Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:68])([CH3:67])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[NH:58][S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl>[CH3:67][C:44]1([CH3:68])[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[NH:58][S:59]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1
Reactant: CC(C)(CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
To a solution of triphenylphosphine oxide (2.74 g) in dichloromethane (25 mL) was slowly added trifluoromethanesulfonic anhydride (0.83 mL) at 0° C. The mixture was stirred for 10 min, and N-[2-(benzylthio)-2-methylpropyl]-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.82 g) was added. The reaction mixture was stirred at room temperature overnight and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.05 g, yield 8%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 176-177° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N:11]=O)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]>[Pd].C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O

Procedure:
A 2 liter Parr bomb was charged with 23.50 g (0.1 mole) 2,6-di-tert-butyl-4-nitrosophenol, 1.0 g of 5% Pd on C catalyst and 600 ml toluene. After purging the assembled bomb with nitrogen, it was pressurized to 50 psi with hydrogen. The mixture was stirred vigorously and uptake of hydrogen was noted. The hydrogenation step producing 2,6-di-tert-butyl-4-aminophenol was completed within 15 minutes. A temperature rise from 23° C. to 25° C. was observed during the hydrogenation. The mixture was allowed to stir under hydrogen atmosphere for a total of 1 hour.
Reaction SMILES: [K:1].[K].[OH:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[K:1].[C:29]([O:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)O)cc2)cc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 2-hydroxy-5-[2-(4-sulfophenyl)ethenyl]benzoate dipotassium salt (37.2 g, 0.09 mol) was added to a boiling solution of acetic acid (20 ml) and acetic anhydride (80 ml). Sulfuric acid (8 ml) was added cautiously and the mixture refluxed until the major part of the solids had dissolved, and then more acetic anhydride (80 ml) was added. After boiling for 1 h, the mixture was cooled to room temperature. Diethyl ether (350 ml) was added and the suspension filtered and washed with diethyl ether. Yield 36.1 g (88%)
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.025 g, 48%). MP: 127-147° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.63 (s, 1H), 6.57 (d, 1H, J=8.3 Hz), 6.32-6.29 (m, 2H), 6.07-5.75 (m, 1H), 5.56 (s, 1H), 5.32 (s, 1H), 4.45 (t, 1H, J=8.3 Hz), 3.86 (s, 3H), 3.07 (s, 1H), 2.97-2.77 (m, 11H), 2.51 (d, 1H, J=8.0 Hz), 2.26 (d, 1H, J=9.1 Hz), 1.68-1.63 (m, 1H). MS: 519.18 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[N:3]=1.C1COCC1.O.[OH-].[Li+]>CO>[OH:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn2ccc(O)nc12
Yield: 68.3 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A; 2.0 g, 9.65 mmol) in a 2:1 mixture of THF:MeOH, (40 mL) was added lithium hydroxide monohydrate (29 mL, 29.0 mmol, 1.0 M in water). The solution was stirred at reflux for 16 hours then cooled and concentrated. The residue was dissolved in water (100 mL) and acidified with 6M HCl. The resulting white precipitate was collected by filtration and washed with water and Et2O, then dried under reduced pressure to afford 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.18 g, 68% yield) as a white solid. 1H NMR (d6-DMSO) δ 8.50 (d, 2H, J=7.7 Hz), 8.02 (s, 2H), 6.07 (d, 2H, J=8.2 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[S:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2ccccc2)c1
Yield: 101.7 %

Procedure:
In an analogous manner to that described in Example 1(B), 40 g(0.165 mol) of methyl 3-(benzyloxy)benzoate were heated at reflux for 8 hours with 33.4 g (0.0826 mol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel, whereby there were obtained 21.7 g (51%) of O-methyl 3-(benzyloxy)thiobenzoate as a red-brown oil which gradually crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:45](=[O:55])[N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[N:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:12]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[C:6]=1[CH2:7][C:8](O)=[O:9].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:68]1([S:71]([NH2:74])(=[O:73])=[O:72])[CH2:70][CH2:69]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH2:51]([N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45]([C:3]1[C:2]([Cl:1])=[C:6]([CH2:7][C:8]([NH:74][S:71]([CH:68]2[CH2:70][CH2:69]2)(=[O:73])=[O:72])=[O:9])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:12]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[N:4]=1)=[O:55])[CH2:52][CH2:53][CH3:54]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CC(=O)O)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CC(=O)NS(=O)(=O)C2CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of 2-(4-chloro-3-(dibutylcarbamoyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazol-5-yl)acetic acid (Example 171, 24 mg, 0.031 mmol) in THF (625 μL) was added CDI (16 mg, 0.10 mmol). The resulting solution was heated at reflux for 30 min and then cooled to room temperature. Cyclopropanesulfonamide (14 mg, 0.12 mmol) was then added followed by DBU (24 μL, 0.16 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with 1N aq. HCl solution (2×) and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5 mg, 16%) as a white solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.74 (s, 1H), 8.16-7.96 (m, 6H), 7.81-7.64 (m, 3H), 7.28-7.05 (m, 3.5H), 6.91 (d, J=7.5 Hz, 0.5H), 4.71-4.33 (m, 1.5H), 4.12-2.55 (m, 11.5H), 1.53-0.84 (m, 15H), 0.76 (t, J=7.4 Hz, 2H), 0.67 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 887.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[NH3:13].CO>O>[CH:11]([N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:13])=[CH2:12]
Reactant: N
Reactant: C=Cn1cnc2c(Cl)ncnc21
Solvent: O
Solvent: CO
Product: C=Cn1cnc2c(N)ncnc21
Temperature: 50 °C

Procedure:
6-Chloro-9-vinylpurine (0.48 g, 3 mmol) was added to saturated ammonia/methanol (20 mL) and the mixture was heated at 50° C. for 15 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9](=O)[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N:18]=[C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[CH:8]1[CH3:7]
Reactant: Nc1nccs1
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1=CC(=Nc2nccs2)C(C)C(C)=C1O
Temperature: 25 °C
Yield: 15 %

Procedure:
Pyridine (3.24 ml) was dissolved in 120 ml of dichloroethane, followed by addition of 1.10 ml of titanium tetrachloride. The mixture was heated under reflux for 15 minutes. Then, 3.00 g of 2,3,5-trimethyl-1,4-benzoquinone and 2.00 g of 2-aminothiazole were added, and the resultant mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad, and the insoluble matter was washed with chloroform. The filtrate was concentrated, and the crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:19 1:4) to give 0.70 g of 4-(2-thiazolylimino)-2,3,6-trimethylphenol as a pale red solid melting at 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)c(Cl)c1
Product: Cc1ccc(Sc2ccc(F)cc2Br)c(Cl)c1

Procedure:
Prepared from 2-chloro-4-methyl-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:16]2[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(-c3ccccc3)nc(Cl)n2)[nH]n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
To a solution of 2,4-dichloro-6-phenyl-pyrimidine (300 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added triethylamine (195 μL, 1.40 mmol) followed by sodium iodide (200 mg, 1.33 mmol) and the reaction mixture is stirred for 15 hours at 90° C. The resulting solution is partitioned between ethyl acetate and water and the organic phase washed with brine, dried over MgSO4 then concentrated in vacuo. The residue is triturated in methanol and the resulting white solid collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (236 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH2:12]O)=[CH:10][CH:11]=1)=[O:5])[CH3:2].P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33]>ClCCl.CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH2:12][S:34][CH2:31][CH2:32][CH3:33])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CO)n(-c2ccccc2)c1=O
Reactant: CCCS
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCSCc1ccc(C(=O)OCC)c(=O)n1-c1ccccc1
Yield: 25.2 %

Procedure:
1,2-dihydro-6-hydroxymethyl-2-oxo-1-phenylpyridine-3-carboxylic acid ethyl ester (5.0 g, 18 mmol) was dissolved in dichloromethane (100 mL), and phosphorus tribromide (1.95 g, 7.2 mol) was added to this solution at −20° C. under a nitrogen atmosphere. The mixture was allowed to react for 4 hours. The reaction mixture was poured into water and a liquid separation was subjected. The organic layer was washed with an aqueous sodium bicarbonate solution and water, dried, and concentrated to obtain 3.30 g of a crude desired product. This crude product was dissolved in N,N′-dimethylformamide (30 mL), and potassium carbonate (2.0 g, 14 mmol) and propyl mercaptan (1.1 g, 14 mmol) were added thereto. The mixture was allowed to react for 2 hours at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid and water, dried, and concentrated. Thus obtained oily product was purified by column chromatography (elution solvent: hexane/ethyl acetate=3/2) to obtain 1.17 g of a desired product (yield: 20%, two stages).
Reaction SMILES: [CH3:1][C:2]1([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([CH3:35])=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:23]3[N:24]=[C:25]4[C:17]([C:15]([NH:14][C:2]5([CH3:1])[CH2:6][CH2:5][NH:4][CH2:3]5)=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[N:27][NH:28]2)=[CH:33][CH:32]=1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCN(C(=O)OC(C)(C)C)C5)c4n3)n[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCNC5)c4n3)n[nH]c2c1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a stirred solution of tert-butyl 3-methyl-3-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)pyrrolidine-1-carboxylate (76 mg, 0.16 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and stirred for one hour. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-methyl-1H-indazol-3-yl)-N-(3-methylpyrrolidin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (18 mg, 22.9%) as a white solid. MS: (M+H)+=376; 1H NMR (300 MHz, DMSO): δ 13.43 (s, 1H), 9.17 (s, 1H), 8.80 (brs, 1H), 8.49 (s, 1H), 8.38 (d, 1H, J=8.1 Hz), 8.29 (s, 1H), 7.47 (s, 1H), 7.16 (d, 1H, J=8.4 Hz), 3.94 (d, 1H, J=12.0 Hz), 3.51-3.20 (m, 3H), 2.57 (s, 3H), 2.30-2.17 (m, 2H), 1.70 (s, 3H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.[H][H]>[Ni]>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [Ni]
Product: CCCCCCCCCCCCCCCCC
Temperature: 240 °C
Reaction time: 12 h

Procedure:
1000 g of 1-octadecanol (Lorol C18 from Cognis) were initially charged in a stirrable pressure vessel with 10 g of a nickel catalyst (Ni-5249 P from Engelhard; Ni content=63% by weight) and heated to 240° C. Subsequently, over a period of 12 h, hydrogen was added through a sparging tube at a pressure of 20 bar and the reaction gases were simultaneously discharged through a valve in the reactor lid. Thereafter, the product was cooled, discharged and filtered. This reaction product was fractionated in a distillation to give pure heptadecane and then deodorized with nitrogen. This gives a colorless, low-odor product which is liquid at 40° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:31])[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]4[CH:30]=3)=[CH:15][CH:14]=2)=[CH:9][O:8]1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[O:8][C:7]([CH3:31])([CH3:6])[C:11](=[O:12])[C:10]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]4[CH:30]=3)=[CH:17][CH:18]=2)=[CH:14][CH:15]=1
Reactant: Cc1cccc2nc(COc3ccc(C4=COC(C)(C)C4=O)cc3)cn12
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2=C(c3ccc(OCc4cn5c(C)cccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 174.3 %

Procedure:
Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of 544-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which, the solids were collected by filtration, washed with 20% DCM in diethyl ether, dried in vacuo to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate (240 mg, 82.7%) as white solid: 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H), 3.85 (s, 3H), 2.6 (s, 3H), 2.5 (s, 3H), 1.25 (s, 6H), HPLC: (98.4%, Condition-A).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:21])=[O:20])[C:9](=[O:11])[CH:10]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24].CO>C(O)(C)C>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:20])=[O:21])[C:9](=[O:11])[CH:10]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Solvent: CO
Solvent: CC(C)O
Product: O=C(NCCO)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 14.5 g of (Intermediate A) and 5.3 g of ethanolamine was reacted under reduced pressure of 30 mmHg at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and dissolved with an additional 30 ml of methanol. 300 ml of isopropanol was further added to the mixture to precipitate crystals. The crystals were filtered off, washed with isopropanol and dried to obtain 13 g (Yield: 86.5%) of 3-(2-hydroxyethylcarbamoyl)-1-(2-sulfobenzyl)pyrazolin-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[Li+].[CH3:22]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([CH3:22])=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (D20) (6 g, 17.08 mmol) in THF (100 ml) was cooled to −78° C. LDA (2M in THF) (21.35 mL, 42.7 mmol) was added at −78° C. and stirred at this temperature for ca. 1 hour. Iodomethane (2.136 ml, 34.2 mmol) was then added. After stirred at −78° C. for further ca. 30 min, the mixture was quenched by addition of saturated NH4Cl solution (150 mL), extracted with ethyl acetate (100 mL×3). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound containing impurities (5.4 g). LCMS (A): m/z (M+H)+ 365/367, C15H13BrN2O2S requires 364/366 (acidic).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C(O)C>[CH2:11]([S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium hydroxide (2.1 g, 52.5 mmol) in water (4 ml) cooled in an ice bath, a solution of 3-aminothiophenol (4.8 g, 38.4 mmol) in ethanol (20 ml) was added drop wise, followed by the addition of solution of benzyl chloride (5 g, 39.5 mmol) in ethanol (5 ml). After the addition, the reaction mixture was stirred at room temperature for 4 hours and became a brown solution with white precipitate. After filtering off the precipitate, the filtrate was concentrated and residue was taken by dichloromethane (40 ml). The dichloromethane solution was washed with aqueous sodium hydroxide solution three times (0.5 M, 3×40 ml) and water once (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford thick yellow oil as crude product. It was further purified by flash chromatography (SiO2, hexanes/CH2Cl2, 0-100%) to afford 3-(benzylthio)aniline (6.77 g, 82%) as a pale yellow oil, which solidified into white solid after staying at room temperature. Thin layer chromatography: Dichloromethane, Rf=0.37; 1H-NMR (CDCl3) δ(ppm) 6.6-7.4 (m, 9H, Ar—H), 4.15 (s, 2H, S—CH2).