Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[NH:40]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:35]3[C:34](=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)[NH:40][CH:29]=2)[CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CC=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1c[nH]c2c(Cl)cc(Cl)cc12
Temperature: 80 °C

Procedure:
An acetic acid solution (5 ml) containing the intermediate from Step B (200 mg, 0.47 mmol), 2,4-dichlorophenyl hydrazine hydrochloride (120 mg, 0.56 mmol) and ZnCl2 (2.29M in AcOH, 0.61 ml, 1.4 mmol) was heated at 80° C. for 30 minutes. The solution was concentrated and the residue dissolved in EtOAc. The EtOAc solution was washed with water, brine and dried over Na2SO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound as a mixture of diastereomers. The mixture was purified further using reverse phase HPLC. The major (and more active) diastereomer, which is also the slower (second) eluting on HPLC, was resolved on a Chiralpak AD-H column (2 cm×25 cm) eluting with 10% EtOH/Heptane at 9 ml/min.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](=[O:20])([O-])[O-:18].[Na+].[Na+]>ClCCl>[C:17]([O:18][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:15])=[CH:10][CH:11]=1)(=[O:20])[C:7]1[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CC
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Oc1ccc(CO)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
4-(Hydroxymethyll)phenol (1.087 g, 8.77 mmol) and triethylamine (1.3 mL, 8.77 mmol) were dissolved in 25 mL of dichloromethane. The solution was shaken at 0° C. for 30 minutes. Benzoyl chloride (1 mL, 8.77 mmol) was added drop by drop and the resulting solution was shaken at 0° C. for 5 hours. Saturated aqueous solution of sodium carbonate (20 mL) was added three times. The organic phase was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure, thus affording a yellowish solid that upon recrystallization from cyclohexane provided 1.600 g (70.16 mmol, yield=80%) of 4-(hydroxymethyl)phenyl benzoate.
Reaction SMILES: [C:1]1([S:7]([N:10]([C:20]2[O:24][N:23]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]=2[Br:29])S(C2C=CC=CC=2)(=O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[Br:29][C:21]1[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][O:24][C:20]=1[NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)c1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1noc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
N-Benzenesulfonyl-N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide (80 mg, 0. 16 mmol) was dissolved in methanol (2 ml). Sodium hydroxide (0.120 g, 3.0 mmol)in methanol was added and the solution was stirred at 45° C. for 20 min. Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide in 94% yield. Further purification was achieved by recrystallization from methanol/water, giving an off white solid, m.p. 108°-109° C.
Reaction SMILES: CO[C:3]1[CH:4]([CH2:10][CH:11]=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:14])[CH:11]=[CH2:12]
Reactant: [NH4+]
Reactant: C=CCC1CCCCN=C1OC
Reactant: [Cl-]
Solvent: CO
Product: C=CCC1CCCCNC1=N
Product: Cl
Yield: 78.3 %

Procedure:
The product of EXAMPLE 105 (90 mg, 0.54 mmol) in 10 mL of MeOH was reacted with ammonium chloride (24.5 mg, 0.46 mmol) by the method of EXAMPLE 27 to yield 68 mg (67%) of the title material.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C.C(OCC)C>C(O)C>[NH2:20][C:19]1[N:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: Cc1cccc(C)c1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc(C#N)c1N
Temperature: 25 °C

Procedure:
3.0 g (17.3 mmol) of 2,6-dimethylphenylhydrazine hydrochloride are suspended with 2.1 g (17.3 mmol) of ethoxymethylenemalononitrile in 40 ml of ethanol, and 7.3 ml (52.1 mmol) of triethylamine are added. The reaction mixture is heated to reflux for 3 h, during which a clear solution forms. After cooling to room temperature, diethyl ether is added to this. The triethylammonium chloride which precipitates is filtered off. The solvent is removed in vacuo, and the residue is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 2.3 g (62% of theory) of the product are obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:14]2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([N:43]=[N+]=[N-])[N:5]=1)=[N+]=[N-].C(Cl)(Cl)Cl>CCO.[Pd]>[NH2:1][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:14]2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([NH2:43])[N:5]=1
Reactant: [N-]=[N+]=Nc1nc(N=[N+]=[N-])c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reaction time: 6 h
Yield: 69 %

Procedure:
Pd-C (5%) (500 mg) was added to a solution of 2,6-diazido-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)purine (IV, 4.8 g, 8.0 mmol) in EtOH (500 ml), and the resulting mixture was hydrogenated at atmospheric pressure for 6 hr. The H2 atmosphere was changed after 30 min. and after 1 hr. The catalyst was removed by filtration and was washed with CHCl3 to dissolve precipitated product. The combined filtrate and washings were evaporated to dryness in vacuo, and the resulting residue was dissolved in boiling EtOH (80 ml). The crystals that formed on cooling the EtOH solution were collected by filtration, washed with EtOH, and dried in vacuo; yield 3.3 g (75%), mp 161°-162°, TLC (19:1 CHCl3 --MeOH). The analytically pure produce was obtained from a previous preparation: yield 69%; mp 162°; [α]D25 +44.4±0.7° (c, 1.06, CHCl3); λmax ]Mμ (ε× 10-3)], pH 1--254 (10.9), 292 (9.0); EtOH--256 (10.8), 283 (9.0); pH 7, 13--256 (9.0), 279 (9.1); vmax (cm-1)3460, 3350, 3310, 3140 (NH, CH), 2940, 2915 2890, 2865 (CH), 1660 (NH), 1590 (C=C, C=N), 1085, 1045, 1015 (COC), 730, 690 (phenyl).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C1(C)C=CC(S([NH:31][NH:32]S(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1COCC1>[N+:31](=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)NNS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
DBU (7.5 mL, 50.2 mmol) was added dropwise to a solution of 2-bromo-1-phenylethanone (2.0 g, 10.05 mmol) and N,N′-bis(p-toluenesulfonyl)hydrazine (6.8 g, 20.1 mmol) in dry THF (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and quenched with aqueous saturated NaHCO3 solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get 2-diazo-1-phenylethanone (1.2 g, yield 82%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.78-7.76 (m, 2H), 7.56-7.53 (m, 1H), 7.48-7.43 (m, 2H), 5.91 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[O:14]([C:5]1[N:4]=[CH:3][CH:2]=[CH:7][N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cncnc1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(Oc2ncccn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-chloropyrimidine (5.00 g, 0.0437 mol), phenol (5.38 g, 57.2 mmol), dibenzo-18-Crown-6 (0.84 g, 0.0023 mol) and ground potassium hydroxide (5.92 g, 0.1055 mol) in toluene (75 ml) was heated at reflux for 3 hours with azeotropic removal of water. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The layers were separated and the aqueous phase was extracted with chloroform three times. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-phenoxypyrimidine as a white powder (95% pure, 4.56 g, 0.0265 mol): 1H NMR (CDCl3, 400 MHz) 8.57 (d, 2H), 7.43 (t, 2H), 7.26 (t, 1H), 7.20 (d 2H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.42.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31](I)=[CH:30][N:29]([S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:45]=[C:46]([CH:64]=[CH:65][CH:66]=1)[CH2:47][N:48]1[C:52]([CH3:53])=[C:51](B2OC(C)(C)C(C)(C)O2)[C:50]([CH3:63])=[N:49]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31]([C:51]5[C:50]([CH3:63])=[N:49][N:48]([CH2:47][C:46]6[CH:64]=[CH:65][CH:66]=[C:44]([F:43])[CH:45]=6)[C:52]=5[CH3:53])=[CH:30][N:29]([S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Yield: 99.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-(4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)phenyl)-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 42) (130 mg, 0.203 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (101 mg, 0.305 mmol) in sodium carbonate (65 mg, 0.602 mmol), Pd(PPh3)2Cl2 (7 mg, 0.0101 mmol), Toluene/ethanol/water (5/2.5/1 ml) to give 155 mg of the crude titled compound. MS: m/z=769.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9]O)=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.O=S(Cl)Cl>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C=NO)c(Cl)n1
Solvent: O=S(Cl)Cl
Product: CSc1nc(Cl)c(C#N)c(Cl)n1
Temperature: 75 °C
Yield: 92.7 %

Procedure:
To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75° C. for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (10 mL, 1:1) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M+H)+1.99 minute; 1H-NMR (CDCl3) δ 2.64(3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:43])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCOc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add acetic anhydride (43 μL, 0.44 mmol) to a solution of (2R,3S,5R)-5-[(1S,2S)-1-Hydroxy-2-amino-3-(3-propoxy-5-fluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (231 mg, 0.44 mmol) and triethylamine (92 μL, 0.65 mmol) in dichloromethane (4.6 mL) and stir at room temperature for 30 minutes. Concentrate reaction mixture under a stream of nitrogen and subject residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCc1cccs1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCc1ccc([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 8 mL of acetic anhydride at −20° C. is added 1.2 mL of nitric acid (d=1.5). The mixture is kept at −20° C., and a solution of 4-thiophen-2-yl-butyric acid methyl ester (1.84 g, 10.0 mmol) in 12 mL of acetic anhydride is added dropwise. The reaction mixture is stirred for 10 minutes after completion of addition, and poured into an ice-water mixture. The product is extracted with ethyl acetate and the organic layer is washed with 10 N aqueous sodium hydroxide solution, dried and concentrated. The residue is purified by flash column chromatography eluting with 1:4 ethyl acetate:hexane to provide 1.32 g of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester as a yellow oil; 1H NMR (DMSO-d6) δ 1.93 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.04 (d, J=5 Hz, 1H), 8.01 (d, J=5 Hz, 1H); MS 229.0 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Add 2,5-dichloropyridine (6.0 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc dust (116 mg, 1.8 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.98 mmol) to a flask containing DMF (40 mL). Heat the mixture to reflux for 5 h, then cool to ambient temperature. Dilute the mixture with EtOAc (300 mL) and wash with 10% aqueous NaCl (3×75 mL). Collect the organic layer, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (2.6 g, 46%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][CH:26]([S:29]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:31])=[O:30])[CH3:28]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 20.7 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with isopropylsulfonyl chloride (0.02 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.015 g of a white solid.
Reaction SMILES: [C:1]([N:4]1[C:18]2[C:19]3[CH:6]([CH2:7][C@@H:8]4[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:10][N:9]4[CH3:28])[CH2:5]1)(=[O:3])[CH3:2].[Br:29]Br>C(O)(=O)C>[C:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C:13]([C:14]=3[C:15]([Br:29])=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:10][N:9]4[CH3:28])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3C(C[C@H]2N(C)C1)CN4C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4C(C)=O)C[C@H]2N(C)C1

Procedure:
The compound is produced by reacting 3-(1-acetyl-9,10-didehydro-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea with elemental bromine in 5% acetic acid, analogously to Example 6.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[N:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)[NH2:35]>CN(C=O)C.O>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:9][N:35]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([O:42][C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=3)[N:33]=2)[CH:3]=1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (15.3 g, 0.121 mol) in dry DMF (600 mL) was added EDCl (23.3 g, 0.121 mol), HOBT (16.4 g, 0.121 mol) and N′-hydroxy-4-(trifluoromethoxy)benzenecarboximidamide (26.7 g, 0.121 mol). The mixture was stirred at rt for 2 h, and then warmed to 140° C. and stirred for further 5 h. After being cooled to rt, the mixture was diluted with water (2 L) and extracted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:40])(=[N:27][C:28](=[O:39])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[CH3:37][N:36]([CH3:38])[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:20][CH:21]=2)([CH3:40])=[O:26])=[O:39])=[CH:35][CH:34]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CN(C)c1ccc(NC(=O)N=S(C)(=O)c2ccc(N)cc2)cc1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3ccc(N(C)C)cc3)cc2)ncc1-c1cccs1
Yield: 21 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (146.4 mg, 0.54 mmol) with (RS)—S-(4-aminophenyl)-N-(4-dimethylamino-phenylcarbamoyl)-S-methylsulphoximide (164 mg, 0.49 mmol) according to procedure 5c, the desired product is obtained in 21% yield (59 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[OH-]>CO>[C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH2:18][CH:17]2[CH3:22])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1CNCCN1c1ccccc1
Reactant: ClCCN1CCOCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC1CN(CCN2CCOCC2)CCN1c1ccccc1

Procedure:
In the same manner as described in Example 1, N-(2-chloroethyl)morpholine is reacted with 1-phenyl-2-methylpiperazine. The trihydrochloride has a melting point 288°-290° (from methanol); Rf=0.63 (MeOH-conc. NH4OH 97:3); IR (nujol) νmax: 2420, 1500, 1405, 1265, 1060, 770, 695 cm-1 ; 1H-NMR (D2O; (CH3)3Si(CD2)2COONa): 1.05 (d, J=6 Hz; 3H; 2.70-4.20 (m; 19H); 7.47 (s; 5H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCCN(CCC)c1c(SC)nc2c(Br)cc(C)cn12
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCCN(CCC)c1c(SC)nc2c(-c3ccc(Cl)cc3Cl)cc(C)cn12
Yield: 72.5 %

Procedure:
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (50 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (6 mL) and water (1 mL). 2,4-Dichlorobenzeneboronic acid (53 mg), barium hydroxide octahydrate (88 mg) and tetrakistriphenylphosphine palladium complex (16 mg) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give N-[8-(2,4-dichlorophenyl)-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (43 mg) as a pale yellow oil.