Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:30][CH:31]=[CH:32][N:33]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[C:43]([N:47]=C=O)([CH3:46])([CH3:45])[CH3:44]>CO>[C:43]([NH:47][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into the solution of 4-{4-[3-(1H-imidazol-2-yl)-phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59.4 mg, 0.118 mmol) in methanol (1.0 mL) was added HCl in methanol (9 M, 11.0 mL). The above mixture was stirred at rt for 4 h. After that time, the mixture was concentrated in vacuo and was then suspended in DMF (2 mL). Into the above suspension were added triethylamine (159 μL, 1.18 mmol) and tert-butyl isocyanate (14.8 μL, 0.130 mmol). The above mixture was stirred at rt under an atmosphere of N2 for 1 h. After that time, the mixture was concentrated in vacuo to obtain brown oil that was purified by HPLC to yield the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.35 (s, 9H), 2.55 (brs, 2H), 3.59 (t, 2H, J=4.2 Hz), 4.05 (brs, 2H), 6.28 (brs, 1H), 6.65 (s, 1H), 7.13 (d, 2H, J=1.2 Hz), 7.42 (t, 1H, J=8.4 Hz), 7.55 (dd, 1H, J=0.8 & 7.6 Hz), 7.74 (dd, 1H, J=0.8 & 8.0 Hz), 7.75-8.19 (m, 1H), 8.23 (d, 1H, J=1.2 Hz). MS (ES+): m/z 457.12 (100) [MH+]. HPLC: tR=2.00 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.[Cl-].[Na+].O>[C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(COC(=O)c2ccccc2)on1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(COC(=O)c2ccccc2)c1Br
Temperature: 90 °C
Yield: 78.9 %

Procedure:
A solution of (3-methylisoxazol-5-yl)methyl benzoate (20.1 g, 92.4 mmol) in acetic acid (77.3 mL) was treated with N-bromosuccinimide (19.7 g, 111 mmol) and heated in a sealed tube at 90° C. for 4 h. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes) gave the desired product (21.6 g, 79%). LCMS calculated for C12H11BrNO3 (M+H)+: m/z=296.0, 298.0. found: 296.0, 298.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][N:20]=2)[N:17]=1>CN(C=O)C.O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:13]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Fc1ccccc1-c1nnc2cc(-c3cccs3)c(Cl)nn12
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.11 g, 1.0 mmol) (prepared using the conditions described in EP-A-421210) in DMF (5 ml) was added sodium hydride (0.04 g of a 60% dispersion in oil, 1 mol eq) and the reaction mixture was stirred at room temperature for 30 min. After this time 6-chloro-3-(2-fluorophenyl)-7-(thien-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (0.19 g, 0.57 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (70 ml) and the precipitate was collected. The solid was purified by boiling in ethyl acetate and collecting the title compound as a yellow solid (0.01 g, 12%). 1H NMR (250 MHz, d6-DMSO) δ 3.83 (3H, s), 5.64 (2H, s), 7.24 (1H, dd, J 4 and 4 Hz), 7.44-7.55 (2H, m), 7.66-7.71 (1H, m), 7.82 (1H, d, J=5 Hz), 7.96-8.01 (3H, m), 8.23 (1H, s). MS (ES+) m/e 408 [MH]+. Anal. Found C, 53.81; H, 3.62; N, 23.42%. C19H14FN7OS.0.9(H2O) requires C, 53.87; H, 3.76; N, 23.14% m.p. 189-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19](N(C)C)=[O:20])[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[OH-:26].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([OH:26])=[O:20])[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COCc2cnc3oc(C(=O)N(C)C)cc3c2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(COCc2cnc3oc(C(=O)O)cc3c2)cc1
Temperature: 25 °C

Procedure:
In a sealed tube, a mixture of a solution of 5-(((4-methoxybenzyl)-oxy)-methyl)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (2.4 g, 7.1 mmol) in methanol (28 mL) and a solution of potassium hydroxide (0.79 g, 14 mmol) in water (7 mL) was heated at reflux for 1 h. After cooling to ambient temperature, the reaction mixture was partitioned between saturated aqueous citric acid solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated to give the title compound. MS: m/z=314.2 (M+1).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 20, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98°-103°C. (0.35 mm).
Reaction SMILES: N.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[H][H]>CO.[Ni]>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ccc2ccnc(N)c2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc2ccnc(N)c2c1
Yield: 25.6 %

Procedure:
Liquid ammonia (210 mL) was added to a mixture of 4.2 g of 1-amino-isoquinoline-7-carbonitrile and 4.0 g of Raney-Ni in 210 mL of methanol in a steel vessel. hydrogen was pressed upon until an initial pressure of 100 atm. was obtained. This mixture was reacted for 16 hours at ambient temperature, the catalyst subsequently removed by filtration and the solvent pumped off. The residue was purified by silica chromatography (methanol/ammonia saturated methanol=85:15, 8:2) yielding 1.1 g (25%) of the title compound as a light yellow solid. M.p. 114-117° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al., J. Chem. Soc., 1954, 3832, 7.5 g, 36.1 mmol) in THF (150 ml) was added 4-aminophenylethyl alcohol (2.47 g, 18.0 mmol), triethylamine (3.65 g, 36.1 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 ml), and the mixture was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 4.0 g (72%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CN(C)C=O.ClCCl>[Cl:1][CH2:2][C:3]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: Nc1ccccc1S
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1nc2ccccc2s1
Reaction time: 18 h
Yield: 65 %

Procedure:
Chloroacetyl chloride (81.6 ml) is added dropwise to a solution composed of 2-aminothiophenol (112 ml, 1.04 mol), dichloromethane (1.2 l) and three drops of dimethylformamide, while the temperature is kept below 40° C. After stirring for 18 hours, the precipitate formed is filtered off by suction and then dissolved in a minimum amount of water. This aqueous phase is extracted with pentane and the extracts are concentrated under vacuum at room temperature, giving 120 g (65%) of a flaky solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31]>ClCCl.CCCCCC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[CH:3]=[C:2]([O:31][C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[F:23])[N:7]=[N:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCCCCC
Product: CSc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (230.0 mg, 0.662 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless plates (dichloromethane-hexane, 216.2 mg, 74.0%). Melting point: 163.2-164.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13]([NH2:15])=[S:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:17]1([C:21](OCC)=[O:22])[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12][C:13]3[S:14][C:17]4([C:21](=[O:22])[N:15]=3)[CH2:20][CH2:19][CH2:18]4)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: NC(=S)NC1(c2ccc(Cl)cc2)CCC1
Reactant: CCOC(=O)C1(Br)CCC1
Product: O=C1N=C(NC2(c3ccc(Cl)cc3)CCC2)SC12CCC2

Procedure:
Synthesis was performed from N-[1-(4-chlorophenyl)cyclobutyl]thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:6]([N:8](C)[C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32]([N:1]([CH3:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of N-Me-Val-N-Me-Tyr-NH2(185 mg, 0.603 mmol) in THF (6 ml), Fmoc-Phe-OH (304 mg, 0.784 mmol), CMPI (200 mg, 0.784 mmol) and TEA (0.168 ml, 1.21 mmol) were added under cooling with ice, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (197 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Fc1ccc2c(c1)Sc1cc(Cl)ccc1CC2Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3cc(F)ccc32)CC1

Procedure:
17 G. of 3,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are treated with 45.5 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 120°-130°C. (internal temperature) for 8 minutes. The mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed to neutrality and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and extracted with methylene chloride. The organic solution is washed with water and dried over magnesium sulfate. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(3-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 168°-170°C.) which is converted into the dimethanesulfonate (melting point 191°-193°C.) by reaction with methanesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: BrBr
Reactant: Clc1ccc2c(c1)CCO2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.5 %

Procedure:
To a stirred solution of (33) (1.84 g, 11.93 mmol) in acetic acid (10 ml) at 0° C., was slowly added a solution of bromine (1.24 ml, 24 mmol) in acetic acid (5 ml). The reaction mixture was stirred at room temperature for 4.5 h. A 10% sodium thiosulphate solution (70 ml) was added and the mixture stirred for 10 min. The bulk of the solvent was evaporated in vacuo. The resulting oil was dissolved in ether (50 ml), washed with water (20 ml), saturated NaHCO2 (2×15 ml), brine (1×15 ml), dried Na2SO4 and evaporated in vacuo to give 2.55 g (92%) of (34) as a oil.
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=O)C.[CH2:26]([CH:28]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][SH:34])[CH3:27].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:26]([CH:28]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][S:34][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:8]3[N:9]2[CH:25]=[CH:6][N:7]=3)=[CH:14][CH:13]=1)[CH3:27]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nccn3c2c1
Temperature: 60 °C

Procedure:
1v (900 mg, 2.4 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), Pd2dba3 (69 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol), and iPr2NEt (1.1 mL, 6.0 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The mixture was heated at 60° C. for 1.5 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 1x.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])(=[O:15])=[O:14]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CS(=O)(=O)c1cccc(Nc2cc(F)ccc2[N+](=O)[O-])c1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (0.571 mL, 5.20 mmol) and 3-(methylsulfonyl)aniline (0.891 g, 5.20 mmol) to give 5-fluoro-N-(3-(methylsulfonyl)phenyl)-2-nitroaniline as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (1H, s), 8.25 (1H, dd, J=9.6, 6.1 Hz), 7.85-7.89 (1H, m), 7.64-7.75 (3H, m), 6.98 (1H, dd, J=11.4, 2.6 Hz), 6.79-6.87 (1H, m), 3.24 (3H, s); LC-MS (ESI) m/z 311.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][C:13](Cl)=[N:14][CH:15]=1.Cl>C(#N)C.O1CCOCC1>[Br:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][C:13]([NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[N:14][CH:15]=1
Reactant: Nc1cccc(O)c1
Reactant: OCCCCNc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: OCCCCNc1nc(Nc2cccc(O)c2)ncc1Br

Procedure:
A reaction mixture of 327 mg (3.0 mmol) of 3-aminophenol and 864 mg (3.1 mmol) of 4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butan-1-ol in 9 ml of acetonitrile is mixed with 0.75 ml of a 4 M solution of hydrochloric acid in dioxane, and it is stirred under reflux overnight. After the cooling, the reaction mixture is filtered, and the filtrate is completely concentrated by evaporation. The oil that is obtained is recrystallized from ethyl acetate/ethanol. The solid is filtered off and then dissolved in water. By adding triethylamine, the solution is made basic and extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 444 mg (1.2 mmol, corresponding to 40% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](Cl)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:23])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(-c2cc3ccccc3c(C)n2)cc1
Yield: 100 %

Procedure:
3-(4-Methoxyphenyl)-1-chloroisoquinoline (3.25 g) was dissolved in tetrahydrofuran (30 ml), followed by the addition of 3.0M ethylmagnesium bromide diethyl ether solution (12 ml) and NiCl2-(dppp) (50 mg) at 0° C. After the mixture was reacted overnight at room temperature, the resulting reaction solution was poured into an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and evaporated, to give 3-(4-methoxyphenyl)-1-methylisoquinoline as an oil (3.3 g, yield; 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+](=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N-].[OH-].[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCCc1ccc(Cc2cccnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COCCc1ccc(Cc2cccnc2)cc1
Yield: 15.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.0 g of 2-[4-(pyridin-3-ylmethyl)phenyl]ethanol, and 980 mg of p-toluene sulfonic acid monohydrate was added thereto with ice-cooling. To the resulting solution was added 2.7 g of ethyl diazoacetate with ice-cooling, after which 700 mg of boron trifluoridediethyl ether complex was dropped into the solution. The resulting mixture was subjected to reaction at the same temperature for one hour. Subsequently, 20 ml of water and 20 ml of methylene chloride were added to the reaction mixture, and the pH thereof was adjusted to 8 with 1N aqueous sodium hydroxide solution, after which the organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (1:1 by volume)], to obtain 220 mg (yield 15.7%) of oily ethyl 2-[4-(pyridin-3-ylmethyl)phenyl]ethyloxyacetate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]4[S:26][CH:25]=[N:24][C:23]=4[CH3:27])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]4[S:26][CH:25]=[N:24][C:23]=4[CH3:27])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCc3scnc3C)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1ncsc1CCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 95 %

Procedure:
Reaction of a compound of Example 11 (0.27 g, 0.52 mmol), AlCl3 (0.42 g, 3.12 mmol) and EtSH (0.19 mL, 2.6 mmol) in CH2Cl2 (10 mL) at room temp. for 0.5 h. according to the procedure described in Example 3 provided a 95% of the desired product as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ9.91 (s, 1H), 9.71 (s, 1H), 8.82 (s, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.86 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (d, J=8.8 hz, 2H), 4.19 (t, J=3.3 Hz, 2H), 3.20 (t, J=3.6 Hz, 2H), 2.32 (s, 3H); IR (thin film) 3299, 1700, 1635 cm-1; MS (FD) 488 (M+) Anal. calcd. for C25H21O4NS2 ; calc'd/found C(66.51/66.88), H (4.34/4.49), N (2.88/2.95).