Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCCCC2)cc1Br
Product: Cc1ccc(S(=O)(=O)N2CCCCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-[(3-bromo-4-methylphenyl)sulfonyl]piperidine (Intermediate 139), the title compound was obtained as a yellow solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Cl-].[Na+]>CN(C=O)C>[CH3:1][O:21][C:20]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([Cl:9])[CH:19]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Potassium carbonate (5.55 g, 40.2 mmol) and methyl iodide (1.88 mL, 30.2 mmol) were added to a DMF (25 mL) solution of commercially available 2-chloro-4-quinolinecarboxylic acid (4.17 g, 20.1 mmol), and the mixture was stirred overnight at room temperature in an argon atmosphere. The reaction solution was added to a saturated aqueous solution of sodium chloride, and the deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound (3.53 g, 15.9 mmol) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[N:21][C:20]1=2)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[N:21][C:20]1=2)[CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]
Reactant: CC(C)(C)OC(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3nccnc32)nc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2nccnc21
Reaction time: 17 h
Yield: 63.5 %

Procedure:
To a solution of 2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydroquinoxalin-5-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (420 mg, 0.723 mmol) in ethanol (20 mL) at room temperature was added hydrazine hydrate (0.20 mL). The mixture was stirred for 17 hours. The mixture was concentrated in vaccuo and the resultant material was purified by column chromatography on silica gel (1:1:10 MeOH:NH4OH:CH2Cl2) to provide COMPOUND 105 as a colourless foam (161 mg, 64%): 1H NMR (CDCl3) δ 1.37-1.48 (m, 5H), 1.70-1.79 (m, 1H), 1.81-1.97 (m, 1H), 2.07-2.16 (m, 1H), 2.18-2.31 (m, 1H), 2.49-2.59 (m, 4H), 2.71-2.78 (m, 1H), 2.90-3.08 (m, 2H), 3.98 (d, 1H, J=16.5 Hz), 4.07 (d, 1H, J=16.5 Hz), 4.06-4.12 (m, 1H), 7.18-7.21 (m, 2H), 7.57-7.59 (m, 2H), 8.41 (s, 1H), 8.54 (s, 1H); 13C NMR (CDCl3) δ 21.2, 22.9, 26.3, 30.5, 32.6, 41.7, 49.8, 51.4, 62.0, 122.3, 142.1, 143.3, 153.8, 155.4, 155.5; ES-MS m/z 351 (M+H). Anal. Calcd. for C20H26N6.0.3CH2Cl2.0.2H2O: C, 64.24; H, 7.17; N, 22.14. Found: C, 64.16; H, 7.41; N, 22.15.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:4]1[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:7]2[S:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2sccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2sccc12
Temperature: 25 °C
Yield: 59.6 %

Procedure:
Sodium hydride (0.014 g, 0.583 mmol) was added to a solution of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.109 g, 0.52 mmol) in DMF (5 mL) at 0° C. The mixture was stirred 1 h at 0° C. before sequential addition of the 1-(chloromethyl)-4-(methylsulfonyl)benzene (0.156 g, 0.762 mmol) and sodium iodide (0.0935 g, 0.624 mmol). The reaction mixture was allowed to warm up to ambient temperature over 4 h. EtOAc was added and the resulting solution washed with water. The layers were separated and the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (heptane/EtOAc: 80/20 to 50/50) to give the title compound (0.117 g, 59.6%): LC/MS (Table 1, Method b) Rt=2.45 min; MS m/z 395 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9](O)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.Cl.Cl.[N:30]1[NH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][CH2:36][CH:35]([CH2:39][NH2:40])[CH2:34]2>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([NH:40][CH2:39][CH:35]2[CH2:36][CH2:37][C:38]3[C:33](=[CH:32][NH:31][N:30]=3)[CH2:34]2)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)(=[O:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)O
Reactant: NCC1CCc2n[nH]cc2C1
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3-({[4 (trifluoromethyl)benzyl]sulfonyl}amino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-y-lmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:27])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NS(=O)(=O)c1ccc(C(=O)O)cc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suspension of 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoic acid (2.90 g) in dichloromethane (30 mL) was added N,N-dimethylformamide (19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath. The mixture was stirred for 0.5 hour at room temperature and refluxed for 1 hour. The resulting mixture was refluxed further for 5 minutes after adding oxalyl chloride (439 mg). The volatile was evaporated off to give a white solid. The solid was triturated in diisopropyl ether to give benzyl[4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a white powder (2.40 g), which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1.Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:33])[CH3:32]>>[CH3:28][O:29][CH2:30][CH:31]([NH:33][C:11]1[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:26])[CH:14]=[CH:13][N:12]=1)[CH3:32]
Reactant: COCC(C)N
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(C)c1
Agent: Cl
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.332 g, 0.74 mmol), prepared substantially as described in Part C of Example 67a, and 2-methoxy-1-methyl-ethylamine HCl (0.263 g, 67 mmol) were treated substantially as described in Part C of Example 67a to produce 0.120 g (54%) of (2-methoxy-1-methyl-ethyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine; MS(AP) m/z 332.1 [(M+H)+, 94].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[N:10]([CH2:54][C:53]2[CH:52]=[CH:51][C:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[C:43]3[N:39]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:40]=[N:41][N:42]=3)=[CH:57][CH:56]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 0.26 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 0.72 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 5 ml of N,N-dimethylformamide was then added, and the reaction mixture was stirred at room temperature for 2 hours and then at 60° C. for 4 hours. At the end of this time, it was dissolved in ethyl acetate and the solution was washed three times with water. The solution was then dried over anhydrous sodium sulfate, after which it was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.62 g of the title compound as an amorphous solid. This was crystallized from diisopropyl ether, to give the title compound as crystals, melting at 167°-168° C. (with decomposition).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([NH:29][CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:33]4[S:34][CH:35]=[C:31]([CH2:30][NH:29][CH:27]=[O:28])[N+:32]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: O=CNCc1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CNC=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 1.2 %

Procedure:
The same procedure as in Example 1 was repeated except that 88 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-(formylamino)methylimidazo[5,1-b]thiazole were used, thereby obtaining 1.2 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(N2CCC3(CC2)OCCO3)ncn1

Procedure:
A solution of 1,4-dioxa-8-azaspiro[4.5]decane (3.04 g, 2.72 mL, 21.2 mmol), 4-chloro-6-methylpyrimidine (3.00 g, 23.4 mmol) and N,N-diisopropylethylamine (4.12 g, 5.56 mL, 31.8 mmol) in dioxane (50 mL) was heated to 140° C. in the microwave for 40 minutes. The reaction mixture was concentrated, then directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as orange oil (4.64 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1cccnc1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1c(N)n(Cc2cccnc2)c(=S)[nH]c1=O
Reaction time: 1 h

Procedure:
The title compound was prepared in accordance with the general method described in Example 1(c) using 6-amino-1-(pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.50 g, 2.27 mmol, obtained from Example 2(a)), sodium nitrite (0.17 g, 2.50 mmol) and sodium dithionite (0.99 g, 5.68 mmol), with the exception that the reaction time was 1 h at r.t. after the addition of sodium dithionite. The crude title compound was obtained as a solid (0.376 g, 66%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH2:12])=[O:6].N#N.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH:12][CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])=[O:6]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in oil, 180 mg, 4.72 mmol) was added to an ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1000 mg, 4.29 mmol) in 25 ml of dimethylformamide in an atmosphere of N2. After 5 min, 2,4-dichloro-1-chloromethyl-benzene (755 mg, 3.86 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 30 min at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×20 mL) and the combined ether layer was dried (MgSO4) and concentrated. The residue obtained was then purified by precipitation. The crude product was taken in 25 ml of ethyl acetate, a yellow precipitate came out which was filtered to obtain 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester, 835 mg (55%). 1H-NMR (DMSO, 400 MHz): 7.67 ppm (m, 2H, Haro); 7.44-7.35 ppm (m, 6H, Haro); 7.26 ppm (s, 1H, Haro); 4.63 ppm (d, 2H, N—CH2); 3.75 ppm (s, 3H, O—CH3)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:27][N:26]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: COc1ncc(B(O)O)cn1
Agent: OBO
Product: COc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cn1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxypyrimidin-5-boronic acid as a boronic acid, 4-(2-methoxy-pyrimidin-5-yl)-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was demethylated in the same manner as Example 1-B-42, to obtain the desired compound.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOCC>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CCCCC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-octyn-3-ol (5.0 g, 0.039 mol) in DMF (50 mL) were added tert-butyldimethylsilyl chloride (7.16 g, 0.0475 mol) and imidazole (3.2 g, 0.0475 mol). The resulting solution was stirred at RT for 18 h then diluted with ether (200 mL) and washed with water (2×200 mL), saturated solution of NH4Cl (200 mL), and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to afford the desired compound (9.0 g, 95%) as a colorless oil used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 0.85-1.00 (t, 3H), 1.20-1.70 (m, 8H), 2.35 (s, 1H), 4.30-4.35 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[C:20]3=[CH:21][CH:22]=[C:23]4[C:32]([CH:31]=[C:30]5[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]5)=[CH:24]4)=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C=O)C>[Br:1][C:24]1[C:23]2[C:32]([CH:31]=[C:30]3[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]3)=[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:20]1=[CH:21][CH:22]=2
Reactant: c1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1c2ccccc2cc2c1ccc1c(-c3ccccc3)cccc12
Reaction time: 3 h

Procedure:
16.9 g (95 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 18.2 g (45 mmol) of 4-phenylbenz[a]anthracene in 500 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C:16]2[C:17](=[O:32])[NH:18][N:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.N>O>[F:9][C:4]1[CH:3]=[C:2]([N:18]2[C:17](=[O:32])[C:16]([O:15][C:14]3[CH:33]=[CH:34][C:11]([F:10])=[CH:12][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:20]=[N:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178–180° C. 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 6.89–7.04 (m, 4H), 7.45–7.52 (m, 1H), 7.45–7.52 (m, 1H), 7.61 (dt, J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8,07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15F3N2O4S.0.5 H2O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.N(OCCC(C)C)=O>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: c1ccsc1
Agent: CC(C)CCON=O
Product: Cc1c(Cl)cccc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.5 %

Procedure:
To a stirred solution of 50.0 g (0.353 mol) of 3-chloro-2-methylaniline in 100 g (1.19 mol) of thiophene was added dropwise 82.7 g (0.706 mol) of isoamyl nitrite during 0.5 hour. Upon complete addition, the reaction mixture was heated to reflux temperature, and stirred for 0.75 hour. The reaction mixture was then allowed to cool to ambient temperature, and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure to give a black residual oil. The oil was subjected to column chromatography on silica gel, eluting with heptane, then heptane:ethyl acetate (40:1). The appropriate fractions were combined to give a red oil which was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 9.2 g of 2-(3-chloro-2methylphenyl)thiophene, b.p. 78° C.±3° C./0.05 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCC(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.120 g, 0.32 mmol) in CH2Cl2 (10 mL) was added Et3N (0.06 mL, 0.48 mmol) and hexanoyl chloride (0.03 mL, 0.28 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The material was purified by flash chromatography, eluting with 2% to 10% of MeOH/CH2Cl2, to afford the title compound (0.050 g, 38%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.75-4.05 (m, 6H), 3.47-3.73 (m, 4H), 3.17-3.43 (m, 4H), 2.20-2.40 (m, 2H), 1.41-1.62 (m, 2H), 1.15-1.38 (m, 4H), 0.76-0.98 (m, 3H); APCI MS m/z 465 [M+H]+.