Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([CH2:21][NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)N.[C:47](C1CCN(CC2C=CC(CCC(NCCN3CCC(OC(=O)NC4C=CC=CC=4C4C=CC=CC=4)CC3)=O)=CC=2)CC1)(=[O:49])[NH2:48]>>[C:47]([CH:5]1[CH2:4][CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([CH2:21][NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:20])=[CH:13][CH:12]=2)[CH2:6]1)(=[O:49])[NH2:48]
Reactant: NC(=O)C1CCN(Cc2ccc(CCC(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Reactant: NC(=O)C1CCN(Cc2ccc(CCC(=O)NCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Product: NC(=O)C1CCCN(Cc2ccc(CCC(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)C1

Procedure:
biphenyl-2-yl-carbamic acid 1-[2-({3-[4(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester, biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([NH:11]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:19]>O1CCOCC1>[Cl-:19].[CH3:1][S:2][CH2:3][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH3+:11]
Reactant: Cl
Reactant: CSC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Solvent: C1COCCO1
Product: CSC[C@@H]([NH3+])c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
(S)-tert-butyl (2-(methylthio)-1-phenylethyl)carbamate (380 mg, 1.421 mmol) was dissolved in HCl (1066 μl, 4.26 mmol) in dioxane and allowed to stir for 30 minutes at rt. The solvents were removed in vacuo to provide (S)-2-(methylthio)-1-phenylethanaminium chloride (275 mg, 1.350 mmol, 95% yield).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH:11]([NH2:14])([CH3:13])[CH3:12].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([N:14]([CH:11]([CH3:13])[CH3:12])[CH:9]1[O:10][CH2:2][C@@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(C)N
Reactant: O=C=NCCCl
Product: CC(C)N(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 67.5 %

Procedure:
3.0 g of D-xylose, 2.5 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.0 g of 1-(2-chloroethyl)-3-isopropyl-3-D-xylopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][CH:13]([C:9]1([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]1)[C:14]([OH:16])=[O:15])(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)C1(NC(=O)OC(C)(C)C)CCC1

Procedure:
(1-Tert-butoxycarbonylaminocyclobutyl)-hydroxyacetic acid (201.5 mg, 0.822 mmol) was stirred with acetic anhydride (95 mL) in pyridine (1.5 mL) for 24 h. The mixture was first concentrated under vacuum, and then diluted with 5 mL EtOAc. The organic solution was washed with 1N HCl (2 mL) followed by saturated aqueous NaCl (2 mL), dried (Na2SO4), and evaporated under vacuum which gave the title compound. LC-UV/MS API-ES− m/z 286 [M−H]−
Reaction SMILES: N1C=CC(=O)NC1=O.C[C@H]1O[C@H]2O[C@H:18]3[C@H:23](O[C@@]2(O)C(=O)C1)[C@@H:22](NC)[C@@H:21](O)[C@@H:20](NC)[C@@H:19]3O.O=[CH:33][C@@H:34]([C@H:36]([C@@H:38]([C@@H:40]([CH2:42]O)O)O)O)O.CC(S[C@@H:48]1O[C@H:52](CO)[C@H:51](O)[C@H:50](O)[C@H:49]1O)C>CO>[CH2:33]=[CH:34][CH:36]=[CH:38][CH2:40][CH2:42][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:18][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=c1cc[nH]c(=O)[nH]1
Solvent: CO
Product: C=CC=CCCCCCCCCCCCCC
Reaction time: 21 h

Procedure:
The genomic DNA encoding ATCC 8456_orf880, which was codon-optimized for expression in E. coli, was cloned into vector OP80 (pCL1920 derivative) under the control of a Ptrc promoter, and E. coli MG1655 ΔfadD was transformed with the resulting vector. The E. coli cells were cultured at 37° C. in an M9 mineral medium supplemented with 20 μg/mL uracil and 100 μg/mL spectinomycin. Glucose (1%, w/v) was the only source of carbon and energy. When the culture reached an OD600 of 0.8 to 1.0, IPTG (1 mM) was added and the temperature was shifted to 25° C. After growth for an additional 18 to 24 hours at 25° C., cells from 10 mL of culture were pelleted, resuspended in 1 mL methanol, sonicated for 30 minutes, and extracted with 4 mL hexane. After solvent evaporation, samples were resuspended in 0.1 mL hexane and analyzed by GC-MS. In contrast to the vector-only control, E. coli cells transformed with the orf880-bearing vector produced the α-olefins 1-pentadecene and heptadecadiene. This result indicates that expression of ORF880 confers the ability to biosynthesize α-olefins to E. coli when cultured on glucose, and that the direct precursors are the most abundant fatty acids in E. coli, namely hexadecanoic acid and vaccenic acid (11-cis-octadecenoic acid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.O.N>O1CCCC1>[NH2:26][C:11](=[O:12])[C@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(Step 3) To (2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (15 g) in tetrahydrofuran (75 ml) solution, 1,1′-carbonyldiimidazole (7.8 g) was added under ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., 28% ammonia water (15 ml) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, distilled water, ethyl acetate, and tetrahydrofuran were added, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with saturated potassium hydrogensulfate aqueous solution and saturated saline, dried over with anhydrous sodium sulfate, and concentrated until a small amount of ethyl acetate remained. Hexane was added to the concentrated solution, and the precipitated solid was collected by filtration to obtain the title compound (13.5 g).
Reaction SMILES: [C:1]([C:7]1[C:8]2[N:9]([CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:10]=[CH:11][C:12]=1[NH:13]C(=O)OCC)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[K+].[Br-]>>[CH2:3]([C:2]1[N:13]=[C:12]2[C:7](=[C:8]3[N:21]=[C:20]([CH3:22])[CH2:19][N:9]3[CH:10]=[CH:11]2)[CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1c(NC(=O)OCC)ccn2cc(C)nc12
Agent: [Br-]
Agent: [K+]
Product: CCCCc1cc2c3n(ccc-2n1)CC(C)=N3

Procedure:
From 25c (yield: 55%); mp 162° C.; IR (KBr) 3061, 2924, 1637, 1528 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.82 (t, 3H, J=7.6 Hz), 1.28 (m, 2H), 1.60 (m, 2H), 2.43 (s, 3H), 2.69 (t, 2H, J=7.6 Hz), 6.56 (s, 1H), 6.82 (d, 1H, J=7.1 Hz), 7.20 (s, 1H), 7.62 (d, 1H, J=7.1 Hz), 10.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 14.2, 22.3, 27.8, 31.5, 98.8, 101.2, 108.9, 114.1, 118.8, 130.4, 139.1, 139.8, 142.0. Anal. Calcd for C14H17N3: C, 73.98; H, 7.54; N, 18.49. Found: C, 74.05; H, 7.51; N, 18.29.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 454 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:30])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[N:11]([N:13]=[C:14]([NH:16]C(=O)C)[N:15]=2)[CH:12]=1)=O.[NH:32]([C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[S:42]([CH3:45])(=[O:44])=[O:43])[NH2:33].Cl.CCOC(C)=O>C(O)CCC>[NH2:16][C:14]1[N:15]=[C:10]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[C:8]([CH3:30])[C:7]([C:5]3[N:32]([C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=4[S:42]([CH3:45])(=[O:44])=[O:43])[N:33]=[CH:3][CH:4]=3)=[CH:12][N:11]2[N:13]=1
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1NN
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2S(C)(=O)=O)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 3.2 %

Procedure:
N-[6-(3-Dimethylamino-acryloyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 25, 247 mg, 0.573 mmol) and 4-hydrazino-3-methanesulfonyl-benzonitrile (Int. 22, 181 mg, 0.86 mmol) were heated at 100° C. in a mixture of n-butanol (10 mL) and conc. HCl (0.3 mL) for 1.5 h. EtOAc was added and the mixture was concentrated in vacuo. The resultant residue was purified by preparative C18 HPLC, eluting with a gradient of 40-90% MeCN in water (+0.1% formic acid) to give the title compound as a yellow solid (10 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH:23]([CH2:25][CH3:26])[CH3:24].O>CN(C=O)C.C(OCC)C>[CH3:24][CH:23]([CH2:25][CH3:26])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21]
Reactant: CCC(C)Br
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 19.58 g (174.5 mmol) of potassium tert-butoxide were initially charged in 200 ml of DMF, the mixture was cooled to 0° C., 30 g (145.4 mmol) of tert-butyl(4-methylphenyl)acetate, dissolved in 50 ml of DMF, were added slowly and the mixture was then stirred at 0° C. for 30 min. 18.95 ml (174.5 mmol) of 2-bromobutane were then slowly added dropwise, and the solution was stirred at 0° C. for another 4 h. 200 ml of water and 200 ml of diethyl ether were then added to the reaction solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 15.5 g (59.1 mmol, 40.6% of theory) of a colorless liquid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].[C:38]([NH-:40])#[N:39].O>CN(C)C=O>[C:38]([NH:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23])#[N:39]
Reactant: N#C[NH-]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCNC#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a solution of (3RS,4RS)-4-[9-iodononyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (381 mg, 0.69 mmol) in anhydrous dimethylformamide (2 ml) were added potassium carbonate (238 mg, 1.72 mmol) and cyanoamide (116 mg, 2.76 mmol), which was then stirred for 4 h at 50° C. Water was added thereto, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (238 mg, yield 74%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:19])[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1nn(-c2ccc(Cl)cc2)c(=O)n1C(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Temperature: 82 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.0192 mole—1.0 equiv.) of 4,5-Dihydro-1-(4-chlorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazol-5(1H)-one and 6.8 grams (0.0192 mole—1.0 equiv.) of F-TEDA in 50 mL of acetonitrile (% Wt/Vol triazolinone to solvent—10%) was stirred at 82° C. for 24 hours. After this time, an additional 6.8 grams (0.0192 mole—1.0 equiv.) of F-TEDA was added. Upon completion of addition, the reaction mixture was stirred at 82° C. for an additional 24 hours. The reaction mixture was analyzed by gas chromatography (GC), which indicated the reaction was 78% complete. The reaction mixture was cooled to ambient temperature, and the acetonitrile was removed under reduced pressure. The resulting residue was taken up in 30 mL of water and then 40 mL of an aqueous 10% hydrochloric acid solution was added. The resulting solution was extracted with three 30 mL portions of ethyl acetate. The organic layer was separated from the aqueous layer, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.9 grams (48% yield) of title compound. The H1 NMR spectrum of the product was consistent with that of a reference sample.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[I:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:9][C:5]1[C:4]([I:10])=[C:3]([CH2:2][C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1
Reactant: Clc1cccc(CBr)c1I
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cccc(Cl)c1I
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 1-(bromomethyl)-3-chloro-2-iodobenzene (7 g, 21 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (2 mL, 42 mmol) in 20 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 3.2 g pale yellow solid. MS m/e: (M+H)+ 278.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1O)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1O)C2
Yield: 108.5 %

Procedure:
A mixture of 6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.04 g), aminoguanidine hydrochloride (0.02 g), concentrated hydrochloric acid (0.041 ml), water (0.041 ml) and ethanol (10 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 26) (0.06 g) as colorless crystals.
Reaction SMILES: [C:1]1(CC(N)=O)[CH:6]=CC=[CH:3][CH:2]=1.[CH:11]1([C:14]2[N:18]([CH3:19])[C:17]([CH:20]=[O:21])=[CH:16][N:15]=2)[CH2:13][CH2:12]1>>[CH2:11]([C:14]1[N:18]([CH3:19])[C:17]([CH:20]=[O:21])=[CH:16][N:15]=1)[C:13]1[CH:12]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)Cc1ccccc1
Product: Cn1c(C=O)cnc1Cc1ccccc1

Procedure:
2-Benzyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 2-phenyl-acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[CH3:23].[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>C1COCC1.O.CCOC(C)=O>[CH3:23][C:3]1[C:2]2[B:29]([OH:30])[O:16][CH2:15][C:14]=2[CH:13]=[C:5]([OH:6])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(O)cc2c1B(O)OC2
Temperature: -78 °C
Yield: 33.3 %

Procedure:
A solution of 2-(4-bromo-3-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.93 g, 7.61 mmol) in anhydrous THF (25 mL) was made before cooling the reaction mixture on a −78° C. bath. Reaction mixture was then treated, dropwise, with n-BuLi (13.08 mL, 20.92 mmol) and allowed to stir for 1.0 h before (i-PrO)3B (77 mL, 25 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 3 h before addition of 12 mL of 1N HCl. The reaction mixture was allowed to stir 20 hr before addition of EtOAc and water (1:1, 50 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol (415 mg, 33%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 2.33 (s, 3H), 4.82 (s, 2H), 6.51 (ds, 1H), 6.53 (s, 1H), 8.57 (s, 1H), 9.59 (s, 1H).
Reaction SMILES: [O:1]([CH2:21][CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([N+:37]([O-])=O)[C:29]=2[N:30]=1)=[O:25])[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N+:18]([O-])=O)[C:10]=2[N:11]=1)=[O:6].O>Cl>[O:1]([CH2:21][CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[C:29]=2[N:30]=1)=[O:25])[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([NH2:18])[C:10]=2[N:11]=1)=[O:6]
Reactant: COc1ccc2sc(C(=O)NCCOCCNC(=O)c3nc4c([N+](=O)[O-])c(OC)ccc4s3)nc2c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COc1ccc2sc(C(=O)NCCOCCNC(=O)c3nc4c(N)c(OC)ccc4s3)nc2c1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
0.33 g (1.5 mmol; 3.4 eq.) of dihydrated tin chloride is added to 250 mg (0.43 mmol) of N,N′-(oxydiethane-2,1-diyl)bis(5-methoxy-4-nitro-1,3-benzothiazole-2-carboxamide) in solution in 10 ml of concentrated hydrochloric acid. The reaction medium is maintained under stirring at 60° C. for 4 hours, then poured into iced water and neutralized with a SN soda solution. The expected product is then extracted with 3 times 25 ml of dichloromethane, then the organic phases are combined, dried over magnesium sulphate and the is solvent evaporated off under reduced pressure. 220 mg of the expected product (gross yield=98%) is obtained in the form of a yellow oil and is used in the following stage without other purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CCOCC1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CCOCC4)cn3n2)c1
Temperature: 180 °C
Yield: 49 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide, 3-aminophenol (436 mg, 4.0 mmol), potassium carbonate (552 mg, 4.0 mmol) and N,N-dimethylformamide (5.0 mL) was stirred with heating at 180° C. for 15 min using a microwave synthesizer. After cooling, the reaction mixture was filtrated, and the filtrate was purified by preparative HPLC to give the title compound (364 mg, 49%) as a dark brown powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][C:14]1[CH:18]=[C:17]([NH2:19])[N:16]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[N:25]3)[N:15]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][C:17]2[N:16]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)[N:15]=[C:14]([CH3:13])[CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A mixture of 4-ethylbenzenesulfonyl chloride (0.033 g, 0.16 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.030 g, 0.13 mmol) in pyridine (1.0 mL) was heated at 80° C. for 2 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.019 g, 0.049 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.86 (dd, J=2.0, 4.0 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.60 (dd, J=7.2, 8.4 Hz, 1H), 7.51-7.46 (m, 3H), 7.27-7.23 (m, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.27 (s, 1H), 2.68 (q, J=7.6 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C21H21N4O2S [M+H]+ 393.2. found 393.2