Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19]>C(Cl)(Cl)Cl>[C:18](=[O:19])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[O:20][CH:21]([Cl:23])[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a ice cooled mixture of 27.8 g of p-nitrophenol, 16.0 g of pyridine and 1 L of chloroform is added, dropwise, 34 g of alpha-chloroethyl chloroformate. After 1 hour, the ice bath is removed and the reaction is stirred for 16 hours at room temperature. The mixture is washed with water, 0.5% sodium hydroxide and water. The organic layer is dried and concentrated in vacuo to give 47.85 g of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N-:14]=[N+]=[N-].[Na+]>C(#N)C.C1COCC1>[NH2:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: NCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11-bromoundecan-1-ol (the compound 31) (15.1 g) was dissolved in 250 ml of acetonitrile, and 15.7 g of sodium azide was added to that, followed by 18-hour reaction caused by refluxing. After cooled down to room temperature, the solid components were removed by filtration. The solvent of the filtrate was distilled away under reduced pressure, to obtain 13.9 g of a transparent, viscous liquid. Of this liquid, 8.34 g was dissolved in 60 ml of THF distilled from calcium hydride in a nitrogen atmosphere, and was cooled in an ice bath. Lithium aluminum hydride (2.53 g) was then dried, and was dissolved in 250 ml of THF. The resultant was dripped, and was then stirred in an ice bath for one hour. After that, 2.5 ml of ion-exchange water, 3.5 ml of 15 wt % aqueous sodium hydride solution, and 7.5 ml of ion-exchange water were added so as to stop reactions. The precipitate generated was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. After the filtrate was dried under reduced pressure, the dried filtrate was dissolved in 60 ml of THF, and the same volume of heptane was added to that. The precipitate generated was collected by filtration, to obtain 5.1 g of a white solid 32.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of example 54 (0.200 g, 0.383 mmoles) in dichloromethane (30 ml), BBr3 (1M in dichloromethane, 2.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.070 g, 36% yield). MP: 280-283° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69 (s, 1H), 8.20 (s, 1H), 8.06 (dd, J=8.2, 1.7 Hz, 1H), 7.80 (m, 1H), 7.51 (m, 2H), 7.39 (m, 2H), 7.17 (m, 2H), 7.11 (dt, J=8.7, 2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 7.00 (s, 1H), 6.86 (dd, J=7.7, 1.8 Hz, 1H), 5.53 (s, 2H). Mass: 479.88 (M+).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>>[CH3:18][N:19]([CH3:21])[C:1]([C:3]1[CH:11]=[CH:12][C:15]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([C:21]([C:24]5([C:27]6[CH:36]=[C:35]7[C:34](=[CH:29][CH:28]=6)[N:33]=[CH:32][CH:31]=[CH:30]7)[CH2:25][CH2:26]5)=[CH:22][N:23]=4)[N:20]=3)=[CH:13][CH:14]=2)=[CH:16][N:17]=1)=[O:2]
Reactant: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(-c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4n3)cc2)cn1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline using procedures analogous to those for Example 94. LCMS: (M+H)=512.3
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29].Cl>O.C(O)C>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([OH:25])=[O:24]
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 739 mg, 2.9 mmol), 4-amino-3-methoxy-benzoic acid (Aldrich, 534 mg, 3.2 mmol), 4:1 Water/Ethanol (6 mL) and concentrated aqueous hydrochloric acid (0.485 mL, 5.8 mmol) were combined and heated at reflux overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water followed by diethylether to give the title compound as an off white solid as the Hydrochloride salt (673 mg, 55%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][NH:10][C:9](=[O:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[N:23].Cl>CN(C)C=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([O:12][CH2:21][C:22]#[N:23])[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]sc2ccc([N+](=O)[O-])cc12
Reactant: N#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCOc1nsc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (17.5 g, 89.2 mmol) in N,N-dimethylformamide is treated with potassium carbonate (18.5 g, 134 mmol), stirred at room temperature for 30 minutes, treated with bromoacetonitrile (16.0 g, 133 mmol), stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and methylene chloride gives the title product as a yellow solid (15.0 g, mp 123-124.5° C.).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH2:21].O1CCCC1>[Cl-].[Zn+2].[Cl-]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([NH2:21])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH:10]=2)[NH:15]1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CC1(C)CC(N)c2cc(Br)ccc2N1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(N)CC(C)(C)N2
Reaction time: 0.17 h

Procedure:
To neopentylmagnesium chloride (1.65 ml, 1.65 mmol) was added zinc(II) chloride (2.19 ml, 1.10 mmol) dropwise—strong exotherm was observed. The resulting mixture stirred for 10 minutes. A solution of 6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0700 g, 0.274 mmol) in tetrahydrofuran (1.37 ml, 0.274 mmol) was then added followed by palladium tetrakistriphenylphosphine (0.0317 g, 0.0274 mmol). The reaction vessel was sealed and heated to 65 deg C. The reaction mixture was stirred for 6 hours. The crude mixture was filtered through a plug of celite with EtOAc and concentrated in the presence of silica gel. The crude mixture was purified with the MPLC (100% DCM to 100% 90:10:1 DCM:MeOH:NH4OH) to provide the desired product. MS m/z: 230 (M−NH2).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12](CO)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[Br:23]C1C=CC=C(Br)N=1>CS(C)=O>[Br:23][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: Brc1cccc(Br)n1
Solvent: Oc1ccccc1
Solvent: CS(C)=O
Product: Brc1cccc(Oc2ccccc2)n1

Procedure:
The 6-phenoxy-2-pyridinylmethanol may be prepared by first reacting phenol with 2,6-dibromopyridine in dimethyl sulfoxide under basic conditions to give 2-bromo-6-phenoxypyridine. This compound is then reacted at -70° C. with n-butyllithium in diethyl ether and then with dimethylformamide at -30° C. to give 2-formyl-6-phenoxypyridine. This aldehyde is in turn reacted with sodium borohydride in methanol, yielding the corresponding 6-phenoxy-2-pyridinylmethanol.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>C(#N)C>[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OC1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Sodium triacetoxyborohydride (1.67 g, 7.89 mmol) was added to a solution of 4-(trifluoromethoxy)-benzaldehyde (1 g, 5.26 mmol) and 4-hydroxy piperidine (798 mg, 7.89 mmol) in acetonitrile (2 ml) while cooling in an ice-bath, and the mixture was stirred for 30 minutes, and then at room temperature overnight. The reaction mixture was poured into 7.5% sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol 10/1) to afford 1-(4-trifluoromethoxybenzyl)piperidin-4-ol (1.21 g, yield 84%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[Li].[C:42]1([C@@H:48]2[CH2:52][O:51][C:50](=[O:53])[NH:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[O:21]=[C:19]([N:49]1[C@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:52][O:51][C:50]1=[O:53])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (7.14 g, 24.85 mmol) in THF (400 mL) at −78° C. were added Et3N (10.39 ml, 74.6 mmol) and pivaloyl chloride (6.12 ml, 49.7 mmol). The mixture was stirred for 15 min at −78° C. then warmed to 0° C. for 1.5 h. The mixture was cooled to −78° C., to which was added n-Butyllithium (1.6 M in Hexanes)(14 mL, 22.4 mmol), then added the lithium salt of (R)-4-phenyl-2-oxazolidinone [prepared by adding n-Butyllithium (1.6 M in Hexanes)(31 ml, 49.7 mmol), to a solution of (R)-4-phenyloxazolidin-2-one (8.11 g, 49.7 mmol)] in THF (200 mL) at −78° C.) via cannula. The reaction was stirred at −78° C. for 2 h then at rt for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution. The organics were removed under vacuum and the aqueous was extracted with EtOAc. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 10-20% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give ((R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate, 7.12 g (66%). ESI-MS (+) m/z 433.4 (M+1).
Reaction SMILES: [CH:1]12[S:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].Cl.[OH2:14]>>[CH:1]12[S:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([OH:14])=[O:9])[CH:2]2[C:11]([OH:10])=[O:12]
Reactant: O
Reactant: O=C1OC(=O)C2C3C=CC(S3)C12
Agent: Cl
Product: O=C(O)C1C2C=CC(S2)C1C(=O)O
Temperature: 700 °C

Procedure:
The compound of Chemical Formula 201, that is 7-thiabicyclo[2.2.1]hept-5ene-2,3-dicarboxylic anhydride (50 g) is well mixed with water (200 ml), and 1 g of hydrochloric acid is added thereto. The resultant mixture is heated under reflux at 700° C. for 20 hours. Upon cooling the mixture to room temperature, crystals are formed. The crystals are dried in vacuo to obtain 7-thiabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid represented by Chemical Formula 167 (yield: 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:12]=[C:11]([O:21]C)[C:10]=1[C:23]1[S:27][C:26]([N:28]([CH3:39])[CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)=[N:25][N:24]=1)C1C=CC=CC=1.CCOC(C)=O>[Pd].CO>[CH3:1][O:8][C:9]1[C:10]([C:23]2[S:27][C:26]([N:28]([CH3:39])[CH:29]3[CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]3)=[N:25][N:24]=2)=[C:11]([OH:21])[CH:12]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:14]=1
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncc(C)o2)cc(O)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.1 %

Procedure:
A solution of 5-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (28.9 mg, 0.053 mmol) in 1:1 EtOAc:MeOH (5 mL) was added to a nitrogen flushed flask containing 10% Pd/C (2.9 mg, 10% by weight) and the resulting mixture placed under a hydrogen atmosphere and left to stir at room temperature for 72 hours. The reaction mixture was purged with nitrogen, diluted with EtOAc (10 mL), filtered through celite, then rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo to afford the crude product as a pale yellow solid. The crude material was purified by preparative HPLC under acidic conditions running a gradient from 20-95% MeCN/water (+0.1% TFA) over 15 minutes. The product containing fractions were loaded directly onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an off-white/pale brown solid (9 mg, 39% yield). LC-MS: Rt 2.08 min; MS m/z 458.4 [M+H]+ [Method B]. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.74 (br. s., 1H), 7.15 (s, 2H), 7.05 (d, J=1.01 Hz, 1H), 4.42-4.33 (m, 1H), 4.04 (s, 3H), 3.03 (s, 3H), 2.41 (d, J=1.01 Hz, 3H), 1.64 (dd, J=11.87, 3.28 Hz, 2H), 1.44 (t, J=12.13 Hz, 2H), 1.22 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH3:22][Sn](C)(C)C>CN(C=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:22])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (197 mg), tetramethyl tin (0.094 mL), and Pd(PPh3)2Cl2 (20 mg) in DMF (2 mL) was heated at 120° C. for 45 min. The reaction was then partitioned between EtOAc and water, the organic phase was subsequently washed with sat. NaCl solution, dried over anhydrous sodium sulfate and then filtered, concentrated; the residue was purified with column to give the title compound (118 mg). ESI MS (m/z): 285 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:19][C@@:18]([C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])([OH:20])[CH2:17][C:16]2[C:15]([OH:28])=[C:14]3[C:5]([C:6](=[O:30])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]3=[O:29])=[C:4]([OH:31])[C:3]1=2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[OH:33][CH2:32][CH2:34][NH:35][C@H:2]1[CH2:19][C@@:18]([C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])([OH:20])[CH2:17][C:16]2[C:15]([OH:28])=[C:14]3[C:5]([C:6](=[O:30])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]3=[O:29])=[C:4]([OH:31])[C:3]1=2
Reactant: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2C(Br)C1)C(=O)c1ccccc1C3=O
Reactant: NCCO
Product: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](NCCO)C1)C(=O)c1ccccc1C3=O

Procedure:
In the same manner as in Example 4-(1), 7-bromo-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (200 mg) obtained in Reference Example 4 was treated with ethanolamine (30 mg) and the reaction product was post-treated to give dark reddish brown crystals of 7(S)-β-hydroxyethylamino-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 100°-103° C. [α]D20 =+166.2° (c=0.1, CHCl3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH2:17]([N:16]1[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C#CCCc1nc2ccccc2n1CCc1ccccc1
Reactant: Ic1ccccn1
Product: C(#Cc1ccccn1)CCc1nc2ccccc2n1CCc1ccccc1
Yield: 25.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (46 mg, 0.22 mmol) and 2-(but-3-ynyl)-1-phenethyl-1H-benzo[d]imidazole (62 mg, 0.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 20 mg of 1-phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a light brown oil (Yield: 25%).
Reaction SMILES: C[O-].[Na+].Cl.Cl.[NH:6]([C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])[N:14]=1)[C:7]([NH2:9])=[NH:8].CO[C:22]1[C:26](OC)=[N:25][S:24](=[O:29])[N:23]=1>CO>[NH:6]([C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:22]2[C:26]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:13]3[N:14]=[C:10]([NH:6][C:7]([NH2:9])=[NH:8])[S:11][CH:12]=3)=[N:25][S:24](=[O:29])[N:23]=2)[N:14]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2NCCSCc2csc(NC(=N)N)n2)cs1
Reaction time: 0.33 h

Procedure:
To a solution of sodium methoxide (2.16 g; 40.0 mmoles) in 100 ml of CH3OH that was cooled to 0° in an ice-water bath was added 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine dihydrochloride (6.09 g; 20.0 mmoles) and, after 20 minutes of stirring, the solution was treated with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10 mmoles). The reaction mixture was stirred at ambient temperature for 65 hours and evaporated under reduced pressure. The residue was chromatographed on 100 g of silica gel (230-400 mesh) by flash chromatography using a gradient elution of acetonitrile-methanol. The appropriate fractions were combined, evaporated and the residue chromatographed on a Preparative HPLC system using μ-porasil silica gel. The appropriate fractions were combined, and evaporated under reduced pressure to give the title compound as an amorphous solid; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.11 mole of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=[O:15])=[O:4].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][C:18]1[CH:22]=[C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:20][N:19]=1)[N:9]=[C:8]2[CH:14]=[O:15])=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(C=O)nn2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 200 mg 3-Formyl-1H-indazole-5-carboxylic acid methyl ester in 4 mL DMF, 273 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] and 320 mg Cs2CO3 were added and the mixture was stirred at room temperature for 1.5 h. This crude reaction mixture was subjected to the subsequent oxidation step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[BH4-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][OH:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCO)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (500 mg) in THF (15 mL) and ethanol (15 mL) was added sodium borohydride (185 mg) in portion during 5 mins. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water, 2 M hydrochloric acid and saturated brine, dried over sodium sulphate and evaporated to give the crude product as an off-white gum, which was purified by ISCO (10% ethyl acetate in hexanes) to afford 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethanol (D126) (450 mg). MS (ES): C22H22ClN3O3 requires 411; found 412.1 (M+H+).