Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:19][C:20]1[C:21]([N:31]2[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]2)=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:25]2[CH:24]=[C:23]3[C:28]([CH:29]=[C:20]([O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:21]([N:31]4[S:35](=[O:36])(=[O:37])[NH:34][C:33](=[O:38])[CH2:32]4)=[CH:22]3)=[CH:27][CH:26]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Product: NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1

Procedure:
5-[7-(3-Aminomethylphenyl)-3-benzyloxynaphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one is prepared according to the general procedure outlined in Example 4, step A, starting with (3-aminomethylphenyl)boronic acid and 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one: (M−H)−=472.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:23]=[N+:24]=[N-:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:23]2[C:1]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)=[CH:2][N:25]=[N:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Product: COc1ccc(-c2cnnn2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 80 °C

Procedure:
To a scintillation vial was added 4-ethynyl anisole (660 mg.; 5 mmol) and 3,4,5-trimethoxyphenyl azide (1.05 g.; 5 mmol) and the mixture was heated at 80° C. for 24 hours. The crude mixture was purified by column chromatography to give 1-(3,4,5-trimethoxy-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,3]triazole.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>C(N(CC)CC)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: CNCCc1ccncc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)CCc1ccncc1

Procedure:
The title compound was prepared according to the method of Example 3 from 4-[β-(methylamino)ethyl]pyridine (4.76 g, 0.035 mole), acryloyl chloride (3.15 g, 0.035 mole) and triethylamine (21 ml) to yield 3.4 g of product, m.p. ca. 129°-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH2:16][CH:17]=O)[CH:14]=[N:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH-].[Na+]>CC(O)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][N:15]2[C:11]([C:9]3[S:8][C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[CH:10]=3)=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:14]2)[CH2:28][CH2:27]1
Reactant: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC=O)cc12
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(CCn2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
[5-(4-Aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]acetaldehyde (Intermediate 74) (100 mg) and N-methyl piperazine (100 μL) were stirred in AcOH (1 mL) for 15 minutes. Na(AcO)3BH (70 mg) was added and the reaction allowed to stir overnight. The reaction was made basic with 2M NaOH (50 mL) and then the product extracted with DCM (3×50 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography on silica eluting with DCM:7N NH3 in MeOH. (95:5) to afford the title compound as a solid (32 mg, 28%);
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42][C:37]=2[S:36][C:35]1=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:41]=[CH:42][C:37]3[S:36][C:35](=[O:52])[N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:38]=3[CH:39]=2)=[CH:7][CH:6]=1
Reactant: COCCn1c(=O)sc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCn1c(=O)sc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Reaction time: 25 h
Yield: 66 %

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 203 mg) in acetonitrile (7 mL) under nitrogen was treated with 3-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one (Example 9, step (ii), 132 mg) followed by aqueous sodium carbonate (2M, 0.392 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h and then allowed to cool. The solution was purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound (155 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH3:16][NH2:17]>O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(OCCCBr)cc1
Solvent: O
Product: CNS(=O)(=O)c1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3.4 g of 4-(3-bromopropoxy)benzenesulfonic acid chloride was suspended in water, and 6.2 ml a 20% aqueous methylamine solution was added to the suspension under ice cooling. The solution was stirred at room temperature for 2 hours and then extracted with chloroform (50 ml×2), and drying and concentration followed to obtain 2.9 g (yield: 87%) of 4-(3-bromopropoxy)-N-methylbenzenesulfonamide in an oily state.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.Cl.[CH3:14]COC(C)=O>CO>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:14])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1nn(C)c(=O)cc1Cl
Temperature: 25 °C
Yield: 7 %

Procedure:
A solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (390 mg, 2.07 mmol) and conc. HCl (0.10 mL) in MeOH (6 mL) was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was redissolved into EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 10 to 20 to 30 to 50% EtOAc in hexanes) to afford 72 mg (7%) of the desired product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Under an argon gas atmosphere, 70.0 g (407 mmol) of 2-naphthalene boronic acid, 115.1 g (407 mmol 1) of 4-bromoiodobenzene, 9.40 g (8.14 mmol) of tetrakis(triphenylphosphine)palladium(0), 1.2 L of toluene and 600 ml of 2M sodium carbonate solution were mixed, and stirred for 20 hours at 90 degrees C. After the reaction in the mixture was over, toluene was distilled away therefrom, and the mixture was added with methanol, such that precipitated solid was separated by filtration. By recrystallizing the obtained solid by acetic ether and methanol and subsequently drying the solid, 77.2 g of 2(4-bromophenyl)naphthalene was obtained with an yield of 67%.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccccn2)CC1

Procedure:
A mixture of 12.5 g of 4-acetamidopiperidine, 15 g of potassium carbonate, 10 g of 2-chloropyridine in 100 ml of dimethylsulfoxide, is heated with stirring for 50 hours to 130° C., then it is cooled, poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried over anhydrous sodium sulfate and evaporated to dryness. Thus, 4-acetamido-1-(2-pyridyl) piperidine is obtained which, after crystallisation in isopropanol and recrystallisation in ethyl acetate, melts at 165° to 168° C. Yield: 4.7 g (24.5% of the theoretical).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:28][CH2:27]2)=[O:25])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 6.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 4-(4-chlorobenzoyl)piperidine (300 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (37 mg) was obtained.
Reaction SMILES: Cl.Cl.[C:3]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]([CH3:39])[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:15][CH2:14]1)=[O:11].[N:46]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:3]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([O:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]([CH3:39])[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:49]3[CH2:50][CH2:51][CH2:52][N:46]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:47][CH2:48]3)=[O:34])=[CH:31][CH:30]=2)[CH2:17][CH2:18]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)O)cc1
Agent: Cl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 20 %

Procedure:
25 mL of 4 N hydrochloric acid-dioxane was added to the compound (1.01 g, 1.56 mmol) obtained in Example 15c, and the mixture was stirred at room temperature for 16 hours. The solvent of the reaction mixture was evaporated under reduced pressure to give crude 4-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)benzoate dihydrochloride as a white solid. The resulting crude carboxylic acid compound and tert-butyl 1,4-diazepane-1-carboxylate (500 mg, 2.50 mmol) were used to give the title compound (240 mg; yield, 20%) as a white solid according to the method described in Example 41a.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 0 °C

Procedure:
A mixture of 5-acetylamino-6-bromo-1-indanone (36.0 g, 0.13 mol) and 6M aqueous hydrochloric acid (800 mL) was refluxed for 1 h. The homogenous solution was then cooled to 0° C. and adjusted to pH 8 with 10M aqueous NaOH (~480 mL). The precipitate formed was collected, washed with water and dried under vacuum to afford 30.0 g (quantitative) of the title compound as a light brown powder. 1H NMR (acetone-d6): δ7.65 (1H, s), 6.90 (1H, s), 5.80 (2H, br s), 2.95 (2H, t), 2.50 (2H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[Cl:32])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[Cl:32][C:25]1[CH:26]=[C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:30]=[CH:31][C:24]=1[O:23][CH2:22][CH2:21][OH:20]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(Cl)c3)nc2c1
Temperature: 150 °C
Reaction time: 17 h
Yield: 14.1 %

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:28]1([CH2:37][C:38](O)=[O:39])[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:28]1[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28 (s, 0.4H), 9.21 (brs, 0.6H), 9.10 (brs, 0.4H), 8.26–8.21 (m, 1H), 7.97–7.89 (m, 3H), 7.33 (d, 0.6H), 7.26 (d, 0.4H), 4.68 (s, 1.2H), 4.45 (s, 0.4H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.07 (s, 1.2H), 3.59 (t, 1.2H), 3.47–3.40 (m, 2H), 3.28 (t, 0.8H), 1.74 (s, 3H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4].[NH3:16]>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:16])[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(S(C)(=O)=O)nc(Cl)n1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
2-Chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl ester (3.7 g, 14.75 mmol) was dissolved in dioxane and 7N ammonia in methanol was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated under vacuum, and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated. The product was purified by column chromatography to provide 6-amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.35 g, 85% yield): 1H NMR (DMSO-d6): δ 7.6 (br s, 1H), 7.00 (s, 1H), 3.84 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=O.[C:24](Br)(Br)([Br:26])[Br:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:25][C:24]([Br:26])=[CH:22][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (1.5 g, 4.58 mmol) and CBr4 (3.04 g, 9.16 mmol) in CH2Cl2 (50 mL) was added PPh3 (3.61 g, 13.74 mmol) at 0° C., and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was directly purified by silica gel flash chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI+) m/z 483.9, 485.9, 481.9, 487.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (4.5 g, 27 mmol) and 4-bromo-benzaldehyde (5.0 g, 27 mmol) in ethanol (150 mL) was prepared. The reaction mixture was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(4-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.3 g, 70%) as a white solid: LC/MS m/e calcd for C16H14BrNO2 M+: 332.2, observed: 332.2, 334.2.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:11][C:12]1[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH:19]=1)[CH:17]=O.CCO.C([BH3-])#N.[Na+]>CC(O)=O>[Cl:11][C:12]1[CH:19]=[C:16]([CH2:17][N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH:15]=[N:14][C:13]=1[Cl:20]
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)N1CCN(Cc2cnc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
1-methanesulfonylpiperazine (1.1 g, 6.8 mmol) followed by a catalytic amount of AcOH (0.020 mL, 0.34 mmol) were added to a stirred solution of 5,6-dichloronicotinaldehyde (1.20 g, 6.8 mmol) in EtOH (100 mL, 1713 mmol), the mixture was stirred at room temperature for 1 h (white precipitate formed), and the resulting suspension was treated portionwise with sodium cyanoborohydride (0.43 g, 6.8 mmol) (slightly exothermic) and stirred for another 2 h. The mixture was concentrated and quenched with 1 N HCl (aq), water (10 mL each) and EtOAc (50 mL). The separated aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified with flash column chromatography (ISCO Combiflash system, pure DCM to 3% 2 M NH3/MeOH in DCM) to give 1-((5,6-dichloropyridin-3-yl)methyl)-4-(methylsulfonyl)piperazine (1.16 g, 52%) as a white solid. LCMS (API-ES) m/z 325 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H) 7.78 (s, 1H) 3.54 (s, 2H) 3.26 (br. s., 4H) 2.80 (s, 3H) 2.57 (br. s., 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:28])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccccc1)COC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Reaction time: 2.5 h

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.96 g, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 2.5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.51 g, 2.67 mmol) was carefully added. Rapid stirring was continued for 2.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 15-25% CMA/CHCl3) gave a light-brown foam. Crystallization from ethyl acetate and a small amount of methanol gave (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (420 mg) fine white needles, mp 184.6-186.2° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:6]4[CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: O=C(O)c1ccc(CN2CCOC2=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCOC4=O)cc3)CC2)c(C)c1
Yield: 86.9 %

Procedure:
Using 4-(2-oxooxazolidin-3-ylmethyl)benzoic acid (133 mg) described in Preparation Example 62 and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (206 mg) was obtained.