Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[NH:23][C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[O:26]C(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[N:23]([CH2:2][CH:3]([F:5])[F:4])[C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[OH:26]
Reactant: FC(F)CBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1c(-c2c(F)ccc(F)c2Cl)c(O)c2nccnc2n1CC(F)F
Temperature: 120 °C

Procedure:
1-Bromo-2,2-difluoroethane (0.754 g) was added to a mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-1)]pyrazin-8-yl ester (Example 1.3) (1.00 g), potassium carbonate (1.76 g) and potassium iodide (catalytic amount) in anhydrous N,N-dimethylformamide (15 ml). The reaction mixture was heated in a microwave for 20 minutes at 120° C. The reaction mixture was allowed to cool to ambient temperature before diluting with water and ethyl acetate. The phases were separated. The organic phase was washed with water, dried over magnesium sulfate, and concentrated. The residue was dissolved in diethyl ether, and the solution was washed with water. The phases were separated and the organic phase was concentrated to give Compound No. B2 of Table B as an orange viscous oil (0.553 g).
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])[CH:9]=2)=O)=[CH:4][C:3]2[CH:40]=[CH:41][CH:42]=[CH:43][C:2]1=2.[BH4-].[Na+]>O1CCCC1.C(O)C>[C:20]([O:19][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:34][C@H:17]1[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:6][C:5]2[S:1][C:2]3[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=3[CH:4]=2)=[CH:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3cc4ccccc4s3)c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3cc4ccccc4s3)c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
The above Benzo[b]thiophen-2-yl (1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl)ketone 92 (440 mg) was dissolved in tetrahydrofuran (6 ml) and ethanol (3 ml). To the solution was added sodium borohydride (137 mg), and the mixture was stirred at room temperature for 60 minutes. The reaction mixture was quenched with cold aqueous HCl solution (0.5 N), and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was dissolved in dichloromethane (8 ml) and acetonitrile (4 ml), and the mixture was cooled to 0° C. under argon atmosphere. To the mixture were added triethylsilane (0.58 ml) and boron trifluoride.diethyl ether complex (0.46 ml). After 30 minutes, the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was collected, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant residue was dissolved in chloroform (20 ml), and to the mixture were added acetic anhydride (0.16 ml), triethylamine (0.2 ml), and 4-dimethylaminopyridine (15 mg), and the mixture was stirred at room temperature for 30 minutes. Then, the solution was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2-6:4) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(benzo-[b]thiophen-2-ylmethyl)indole 93 (290 mg). APCI-Mass m/Z 611 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2I.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.Cl.C(Cl)Cl>O1CCOCC1.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>[C:42]([C:13]1[C:14]([OH:34])=[CH:15][CH:16]=[C:17]2[C:12]=1[O:11][C:10](=[O:36])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[C:18]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=[O:44])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc12
Temperature: 25 °C
Yield: 13.5 %

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-chromen-2-one (187 mg, 0.294 mmol), tributyl(1-ethoxyvinyl)tin (119 μL, 0.353 mmol) and Pd(Ph3P)4 (34 mg, 0.0294 mmol) in anhydrous dioxane (6 mL) was stirred at reflux temperature for 2 h. After cooling to room temperature, aqueous 1M HCl was added, and the resulting mixture was stirred for 20 min. CH2Cl2 was added and the layers were separated. The aqueous layer was further extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using flash chromatography (silica gel, 19:1→9:1 CH2Cl2:MeOH) to afford a light brown solid (48 mg, 84% pure by HPLC) that was recrystallized from AcOEt/hexane to provide the title compound as a yellow solid (22 mg, 14%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1.N1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]([CH3:14])[CH3:13])[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)Nc1nc2c(Br)c(Cl)c(Cl)cc2[nH]1
Yield: 608.4 %

Procedure:
3-Bromo-4,5dichloro-1,2-phenylenediamine (25.0 g, 97.7 mmol), isopropyl isothiocyanate (11.2 g, 110.5 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (56.8 g, 134.1 mmol) and pyridine (500 mL) were used according to general procedure I. The product was isolated by silica gel chromatography using 7:3 hexane/ethyl acetate to afford 192 g (62%) of a tan solid; m p. 247-249° C. Anal. Calcd for C10H10BrCl2N3-(0.08 C6H14): C, 38.15; H, 3.40; N, 12.74. Found: C, 38.15; H, 3.39; N, 12.77.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12]2=[O:34])[CH:5]=1.[Li+].[OH-]>C1COCC1.O>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:14]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12](=[O:34])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:35])=[O:2])[C:16](=[O:17])[CH:15]=2)[CH2:19]1
Reactant: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(C(=O)O)c2)c1=O

Procedure:
A crude mixture of compound 24 (˜50 mg) was treated with LiOH in THF-water (10:1) to give the title compound 25. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.90 (s, 1 H), 7.86 (d, J=7.6 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1 H), 7.45 (d, J=7.3 Hz, 1 H), 7.26-7.36 (m, 2H), 7.17 (d, J=8.1 Hz, 1 H), 5.39 (s, 1 H), 5.10-5.25 (ABq, J=36.9, 15.5 Hz, 2H), 5.03 (s, 2H), 3.31 (m,2H), 2.95 (m, 1 H), 2.81 (m, 1 H), 2.64 (m, 1 H), 2.07 (m, 1 H), 1.82 (m, 1 H), 1.51-1.68 (m, 2 H). MS (ES) [m+H] calc'd for C25H26N5O4, 460.2. found 460.2.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)=[O:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (186 g, 1.23 mol) in pyridine (2 L) was treated with trimethylacetyl chloride (475 g, 3.94 mol, 485 mL, 3.2 eq) at 90° C. for 2 h, to give a mixture of N(2)-monoacylated and N(2), N(7)-bisacylated material. The solvent was evaporated and the residue was taken up in aqueous ammonia (37% NH3, 310 mL) and MeOH (2 L), and stirred at rt for 30 min, to selectively cleave the N(7)-pivaloyl group. The solid was collected by filtration, washed with water (500 mL×5), and dried on high vacuum to give the title compound as a solid (193 g). Concentration of the mother liquor provided additional solid material, which was collected, washed with water (50 mL×5), and dried (77 g). The combined yield was 93% (HPLC purity 98.6%). tR: 4.57 min. 1H-NMR (DMSO-d6) δ 12.00, (br. s, 1H), 7.40 (br. s, 1H), 6.96 (q, 1H), 6.40 (q, 1H), 1.24 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][CH:17](O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH:17]([CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)O)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: COc1ccc(C(C)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
Similarly, 4,6-di-t-butyl-2-(α-methyl-4-methoxybenzyl) phenol was prepared from 2,4-di-t-butylphenol and α-methyl-4-methoxybenzyl alcohol. A yellow oil (b.p. 180° at 1.0 mm Hg) which crystallized was obtained. The product was recrystallized from methanol to give colorless needles melting at room temperature (Found: C, 81.0; H, 9.45 Calc. for C23H32O2 : C, 81.1; H, 9.47%). The pmr spectrum determined as above exhibited the following: δ1.35, 9H, S; δ1.37, 9H, S; δ1.63, 3H, D (J=7 Hz); δ3.78, 3H, S; δ4.17, Q, 1H (J=7 Hz); δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.10-7.30, 4H, M.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(OC)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.04 g, 3.73 mmol) in tetrahydrofuran/water/methanol (9.3 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (3.73 mL, 3.73 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (707.8 mg, 71.3%) as a white solid: mp 149-151° C.; EI-HRMS m/e calcd for C15H19F O3(M+) 266.1318 found 266.1317.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:19])[C:4]=2[CH:3]=1.[CH3:20]OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:20])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:19])[C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Clc1ccc2[nH]c3c4ccccc4nc-3c(Cl)c2c1
Solvent: Cc1ccccc1
Product: C[NH+]1C2=c3ccccc3=NC2=C(Cl)c2cc(Cl)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-chloro-11-chloroquindoline from Example 49 (0.3 g, 1.0 mmol) in anhydrous toluene (12 mL) was added methyltriflate (0.25 mL, 200 mol %). The reaction mixture was stirred for 20 h at rt after which TLC analysis still showed starting material. Additional methyl triflate (100 mol %) and toluene (5 mL) were added. The reaction mixture was stirred overnight, filtered, washed with ether and dried to afford the crude title compound; MS (-FAB, m/z) 149.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1COC(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)=N1
Agent: ClC(Cl)(Cl)CBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)n1
Yield: 49.2 %

Procedure:
The same operation as in Example (108d) was performed using methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (109c) (1.43 g, 3.88 mmol), bromotrichloroethane (414 μL, 4.1 mmol), DBU (628 μL, 4.1 mmol) and dichloromethane (10 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1) to obtain 0.7 g of the title compound as a colorless solid (49%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN.[Li].O>O1CCCC1.C(O)CCC>[CH2:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCO
Solvent: O
Product: C1=CCC2CCNCC2=C1
Temperature: -10 °C

Procedure:
Typically, the tetrahydroisoquinoline was suspended or dissolved in a cosolvent such as tetrahydrofuran ort-butyl alcohol. This mixture was cooled to −10° C. and methylamine was added and the temperature was maintained at −10° C. The lithium metal was charged in portions and the reaction mixture was stirred at −10° C. for another 30 minutes to about 2 hours after sufficient lithium metal was charged. The reaction mixture was warmed to room temperature and then added to water to produce the product hexahydroisoquinoline as a precipitate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:30][CH2:29][CH2:27][OH:28])[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: NCCO
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCCCNCCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and ethanolamine were converted to yield 2-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butylamino}-ethanol as colorless amorphous solid, MS: 424 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[N:7]=1.[CH3:16][NH2:17].O1CCCC1>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:17][CH3:16])=[O:13])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)c1cn2nc(I)ccc2n1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.6 %

Procedure:
To a suspension of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (4.5 g, 14.8 mmol) in methanol (13.5 mL) was added dropwise a solution of methylamine/tetrahydrofuran (2 mol/L, 37.1 mL, 74.2 mmol), and the mixture was stirred at room temperature for 96 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, saturated brine and water to give the title compound (3.2 g, 71%) as a dark brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[CH3:28])=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:24][C:22]1[CH:23]=[C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([I:29])[C:11]=23)[C:19]([CH3:28])=[CH:20][C:21]=1[NH2:25]
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4C)ccnc32)cc1
Temperature: 0 °C

Procedure:
To a 100 mL round bottom flask added 1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (544 mg, 0.99 mmol) and suspended in absolute ethanol (10 mL). Added tin(II)chloride dihydrate (1.1 g, 4.94 mmol) and stirred at 25° C. under N2(g) for 18 hours, during which a white precipitate formed. The reaction mixture was cooled to 0° C. and the solid was removed by filtration and washed with cold ethanol. The solid was air-dried to afford the desired product as white solid. Yield: 417 mg, 81%. LRMS (APCI pos) m/e 521.1 (M+H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].[H][H].[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[ClH:12].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Clc1nc2ccccc2cc1-c1ccccc1
Reactant: CN(C)CCS
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccccc1
Temperature: 0 °C

Procedure:
2-Dimethylaminoethanethiol hydrochloride (58.40 g. of 80% w/w) was added to a suspension of sodium hydride (31.68 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (500 ml.) at 0° to 5°. When all the hydrogen had evolved, a solution of 2-chloro-3-phenylquinoline (72.70 g.) in dimethylformamide (100 ml.) was added and the mixture stirred and heated at 75° for 5 hr. The reaction mixture was then poured into ice water (4000 ml.) and extracted with ethyl acetate (6×500 ml.). The ethyl acetate extract was washed succesively with water (1000 ml.) and saturated brine (1000 ml.), and then dried (MgSO4). The ethyl acetate solution was evaporated and the residual oil was chromatographed on basic alumina (1200 g.; Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether. The elutate obtained with 10% v/v chloroform in petroleum ether was evaporated. The residual solid was dissolved in ethanol (800 ml.) and treated with concentrated hydrochloric acid (25.2 ml.). The ethanol was evaporated, and the oily residue was azeotroped with toluene. The solid obtained was recrystallised from ethanol-diethyl ether and was then washed with a small volume of cold acetone. The mixture was filtered and there was obtained as the solid residue 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride, m.p. 195°-8° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:46]3[CH:47]=[CH:48][C:43]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:44][CH:45]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Oc5ccccc5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-phenoxyphenylboronic acid (43 mg, 0.2 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4′-phenoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:45]2[N:44]([C:48]#[CH:49])[C:43]3[CH2:50][CH2:51][N:52]([CH3:54])[CH2:53][C:42]=3[C:41]=2[CH:40]=1>C(#N)C.O>[Cl:38][C:39]1[CH:47]=[CH:46][C:45]2[N:44]([C:48]#[C:49][C:2]3[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[C:43]3[CH2:50][CH2:51][N:52]([CH3:54])[CH2:53][C:42]=3[C:41]=2[CH:40]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C#Cc2ccc(C(F)(F)F)nc2)C1
Temperature: 80 °C
Yield: 3.8 %

Procedure:
A mixture of 5-bromo-2-(trifluoromethyl)pyridine (4.6 g, 0.02 mol), triphenylphosphine (0.053 g, 0.00020 mol), triethylamine (1.7 mL, 0.01227 mol) and 8-chloro-5-ethynyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 0.00409 mol) was dissolved in acetonitrile (30 mL) and heated by microwave at 80° C. for 30 min. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to RT and diluted with water (100 mL). The mixture was extracted with EtOAc (3×100 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product. Product was purified by column chromatography using silica (100-200 mesh) and 3% MeOH:DCM as eluent, diameter of column—5 cm, height of silica—approx. 5 inch) then further purified by preparative TLC to give the desired compound as a yellow colored solid (0.06 g, 4% yield). The product (0.02 g, 0.000051 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.007 g, 0.000055 mol) in THF (2 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as an off-white solid (0.015 g, 60% yield). 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.90 (s, 1H), 8.25 (d, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.40 (d, 1H), 4.50 (m, 2H), 3.80 (m, 2H), 3.40 (m, 1H), 3.18 (m, 1H), 3.10 (s, 3H).