Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH:31]3O)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30]([CH3:37])=[CH:31]3)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1Cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2C1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (1.57 g, 8.26 mmol, 0.2 equiv), compound 10 (15 g crude, ˜41.32 mmol, 1.0 equiv) and toluene (300 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified over silica gel (300 g) eluting with heptanes to give compound 11 (10.8 g, 82% overall yield for 2 steps) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]([Si:23]([CH3:33])([CH3:32])[O:24][CH2:25][C@H:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30])([CH3:22])[CH3:21].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([O:31][C@H:26]([CH2:27][O:28][CH2:29][CH3:30])[CH2:25][O:24][Si:23]([C:20]([CH3:19])([CH3:21])[CH3:22])([CH3:32])[CH3:33])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: CCOC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.43 g), (2R)-1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-ethoxy-2-propanol (product of step iii) (0.47 g), THF (20 mL) and 60% sodium hydride (67 mg), to give the subtitle compound as a colourless oil. Yield: 0.7 g
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([CH:24]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([CH:24]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-2-methylbenzoate (2.80 g) in methanol (50 mL) and THF (50 mL) was added a solution of sodium hydroxide (3.30 g) in water (50 mL), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was concentrated. Water (30 mL) was added to the residue, and the mixture was adjusted with 2N hydrochloric acid to pH<2. The precipitated crystals were collected by filtration, and dried to give the title compound (1.70 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.[F:45][C:46]1[C:51]([C:52]#[N:53])=[C:50]([F:54])[C:49]([F:55])=[C:48](F)[C:47]=1[F:57].C(=O)([O-])[O-].[K+].[K+].CN1CCN(C)C1=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:48]3[C:47]([F:57])=[C:46]([F:45])[C:51]([C:52]#[N:53])=[C:50]([F:54])[C:49]=3[F:55])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1F
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CCc1cc(NC(CC)c2ccc(Oc3c(F)c(F)c(C#N)c(F)c3F)cc2)nc(Cl)n1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of 0.76 g of dl-5-chloro-6-ethyl-4-(αethyl-4-hydroxybenzylamino)pyrimidine, 0.5 g of pentafluorobenzonitrile, 0.4 g of anhydrous potassium carbonate and 20 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was heated under stirring at 70 .C for 8 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and then toluene was evaporated under reduced pressure. The oily product obtained was isolated by column chromatography (Wako gel C-200, eluted with toluene:ethyl acetate=10:1) to give 0.8 g of the desired product as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1

Procedure:
The title compound was prepared according to the method described for Preparation 25 using 4-amino-3-(trifluoromethoxy)benzoic acid and 4-amino-1-methylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](Cl)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24]([NH2:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17]([NH:32][C:24]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:22]([C:21]([F:20])([F:33])[F:34])[CH:23]=3)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl chloride (0.050 g) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.034 g) and N,N-diisopropylethylamine (0.026 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL) workup followed by washing with brine (saturated NaCl, 2×5 mL), drying over MgSO4, and concentration. The crude compound was purified by column chromatography eluting with ethyl acetate/hexanes (4:1) to afford the title compound (0.047 g, 58% yield). 1H NMR (CDCl3) δ 8.12 (s, 2H), 7.83 (bs, 1H), 7.70 (s, 1H), 7.68 (d, 2H, J=0.017 Hz), 7.47 (d, 2H, J=0.017 Hz), 7.03 (s, 1H). ES-MS negative Q1 (m/z) 501.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1(C)[CH:11]([S:12][CH3:13])[S:10][C:9]([C:14]#[N:15])=[C:8]1[CH3:16])=O.[C:19]1([NH:25][C:26]([NH2:28])=[NH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.CO>[CH3:16][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:28]=[C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:27]=2)=[C:11]([S:12][CH3:13])[S:10][C:9]=1[C:14]#[N:15]
Reactant: N=C(N)Nc1ccccc1
Reactant: CSC1SC(C#N)=C(C)C1(C)C(=O)C=CN(C)C
Solvent: CO
Solvent: CC#N
Product: CSc1sc(C#N)c(C)c1-c1ccnc(Nc2ccccc2)n1

Procedure:
4-(3-Dimethylamino-acryloyl)-3,4-dimethyl-5-methylsulfanyl-4,5-dihydro-thiophene-2-carbonitrile (0.2 mmol) was combined with N-phenyl-guanidine (0.2 mmol) in acetonitrile (0.25 mL) and the resulting mixture heated at reflux for 24 hours. The reaction mixture was diluted with methanol (3mL) and the resulting slurry filtered and the solid was washed with methanol (2 mL) then dried under nitrogen to afford IIa-37. M+H=507.1, HPLC: Rt=6.196 minutes, 1H NMR (500 Mz, DMSO) 9.77(s, 1H), 8.25(d, 1H, J=5.3 Hz), 7.69(s, 1H), 7.48(m, 2H), 7.48(m, 4H), 7.41(t, 2H, J=7.3 Hz), 7.34(t, 1H, J=7.2 Hz), 7.25(d, 1H, J=8.3 Hz), 7.21 (t, 1H, J=8.0 Hz), 6.67(d, 1H, J=6.7 Hz), 6.01(d, 1H, J=5.3 Hz), 5.11(s, 2H), 3.32(s, 3H, CH3), 2.68(s, 3H, CH3).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O=[C:6]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH:7]=O.[BH4-].[Na+]>C(O)C>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:6]1[CH2:7][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: NCCN
Reactant: O=CC(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1coc(C2CNCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
A solution of 10.25 g of ethylene diamine in 250 ml of ethanol was added to a solution of 19.53 g of the above aldehyde in 250 ml of ethanol at 0° C. The mixture was stirred at room temperature for 1.5 hours, then recooled to 0° C. and 9.6 g of sodium borohydride added. This mixture was stirred overnight, quenched with water and the ethanol removed. The residue was extracted with dichloromethane, washed with water, dried and the solvent evaporated. The residue was crystallized from hexaneether, giving 13.8 g of 2-(2-furanyl)piperazine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.Cl.Cl.[CH2:58]([N:60]1[CH2:65][CH2:64][NH:63][C@H:62]([CH3:66])[CH2:61]1)[CH3:59].Cl>O.C(O)C.CN(C=O)C>[CH2:58]([N:60]1[CH2:65][CH2:64][N:63]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[C@H:62]([CH3:66])[CH2:61]1)[CH3:59]
Reactant: CCN1CCN[C@H](C)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.312 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (50.6 mg, 0.375 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (71.8 mg, 0.375 mmol), DMF (Volume: 624 μl), and N-ethyl-N-isopropylpropan-2-amine (273 μl, 1.561 mmol). The solution was stirred at ambient temperature for 5 minutes then (R)-1-ethyl-3-methylpiperazine dihydrochloride (69.1 mg, 0.343 mmol) was added. The reaction was stirred at ambient temperature for 12 h. The reaction was diluted with a pre-made solution of water:ethanol (1:1, 10 mL). The reaction was acidified to pH 5 using 1N HCl and left to stir slowly at ambient temperature overnight. The precipitate was filtered and the solids were washed with water:ethanol (1:1, 2 mL), then dried on the filter paper. The white solids were collected and dried further under vacuum. The dried solids were taken up in 10 volumes of water:ethanol (1:1) and stirred at reflux until the solution was almost completely translucent. The hot solution was filtered and then slowly cooled to ambient temperature and stirred slowly at ambient temperature overnight to give solids. The solids were filtered and washed with water:ethanol (1:1, 2 mL), partially dried on filter paper, then collected and dried under vacuum to give the title compound (67.7 mg, 0.157 mmol, 50.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (s, 3 H) 1.21-1.37 (m, 3 H) 1.92-2.06 (m, 1 H) 2.09-2.21 (m, 1 H) 2.42 (s, 5 H) 2.67-2.99 (m, 2 H) 3.05-4.61 (m, 3 H) 7.61 (dd, J=8.08, 1.52 Hz, 1 H) 7.68 (s, 1 H) 7.86 (d, J=8.08 Hz, 1 H) 8.00 (dd, J=8.59, 2.27 Hz, 1 H) 8.08 (s, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H). ESI-MS m/z [M+H]+ 431.3, ret time: 0.80 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CCO>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:22]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCN3CCN(C)CC3)c2)c1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the suspension of 3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide (24 mg, 0.05 mmol) in EtOH (1 ml) was added 1-methylpiperazine (100 mg, 1 mmol) and the mixture was stirred at 80° C. overnight. The solvent was removed, residue was dissolved in EtOAc, washed by water, dried over Na2SO4. Solvent was removed, desired product was obtained as a colorless oil (18 mg, 72%). HPLC (4 minute gradient) tR 1.33 min; MS m/z 503.29 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][C:9]=3[N:10]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
tert-Butyl 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., from Step 1) was dissolved in anhydrous DMF (0.42 M) and sodium hydride (2 eq, 60% suspension in mineral oil) was added. The resulting suspension was stirred at RT for 30 min. Methyl bromoacetate (3 eq.) was then added and the solution was stirred at 50° C. for 1 h. After cooling down, the reaction mixture was diluted with EtOAc and washed sequentially with 1 N hydrochloric acid, saturated NaHCO3 solution and brine, dried over sodium sulfate and evaporated in vacuo. Purification by flash chromatography (PE:EtOAc, 9:1) afforded the title compound (85%). 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.72 (s, 1H), 7.06 (s, 1H), 5.05 (s, 2H), 3.69 (s, 3H), 2.56-2.50 (m, 1H), 1.99-1.67 (m, 5H), 1.52 (s, 9H), 1.43-1.19 (m, 5H). MS (ES+) m/z: 378 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In this way one obtains an enzymatic complex which is soluble in water (at a pH of more than 4.5) and has an enzymatic activity corresponding to 1500 enzyme units per g of complex (an enzyme unit being defined by the amount of fructose, expressed in micromols, produced in 30 minutes, at 50° C, from an 0.66 M glucose solution containing this enzymatic complex in solution.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
2N Aqueous sodium hydroxide (5 mL) was added to a solution of methyl 2-methoxy-4-phenylbenzoate (410 mg, 1.69 mmol) in methanol (5 mL), and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. 2N hydrochloric acid was added to the obtained residue and the separated crystal was filtered to give the title compound (371 mg, 96.0%) as a crude product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.307 g, 5.75 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.75 mmol) dissolved in water (2 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.75 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.682 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.83-1.94 (m, 1H), 2.16-2.29 (m, 2H), 2.34-2.43 (m, 1H), 3.06-3.18 (m, 1H), 3.51 (ddd, 1H), 3.64 (s, 3H), 4.12 (ddd, 1H), 5.10-5.22 (m, 1H), 5.57 (s, 1H), 7.40 (d, 2H), 7.58 (d, 2H). MS m/z 371 (M+H)+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]2=[NH:16])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[N:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11]/[C:10]/2=[N:16]\[C:31]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:32])=[CH:7][CH:8]=1
Reactant: Cc1sc(=N)n(-c2ccc(Cl)cc2)c1C
Reactant: O=C(Cl)N1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1s/c(=N\C(=O)N2CCCC2)n(-c2ccc(Cl)cc2)c1C
Temperature: 75 °C

Procedure:
To a suspension of 3-(4-chlorophenyl)-4,5-dimethyl-1,3-thiazol-2(3H)-imine hydrochloride (90 mg, 0.33 mmol, Example 160A) in acetonitrile (2.0 mL) containing diisopropylethylamine (102 mg, 0.79 mmol) was added 1-pyrrolidinecarbonyl chloride (53 mg, 39 mmol). The mixture was heated at 75° C. for 18 hours, then concentrated. The residue was dissolved in dichloromethane (10 mL). The organic layer was washed with dilute aqueous ammonium chloride (5 mL) and water (2×5 mL) and the dichloromethane was removed under reduced pressure. The residue was purified on a Waters Symmetry C8 30×100 mm column (flow rate 40 mL/min, 5-95% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid) to afford the title product.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]Br)=[CH:4][C:3]=2[O:2]1.[I-:17].[Na+]>CC(C)=O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][I:17])=[CH:4][C:3]=2[O:2]1
Reactant: [I-]
Reactant: BrCCC=CCCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCC=CCCc1ccc2c(c1)OCO2

Procedure:
6-(3,4-Methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 12.9 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C2) and 7 g. of sodium iodide in 120 ml. of acetone, refluxed for three hours, affording 12.5 g. of product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].Cl>[Pd].O.CO>[CH:17]1[C:16]([NH2:19])=[CH:15][CH:14]=[C:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH:18]=1
Reactant: [H][H]
Reactant: Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Yield: 91.9 %

Procedure:
In a hydrogenation vessel 4-(4′-Nitro-benzenesulfonyl)-phenylamine (100 g), p-toluensulfonic acid (68.4 g), methanol (350 ml), water (150 ml) and 10% palladium on charcoal (7.6 g) are charge. The mixture is allowed to react with hydrogen at approximately 50° C. and 5 bar pressure. At reaction completion, hydrochloric acid is added, the catalyst is filtered and dried. 82 g of crude Dapsone are obtained (82% yield; >99.5% purity).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].Br[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CCOC(C)=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([C:39]5[N:44]=[CH:43][CH:42]=[CH:41][N:40]=5)[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: Brc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(c5ncccn5)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 20.2 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30 mg, 0.069 mmol) in acetonitrile (690 μL, 0.069 mmol) was added K2CO3 (38 mg, 0.28 mmol) and 2-bromopyrimidine (12 mg, 0.076 mmol). The reaction mixture was heated to 45° C. for 3 days. After diluting in EtOAc, the mixture was washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to a clear colorless oil. The oil was purified by reverse phase HPLC using 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(pyrimidin-2-yl)azetidin-3-yl)acetonitrile (6.1 mg, 20% yield) as a white solid. MS (apci) m/z=438.2 (M+H).