant: OC1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-hydroxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][C:31]([I:34])=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccc(I)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(I)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-iodo-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 6): tR=1.24 min; Mass spectrum (ESI+): m/z=562 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[ClH:16].[Cl:16][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2cccnc12
Product: Cl
Product: O=C(Cl)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
Quinoline-8-carboxylic acid (1.0 g) was added to 3 ml of thionyl chloride, and the reaction mixture heated at reflux for one hour. The reaction mixture was allowed to stir at room temperature and was then concentrated in vacuo. The residue was washed with benzene (2×10 ml) and was used in the next reaction.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH3:13])=[N:7][N:6]2[C:14]=1[S:15]([NH2:18])(=[O:17])=[O:16])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:22]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([O:20][CH3:19])[N:22]=[C:23]([NH:29][C:30]([NH:18][S:15]([C:14]2[N:6]3[N:7]=[C:8]([S:11][CH2:12][CH3:13])[CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:1][CH3:2])(=[O:16])=[O:17])=[O:31])[N:24]=1
Reactant: CCSc1ccc2nc(CC)c(S(N)(=O)=O)n2n1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1ccc2nc(CC)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in the above reaction scheme, 2-ethyl-6-ethylthioimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.19 g, 0.66 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.20 g, 0.73 mmol) were suspended in acetonitrile (5 ml) and stirred at room temperature, during which DBU (0.11 g, 0.73 mmol) was added thereto. After the mixture was stirred at room temperature for 2 hours, the reaction solution was poured into water (50 ml) and adjusted to pH 2 with dilute hydrochloric acid. The precipitated crystals were collected by filtration, and washed with water and ether in this order. The crystals were dried under reduced pressure to give the title compound as colorless crystals. The yield was 0.18 g (58%), and the melting point was 160 to 165° C. (dec.).
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[OH2:13].O1CCO[CH2:16][CH2:15]1>>[CH3:15][C:16]1[C@@H:12]([OH:13])[CH2:2][C:7](=[O:1])[C:6]=1[CH2:5][CH:4]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: C1COCCO1
Product: C=CCC1=C(C)[C@@H](O)CC1=O

Procedure:
A mixture of 2.7 g of (3R, 3aR, 4S, 7R, 7aS) 3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one, 0.25 g of p-toluene sulfonic acid monohydrate, 30 ml of water and 20 ml of dioxane was refluxed for 24 hours and then the solvent was evaporated under reduced pressure. The mixture was neutralized with triethylamine to a pH of 7 and was then evaporated to dryness under reduced pressure. The 2.8 g of residue was chromatographed over silica gel and was eluted with a 1--1 benzene-ethyl acetate mixture containing 0.1% of triethylamine to obtain 1 g of (S) allethrolone, 0.4 g of lactone and 0.7 g of a mixture of (S) allethrolone-lactone. The (S) allethrolone had a specific rotation of [α]D20 =+6.5°±1° (c=1.5% in benzene).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:18]#[N:19]>CN1CCCC1=O.Cl>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1)#[N:19]
Reactant: N#C[Cu]C#N
Reactant: Brc1ccc2c(-c3ccccc3)csc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(-c3ccccc3)csc2c1

Procedure:
Combine 6-bromo-3-phenylbenzothiophene (0.5 g, 1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux 3 h in 1-methyl-2-pyrrolidinone (1.73 mL). Add ferric chloride (2.11 g, 7.79 mmol) in concentrated HCl (1.73 mL) and stir 1.5 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4, filter and evaporate onto silica gel. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give the desired intermediate that is used without further purification (0.27 g, 67%). MS (GCMS) m/z: 235 Mt
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(=O)(=O)C(C)C)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and propane-2-sulfonic acid [5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide (which was obtained in Example 27) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.20-1.40 (m, 4H), 1.25 (d, J=6.8 Hz, 6H), 1.55-1.75 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.75 (m, 5H), 2.92 (t, J=7.7 Hz, 2H), 3.05-3.15 (m, 1H), 3.45-3.60 (m, 2H), 4.46 (dd, J=7.8, 4.5 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 7.23 (d, J=2.0 Hz, 1H); MS (ES) m/z: 569.0 (MH+); HRMS Calcd. for C26H41N4O6S2 (MH+): 569.2462. Found: 569.2458.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=S)=[CH:7][C:5]=2[N:6]=1.[BrH:15].C1(SC([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=N)C=CC=CC=1>C(O)C.C(OCC)C>[BrH:15].[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:14])=[CH:7][C:5]=2[N:6]=1
Reactant: NC(=S)Nc1ccc2sc(N)nc2c1
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CCO
Solvent: CCOCC
Product: N=C(Nc1ccc2sc(N)nc2c1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of the amino urea compound (Example 18, 35 mg, 0.21 mmol) in ethanol (1.4 mL) was added thiophene-2-carboximidothioic acid phenyl ester hydrobromide (63.7 mg, 0.21 mmol). The mixture was stirred at room temperature for 17 hours and then diluted with diethyl ether. The light yellow precipitate was collected by filtration (64.8 mg, 93%). 1H-NMR (DMSO d6) δ: 11.36 (br s, 1H), 9.72 (br s, 1H), 8.83 (br s, 1H), 8.17 (d, 1H, J=4.68 Hz).
Reaction SMILES: [Na].CO[C:4]1[N:5]=[N:6][C:7]([S:10]([C:13]2[N:14](S(C3C=CC=CC=3)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=1.[CH3:31][OH:32]>>[CH3:31][O:32][N:5]1[CH:4]=[CH:9][CH:8]=[C:7]([S:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:11])=[O:12])[NH:6]1
Reactant: COc1ccc(S(=O)(=O)c2cc3ccccc3n2S(=O)(=O)c2ccccc2)nn1
Reactant: CO
Agent: [Na]
Product: CON1C=CC=C(S(=O)(=O)c2cc3ccccc3[nH]2)N1
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of sodium metal (18.6 mmol, 428 mg) dissolved in methanol (8 mL) was added a solution of 3-methoxy-6-(N-phenylsulfonylindole-2-sulfonyl)-pyridazine (1.86 mmol, 850 mg) and the reaction was stirred for 10 minutes. The reaction mixture was quenched with H2O (10 mL) and CHCl3 (25 mL). The CHCl3 layer was collected, dried, filtered, and the filtrate was evaporated to obtain 2-methoxy-6-(indole-2-sulfonyl)-pyridazine (82%, 440 mg).
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH:27]C(C)=O)[N:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[CH:19]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)C.S(=O)(=O)(O)O>C([O-])([O-])=O.[Na+].[Na+]>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH2:27])[N:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[CH:19]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)cn1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)cn1-c1ccccc1Cl

Procedure:
From Example 37, 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-(2-chlorophenyl)-2-amino-1H-imidazole 127 (27 mg, 0.062 mmol) was added to ethanol (2 mL, 30 mmol) containing 1 ml of 10% aqueous sulfuric acid. The reaction was microwaved on 300 watts at 100° C. for 15 minutes. The reaction mixture was mixed with 10 ml of 1 M aq Na2CO3 and extracted with ethyl acetate twice. The organic layer was washed with brine and dried over K2CO3. The solvent was evaporated to afford 128. (18 mg, 74%). MS(ESI+) 395.1