Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[F:2][C:3]([F:35])([F:34])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:32])[C:6]=1[CH3:33].C([Li])CCC.[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=O)[CH3:42].O>C1COCC1>[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=[CH:12]/[C:8]1[C:9]([CH3:11])=[CH:10][C:5]([O:4][C:3]([F:2])([F:34])[F:35])=[C:6]([CH3:33])[C:7]=1[CH3:32])[CH3:42]
Reactant: Cc1cc(OC(F)(F)F)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 12.2 g (24 mmol) of (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyltriphenylphosphonium chloride in 490 ml of dry THF was cooled to 45° C. and treated rapidly (over ~5 minutes) with 11.1 ml (25.5 mmol) of n-butyl lithium (2.3M in hexane) at -35° to -45° C. The reaction mixture was maintained at that temperature for 15 minutes, allowed to warm slowly to -25° C. at which time it became a slightly turbid orange solution. The mixture was cooled to -45° to -50° C. and 7.0 g (33 mmol) of ethyl-(2E,4E,6E)-3,7-dimethyl-8-oxo-octatrienoate in 50 ml of dry THF was added rapidly. The orange color disappeared; the reaction mixture was stirred at -25° C. for 2 hours, then allowed to warm to 0° C. over 1 hour and maintained at that temperature for 2 hours. The mixture was then poured into 1 liter of cold water and extracted with 250-ml portions of hexane. The organic phase was combined, washed successively with 500 ml of cold water, 2×500 ml of a 60% by volume methanol-water solution, and 500 ml of saturated NaCl solution, dried (MgSO4), filtered and concentrated. The resulting yellow oil was purified by HPLC (2 silica gel columns, 2% ethyl acetate in hexane as elutant) to give 5.79 g of ethyl-(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate; mp 47°-49° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([NH2:20])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].[NH4+].[OH-].O>C1COCC1>[CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]([NH2:23])=[S:22])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Reaction time: 19 h
Yield: 87 %

Procedure:
3-Cyclopentyloxy-5-phenoxy-pyridine-2-ylamine (0.33 mmol) is dissolved in THF (5 ml) and 1,1′-thiocarbonyldiimidazol (4 eq.) is added. The reaction solution is stirred 19 hours. 32% NH4OH (20 eq.) is added and stirred 3 hours at room temperature. Water (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as brown oil in a yield of 87%; HPLC (method C): 2.13 min; LC-MS (method A): 2.18 min, 330.15 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH2:16])[CH3:15])[CH2:3][CH2:2]1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH:16][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:15])[CH2:3][CH2:2]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of (S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (166 mg, 0.76 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (180 mg, 0.76 mmol) and DIPEA (0.7 mL, 3.8 mmol) in n-butanol (3 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 374 as a white solid (125 mg, 49%). LCMS (Method K): RT 2.72 min [M+H]+ 338.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.23-8.09 (2H, m), 7.90 (1H, br s), 7.56 (1H, dd, J=8.77, 4.94 Hz), 7.37 (1H, dd, J=9.27, 2.53 Hz), 7.05-6.97 (1H, m), 5.94 (1H, br s), 3.43-3.36 (1H, m), 1.69 (3H, d, J=6.80 Hz), 1.33-1.00 (4H, m)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CO.CS(O[C@H:14]1[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]1)(=O)=O>O>[CH3:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15][CH2:16]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](C)CC1
Reactant: C1CNCCN1
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Piperazine (54.9 g) and methanol (5 ml) was stirred at 120° C. to melt for 15 minutes. To the solution was dropwise added trans-4-methylcyclohexyl methanesulfonate (33.0 g) and the mixture was stirred at the same temperature for 2 hours. After cooling, to the reaction mixture was added water (150 ml) and extracted three times with a mixture of ethyl acetate (100 ml) and THF (100 ml). The extracts were collected, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane, methanol and conc. ammonium hydroxide (4:1:0.1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give cis-1-(4-methylcyclohexyl)piperazine (17.76 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13](=O)[NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][C:16]=2[NH2:28])=[N:10][NH:11][CH:12]=1)(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[N:22]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]3[NH:14][C:13]([C:9]4[C:8]([NH2:7])=[CH:12][NH:11][N:10]=4)=[N:28][C:16]=3[CH:17]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 85 °C
Yield: 79.1 %

Procedure:
A mixture of [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (12.0 g, 28.8 mmol) and 2M aqueous HCl solution (50 mL) was heated at 85° C. for 14 h, then allowed to cool to ambient temperature. Solid Na2CO3 was carefully added until mixture was pH˜8.5 and solution was saturated. A dark coloured gummy liquid was formed. The mixture was allowed to settle and the solvent decanted. To the remaining residue was added EtOH (60 mL), the mixture heated at reflux for 1 h and then hot filtered, washing with EtOH (2×20 mL), to remove inorganic residues. The filtrate was reduced in vacuo to give a glassy solid which was then stirred in Et2O (60 mL) for 1 h and the resultant purple coloured powder collected by filtration and dried in vacuo to give 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (6.8 g, 80%, ˜90% purity).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH:15]([CH3:39])[CH2:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH2:12][NH:11][C:9]=2[N:10]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH:15]([CH3:39])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH2:12][NH:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CC(C)C2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(Cc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C1CNc2nc(N)nc(O)c2C1
Reaction time: 72 h
Yield: 67.3 %

Procedure:
A homogeneous solution of 17.5 mg of diethyl N-(4-[2-(2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)propyl]benzoyl)-L-glutamate in 2 mL of methanolic sodium hydroxide solution was allowed to stand at room temperature for 72 hours. Most of the solvent was then removed under reduced pressure and the mixture was diluted with water and acidified with acetic acid. The precipitate was collected by filtration, washed with water, and dried under reduced pressure (0.1 mm) for 48 hours to give 9.7 mg (67%) of the title compound, which may be alternatively named as 5,10-dideaza-10-methyl-5,6,7,8-tetrahydrofolic acid. mp>250° C., NMR delta 0.87-0.88(brs, 1H each), 1-2.8(m, 11H), 3.13(m, 1H), 4.59(m, 1H), 6.96(d, 2H, J=9 Hz), 7.34(d, 2H, J=9 Hz.
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([Cl:25])[C:21]([Cl:24])=[C:22]([Br:23])[C:16]=3[N:15]=2)[CH:13]=1)=[O:8])C.C1COCC1>O>[Br:23][C:22]1[C:16]2[N:15]=[C:14]([N:12]3[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]3)[NH:18][C:17]=2[CH:19]=[C:20]([Cl:25])[C:21]=1[Cl:24]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
LiOH.H2O (0.046 g, 1.09 mmol) was added to a mixture of 1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.088 g, 0.22 mmol), THF (1 mL), and water (0.33 mL), and the mixture was stirred 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.068 g, 83%). MS (ESI/CI): mass calcd. for C11H6BrCl2N4O2, 374.9; m/z found, 375.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40].S>C(O)C>[C:1]1([C:7]2[S:40][C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:9][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1cc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc(OC)c1OC
Temperature: 10 °C
Reaction time: 3 h
Yield: 193 %

Procedure:
In a 1-liter stirred stainless steel autoclave were placed 40.4 g 1,2-diphenyl-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 22.2 g of phosphorus pentasulfide and 128 g of hydrogen sulfide. The reaction mixture was heated with stirring for 3 hours at 160°-168° C. (1210-1250 psig. pressure). The reactor was cooled to 10° C. and the hydrogen sulfide was released. The residue was stirred with 150 ml of ethanol to decompose unreacted phosphorus pentasulfide. Filtration and evaporation gave 38.8 g (96.4%) of 2,3-diphenyl-5-(3,4,5-trimethoxyphenyl)thiophene.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccnc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 21 h
Yield: 82.4 %

Procedure:
2-Chloro-3-fluoropyridine (0.4380 g, 3.33 mmol), 4-chlorophenylboronic acid (0.6248 g, 3.996 mmol), palladium tetrakistriphenylphosphine (0.1924 g, 0.1665 mmol), sodium carbonate (0.4235 g, 3.996 mmol), toluene (10 mL), and water (1 mL) were placed in a teflon lined vial. The vial was sealed and stirred at 125° C. for 21 hour. The mixture was cooled to ambient temperature and the whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 569.4 mg of the title compound as white solid (82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]1=[O:23].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:28])[C:13]1=[O:23]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(Cl)cc(Cn2c(=O)cc(C(F)(F)F)[nH]c2=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(Cl)cc(Cn2c(=O)cc(C(F)(F)F)n(C)c2=O)c1Cl
Yield: 65.2 %

Procedure:
By the method of Example 1, Step H, 8.95 grams (0.024 mole) of 3-(2,5-dichloro-3-methoxyphenylmethyl)-6-trifluoromethyluracil, 5.03 grams (0.036 mole) of dimethyl sulfate, and 8.99 grams (0.048 mole) of potassium carbonate were reacted in 800 mL of acetone, yielding 6.0 grams of 3-(2,5-dichloro-3-methoxyphenylmethyl)-1-methyl-6-trifluoromethyluracil as a viscous, yellow oil, which became a glass upon cooling. This glass crystallized after standing for a period of time, m.p. 117°-123° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14].C(O)C>CO>[CH3:16][O:15][C:13](=[O:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:2]=1[Br:1])=[CH:11][C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(N)c(Br)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Solvent: CCO
Product: COC(=O)C=C(Nc1ccc(OC)cc1Br)C(=O)OC
Yield: 93 %

Procedure:
A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The filtrates were combined and purified by flash chromatography on silica gel using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 1H NMR (300 MHz, DMSO, d6) δ 9.60 (s, 1 H, NH), 7.26 (d, 1 H, Jm=2.7 Hz, ArH3), 6.93 (dd, 1 H, Jo=8.7, Jm=2.7 Hz, ArH5), 6.87 (d, 1 H, Jo=8.7 Hz, ArH6), 5.34 (s, 1 H, C═CH), 3.76 (s, 3H, OCH3), 3.68 (s, 3 H, CHCO2CH3), 3.66 (s, 3 H, CNCO2CH3); Mass Spec.: calc. for [C13H14BrNO5+H]+ Theor. m/z=344, 346; Obs. 344, 346.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=[N:9]O)[S:5][C:6]=1[CH3:7]>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:8][NH2:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C=NO)sc1C
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(CN)sc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude 4,5-dimethylthiazole-2-carbaldehyde oxime (300 mg, 2 mmol) was dissolved in acetic acid (25 mL), zinc dust (1.8 g, 27.5 mmol) was added portionwise at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered over a pad of celite and rinsed with methanol. Toluene was added and the filtrate was concentrated. An aqueous solution of NH4Cl was added, the solution was acidified to pH=2 with HCl (1N) and extracted with diethyl ether and ethyl acetate. The aqueous layer was basified with aqueous NaOH to pH=10, and then extracted with diethyl ether and ethyl acetate. Combined organic extracts were dried over sodium sulfate, filtered and evaporated to give crude (4,5-dimethyl-1,3-thiazol-2-yl)methylamine as a pale yellow oil which was used in the next step without purification. LCMS m/z (M+H) 143.1 found, 143.1 required.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](Br)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][C:31](B(O)O)=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[NH:26][CH:27]=[CH:28]3)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Br)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1

Procedure:
Ethyl 1-benzyl-5-nitro-1H,1′H-3,5′-biindole-2-carboxylate was prepared from ethyl 1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate and indole-5-boronic acid followed the procedure of Example 17 Step 2 as a yellowish solid: 1H NMR (DMSO-d6) δ 0.90 (t, J=7.1 Hz, 3H, 4.10 (q, J=7.1 Hz, 2H, 5.89 (s, 2H, 6.52 (t, J=1.1 Hz, 1H, 7.11 (d, J=8.4 Hz, 2H, 7.20 (dd, J=8.3, 1.7 Hz, 1H, 7.22-7.35 (m, 3H, 7.42 (t, J=2.7 Hz, 1H, 7.52 (d, J=8.4 Hz, 1H, 7.66 (s, 1H, 7.90 (d, J=9.3 Hz, 1H, 8.21 (dd, J=9.2, 2.2 Hz, 1H, 8.40 (d, J=2.2 Hz, 1H, 11.23 (s, 1H; MS (ESI) m/z 440 (MH+); MS (ESI) m/z 438 [M-H]−; HRMS calcd for C26H22N3O4: 440.1608; found (ESI+): 440.1596; Anal. calcd for C26H21N3O4.0.25H2O: C, 70.34; H, 4.88; N, 9.47. Found: C, 70.23; H, 4.89; N, 9.58.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][NH2:28].C(O)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:28][CH3:27])=[CH:13][CH:12]=1
Reactant: CN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)cc1
Reaction time: 8 h

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. MH+ (ESMS): 326.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH2:21]([O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:17]=[CH2:18]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1cc(Cl)ccc1C=O
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzaldehyde (254 mg, 1.62 mmol) and cesium carbonate (793 mg, 2.43 mmol) in THF (3 mL) was heated to reflux for 3 h. After the reaction mixture was cooled at room temperature, the solvent was evaporated and the residue partitioned between ethyl acetate and hydrochloric acid (1N). The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (AcOEt/Hexanes, 1:9) to give the title product (97%): 1H NMR (400 MHz, Cl3CD) δ 10.46 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.05 (dd, J=0.78, 8.3 Hz, 1H), 6.99 (d, J=0.78 Hz, 1H), 6.09 (m, 1H), 5.45 (m, 2H), 4.67 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23](N)=[O:24])[CH2:4][CH2:3]1.[OH-:32].[Na+].Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23]([OH:24])=[O:32])[CH2:4][CH2:3]1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(N)=O)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(=O)O)CC1
Temperature: 125 °C

Procedure:
To 4-(1-methyl piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid amide (example 254) (250 mg, 0.6 mmole) is added 30% aqueous NaOH solution (2 mL). The reaction mixture is heated to 125° C. overnight. Water (2 mL) is added as well as 1N HCl to pH 6-7. The solvent is removed under reduced pressure. The residue is dissolved in absolute EtOH and filtered to remove inorganic salts. EtOH is removed under reduced pressure. The residue is triturated in Et2O, filtered to afford 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid melting at 185° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(C)=O.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[O:13])[N:10]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1csc(-c2ccco2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1csc(-c2ccco2)n1
Reaction time: 3 h
Yield: 43.2 %

Procedure:
A solution of 2-(2-furyl)-4-thiazolecarboxylic acid (300 mg) and CDI (373.8 mg) in a mixed solvent of dry DMF (10 mg) and dry DMSO (2 ml) was prepared at 100° C. and allowed to react under the same condition for 1 hour. Then a solution of 5-aminotetrazole (156.9 mg) in dry DMF (2 ml) was added dropwise thereto and the reaction was continued for additional 3 hours. The solvent was removed from the reaction mixture. The residue was treated with water and acidified with 2N-HCl. The produced solids were filtered, washed sufficiently with water and then with ether, and dried to give yellow ocher solids of 2-(2-furyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (174 mg, 43%), m.p. 275°-277° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:6]=2[CH:18]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]=4)[N:16]=3)[C:6]=2[CH:18]=1
Reactant: Nc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Reactant: CCOC(=O)C(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
A mixture of 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)pyridazin-3-amine 10G (4.8 g, 15.73 mmol), ethyl 3-bromo-2-oxopropanoate (4.60 g, 23.60 mmol) and NaHCO3 (4.0 g) in dioxane was heated at 60° C. for 1 hr. Additional ethyl 3-bromo-2-oxopropanoate (1.5 g, 7.87 mmol, 0.5 eq) was added and stirred at 60° C. for an additional hour. The reaction mixture was filtered and rinsed with dioxane. 4-Methylbenzenesulfonic acid (2.71 g, 15.73 mmol) was added to the filtrate, and the reaction was heated at 75° C. for 2 hrs. The reaction was evaporated to dryness via rotary evaporation and the resulting residue was dissolved in EtOAc. The organic phase was washed with saturated NaHCO3 followed by 0.1 N NaOH (3×150 mL). The solution was dried with MgSO4, filtered, concentrated to dryness and purified by MPLC (10% MeOH/CH2Cl2) to provide the title compound, ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate 13A (4.7 g, 11.6 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.07 Hz, 3 H) 4.30 (q, J=7.07 Hz, 2 H) 6.26 (s, 2 H) 7.33 (d, J=9.60 Hz, 1 H) 7.59 (dd, J=8.72, 1.64 Hz, 1H) 8.08 (d, J=8.84 Hz, 1 H) 8.23 (d, J=9.60 Hz, 1 H) 8.31 (d, J=1.26 Hz, 1 H) 8.77 (s, 1 H). MS:m/z 401.2 (M+H)+.