Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][NH:13][C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].CS(O)(=O)=O.[OH-].[K+]>O1CCOCC1.C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:8]3[NH:13][CH:14]=[C:15]([CH3:16])[C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(Cl)c2[nH]cc(C)c12
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid ethyl ester (180 mg), 3-chloroaniline (160 μl), and methanesulfonic acid (98 μl) in 1,4-dioxane (5 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was suspended in ethanol (6 ml) and treated with a solution of potassium hydroxide (170 mg) in ethanol (2 ml) and then refluxed overnight. The ethanol was evaporated and replaced with methanol (8 ml) and potassium hydroxide (56 mg) added and then the mixture was refluxed overnight. The mixture was evaporated to dryness and the residue dissolved in water which washed twice with diethyl ether. The aqueous was then acidified with concentrated hydrochloric acid to afford a precipitate. The precipitate was filtered off and washed with water. The solid was then sucked dry and dried to afford the title compound (178 mg).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].C>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Product: CC(=O)Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.45 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo [4,3-b]pyridazine was boiled under reflux with 22 ml. acetic anhydride for 1.5 hours at 160° C. bath temperature, the solution obtained was then mixed with charcoal, suction filtered while still hot, washed with a little acetic anhydride and then with ether and dried for 3 hours at 120° C. There was thus obtained 0.79 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-acetamido-s-triazolo [4,3-b]pyridazine in the form of yellow-white crystals which melt at 238° - 239° C. and show a change above 230° C.
Reaction SMILES: [OH:1][C@@:2]12[C:20](=[O:21])[O:19][C@@H:4]([C@H:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH:6]=[CH:7]1)[CH2:3]2.[OH-:22].[Li+]>C1COCC1.O>[OH:1][C@@:2]1([C:20]([OH:19])=[O:21])[CH:7]=[CH:6][C@@H:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C@H:4]([OH:22])[CH2:3]1
Reactant: O=C1O[C@@H]2C[C@@]1(O)C=C[C@H]2OCc1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@]1(O)C=C[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](O)C1
Yield: 74 %

Procedure:
A solution of carbolactone VIII (28 mg, 0.10 mmol) in 1 mL of THF and 0.5 mL of a 0.5 M lithium hydroxide aqueous solution was stirred at room temperature for 1 hour. The resulting solution was diluted with milliQ water (5 mL) and treated with Amberlite IR-120 (H+) to pH 6. The resin was filtered and washed with milliQ water (15 mL). The filtrate was concentrated under reduced pressure to give 23 mg of acid IX (74%) in a pale solid yellow form. [α]25D−121° (c 1.1 in CH3OH); 1H-NMR (250 MHz, CD3OD, δ) 8.20 (d, 2H, J 8.8), 7.65 (d, 2H, J 8.8), 5.93 (dd, 1H, J 10.0 and 1.8), 5.73 (d, 1H, J 10.0), 4.84 (s, 2H), 4.04 (m, 1H), 3.93 (dt, 1H, J 7.9 and 1.8) and 2.07 (m, 2H); 13C-NMR (63 MHz, CD3OD, δ) 176.8, 147.6, 147.1, 130.4, 129.3, 128.1, 123.4, 81.1, 73.5, 70.4, 68.2 and 40.2; IR (KBr)/cm−1 3528 and 1596; EM-IQ+ (m/z) 310 (MH+); HRMS calculated for C14H16NO7 (MH+): 310.0928, 310.0928 found.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:19]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Cc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Methylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Cl)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1)=[O:38]
Reactant: O=C(Cl)CBr
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2R)-2-[(4-aminobenzyl)-(4-chloro-benzenesulfonyl)amino]-4-methyl-pentanoic acid amide (248 mg, 0.56 mmol) and Et3N (176 mg, 1.74 mmol) in CH2Cl2 (3 mL) was added bromoacetylchloride (105 mg, 0.67 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with CH2Cl2 (5 mL), washed with 1 N HCl, brine, and dried through a cotton plug. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% acetone/CH2Cl2) afforded the title compound (124 mg) in 42% yield. MS (ESI), (M+H)+ 531.86, 1H NMR (CDCl3, 400 MHz) δ 8.78 (br s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30 (s, 2H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH3:27][C:28]([N:30]([CH3:32])[CH3:31])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:31][N:30]([CH3:32])[C:28](=[N:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26])[CH3:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N=C(C)N(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.73 g of 5-amino-4-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole, prepared as described by Suzuki and Kumashiro, Chem. Abstracts 71, 12561n (1969), and dimethylacetamide (0.70 g) in acetonitrile (5 ml) is added dropwise phosphoryl chloride (0.61 g) and the mixture is stirred under nitrogen for 20 hours at room temperature. The mixture is poured into 5% aqueous sodium carbonate and extracted with ethyl acetate and the organic layer washed with saturated sodium chloride solution and dried over sodium sulfate. The organic extract is concentrated to dryness at reduced pressure to afford 5-[1-(dimethylamino)-ethylideneamino]-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole-4-carbonitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-5-methylphenol (10) (250 g, 1.75 mol) in CH3N (2.5 L) was added Me2SO4 (184 mL, 1.93 mol) and K2CO3 (314 g, 2.28 mol). The reaction mixture was heated to reflux for 6 h with mechanical stirring. The reaction mixture was cooled to ambient temperature and filtered through Celite. The filtrate was evaporated. The residue was diluted with EtOAc (1.5 L), washed with water (1.5 L*2) and brine (1.5 L) successively, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-chloro-5-methylanisole (11) as a light yellow oil (274 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.20-7.25 (d, 1H), 6.73 (s, 1H), 6.68-6.71 (d, 1H), 3.86 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([NH:39][C:40]([C@@H:42]1[CH2:47][NH:46][CH2:45][CH2:44][NH:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:46]4[CH2:45][CH2:44][NH:43][C@H:42]([C:40]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:47]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1
Product: CC(C)(C)NC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-tert-butylpiperazine-2-(S)-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-(S)-carboxylic acid tert-butylamide following General Procedure C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:32])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H21N5O2S, 383.14; m/z found, 384.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 2H), 8.62 (dd, J=2.3, 0.9, 1H), 8.34 (d, J=1.8, 1H), 8.01 (dd, J=8.0, 1.6, 1H), 7.94 (dd, J=8.2, 2.3, 1H), 7.87 (dd, J=8.2, 0.9, 1H), 7.65 (d, J=7.9, 1H), 2.84 (q, J=7.2, 2H), 1.01 (t, J=7.2, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:31])(=[O:32])[NH2:33]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 470.5 [(M+H)+]; mp 252-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH:32]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([N:45]1[CH2:50][CH2:49][N:48]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:22])[CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=680.97 (M+H+); retention time=1.03 minutes.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7])(=[O:4])=[O:3].[CH3:16]C(O)CCCCCCCCC.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:7])(=[O:4])=[O:3]
Reactant: CCCCCCCCCC(C)O
Reactant: CCCCCCCCC(C)OS(C)(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCC(C)OS(C)(=O)=O
Reaction time: 3.5 h
Yield: 95 %

Procedure:
2-Methanesulfonyloxyundecane was prepared as described for 2-methanesulfonyloxydecane from 2-undecanol (30.0 ml, 144 mmol), methanesulfonylchloride (15.5 ml, 200 mmol) and diisopropylethylamine (30.8 ml, 177 mmol) in dry CH2Cl2 (240 ml). After stirring for 3.5 hrs, the reaction was processed as previously stated but at 4 times the volumes to provide 2-methanesulfonyloxyundecane (31.35 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O>C(O)C>[CH:11]1([C:4]2[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:18]=[C:19]3[CH3:21])[N:3]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)c1[nH]c(C2CC2)nc1N
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1[nH]c(C2CC2)nc1-n1c(C)ccc1C
Yield: 95.6 %

Procedure:
A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][NH:20][C:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([CH:29]=O)[N:28]=1)=[O:22].[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][NH:20][C:21](=[O:22])[NH:23][C:24]1[S:25][CH:26]=[C:27]([CH2:29][NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[N:28]=1
Reactant: O=Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNCc1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
Sodium triacetoxyborohydride (937 mg, 4.42 mmol) was added to a CH2Cl2 (50 mL) solution of 1-(3-fluorobenzyl)-3-(4-formylthiazol-2-yl)urea (620 mg, 2.21 mmol) and tert-butyl 2-aminoethylcarbamate (532 mg, 3.32 mmol) at 0 C. Upon completion of the reaction, it was quenched with dilute NaHCO3. The organics were dried and evaporated. Flash chromatography afforded tert-butyl 2-((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methylamino)ethylcarbamate. 1H NMR (400 MHz, CDCl3): δ 8.05 (1H, br), 7.28 (m, 1H), 7.00 (m, 3H), 6.61 (s, 1H), 4.80 (s, 1H), 4.49 (d, 2H), 3.73 (s, 2H), 3.17 (m, 2H), 2.63 (t, 2H), 1.41 (s, 9H). MS (ES+): M/Z 424 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([Si](C)(C)C)[CH:10]=2)[CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>CC#N.C([O-])([O-])=O.[Na+].[Na+]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:3]=[CH:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)c1cc2cnc(Br)cn2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(-c2cn3nccc3cn2)cc1
Temperature: 150 °C
Yield: 28.5 %

Procedure:
A mixture of 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine (60 mg, 0.23 mmol), 4-fluorophenylboronic acid (40 mg, 0.29 mmol) and PdCl2dppf (10 mg, 0.014 mmol) in CH3CN (1 ml) and 2N Na2CO3 (aq, 1 ml) in a microwave vial was deoxygenated by bubbling N2 through for 20 seconds. The vial was sealed and then stirred and heated at 150° C. in the microwave for 20 minutes. After cooling the reaction mixture was partitioned between CH2Cl2/H2O. The mixture was passed through a phase separating cartridge. The organic layer was evaporated and the residue was purified by chromatography on silica (5→20% EtOAc/Petrol) to give the title compound (14 mg, oil) 1H NMR (400 MHz, CDCl3): 9.15 (1H, d), 8.75 (1H, s), 8.06 (1H, d), 7.98-7.92 (2H, m), 7.24-7.14 (2H, m), 6.84 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.CO[CH:42](OC)[N:43]([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[CH:27]([O:26][C:24]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[C:4]1[S:3][C:2]([N:1]=[CH:42][N:43]([CH3:45])[CH3:44])=[N:6][CH:5]=1)[CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]2=[O:23])=[O:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C=Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 51.3 %

Procedure:
A solution of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4 g) in tetrahydrofuran (50 cc) is treated with dimethoxy(dimethylamino)methane (1.13 g). The reaction mixture is stirred for 25 minutes at 20° C., then diluted with ethyl acetate (150 cc), washed with distilled water (4×150 cc) and with a saturated sodium chloride solution (150 cc) and dried ove magnesium sulphate. The residue obtained after evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C. is chromatographed on a column (height: 28 cm; diameter: 5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.6 bar (60 kPa) with ethyl acetate, and 100 cc fractions being collected. Fractions 9 to 23, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylaminomethyleneamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (2.25 g) is obtained in the form of an orange froth whose characteristics are identical to those of the product obtained in A.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([Br:16])[CH:8]=1)=[O:6].CO>O>[Br:16][C:9]1[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: COC(=O)c1cc(Br)c2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)c2cc[nH]c2c1
Reaction time: 2.5 h

Procedure:
A solution of sodium hydroxide (14.08 g, 352.1 mmol) in water (100 mL) was added a to a solution of 4-bromo-1H-indole-6-carboxylic acid methyl ester in methanol (14.91 mL, 58.7 mmol) at room temperature and stirred for 2.5 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added, and the product was extracted with ethyl acetate to give 13.0 g of 4-bromo-1H-indole-6-carboxylic acid, which was used in the next step with no further purification. 1H NMR (400 MHz, CD3OD) δ 8.13 (t, J=1.0 Hz, 1H), 7.87 (d, J=1.3 Hz, 1H), 7.53 (t, J=3.4 Hz, 1H), 8.13 (d, J=4.2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[OH-].[Ca+2].[OH-].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O1CCOCC1.O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[C:5]([CH3:9])=[N:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCn1nc(C)cc1O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1O
Temperature: 110 °C
Reaction time: 3.5 h

Procedure:
A suspension of 1.4 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol, 1.6 g of calcium hydroxide and 1.3 ml of benzoyl chloride in 70 ml of 1,4-dioxane was stirred at 110° C. for 3.5 h. 1 ml of water was added and the mixture was stirred at 110° C. for 2 h. 25 ml of 2N hydrochloric acid was added. The mixture was stirred at room temperature for 16 h and extracted three times with 60 ml of ethyl acetate. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 3.1 g of (1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification. Mass spectrum (ES) m/z 231 [M+H]+, 272 [M+H+CH3CN]+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[Cl:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:10][C:11]1[C:16]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1nccnc1Cl
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Hexanol was added to a slurry of sodium hydride in THF, and the mixture stirred for 30 minutes. The slurry was cooled to -5° C. and a solution of 2,3-dichloropyrazine added. The mixture was stirred for 1.5 hours, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel using varying concentrations of methanol in chloroform. Fractions containing the desired product were evaporated, yielding 2-chloro-3-hexyloxypyrazine as an oil.