Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([NH:41][CH3:42])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>O>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([N:41]([CH3:42])[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CNC1CN(Cc2ccccc2)CCC1C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CN(Cc5ccccc5)CCC4C)ncnc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 6.37 mmol, 2.00 equiv.) and potassium carbonate (2.7 g, 19.4 mmol, 6.00 equiv.) were added to a solution of (1-benzyl-4-methyl-piperidin-3-yl)-methyl-amine (700 mg, 2.89 mmol, 1.00 equiv.) in water (30 mL). The solution was stirred at about 100° C. for about 16 hours, and then was cooled to ambient temperature. Following standard extractive workup with ethyl acetate (3×100 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum (1:1)) to give the title product as a light yellow solid (1.5 g; yield=96%). 1H NMR (300 MHz, CDCl3) δ: 8.36 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.45 (d, J=4.2 Hz, 1H), 7.20-7.42 (m, 7H), 6.75 (d, J=4.2 Hz, 1H), 5.05-5.20 (m, 1H), 3.40-3.65 (m, 5H), 2.70-2.92 (m, 2H), 2.50-2.70 (m, 1H), 2.42 (s, 3H), 2.23-2.42 (m, 1H), 2.10-2.23 (m, 1H), 1.55-1.75 (m, 2H), 0.92 (d, J=6.9 Hz, 3H). LC-MS: m/z=490 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:40](F)[CH:39]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]>CS(C)=O.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:39]=[CH:40][C:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[C:49]([NH:16][CH:11]5[CH2:10][CH:9]6[N:8]([CH3:7])[CH:13]([CH2:14][CH2:15]6)[CH2:12]5)[CH:50]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: CN1C2CCC1CC(N)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Yield: 27 %

Procedure:
0.89 g of potassium carbonate and 6 g of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 100° C. for 1 hour and 40 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (92/8 as mixtures), so as to give 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14].O1CCCC1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of 16.3 g (100 mmol) of isatoic anhydride in 100 mL of H2O is added portionwise 100 mL of 2N methylamine-tetrahydrofuran solution (200 mmol) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give 13.79 g of desired product, 2-amino-N-methyl-benzamide (92 mmol, 92%) as colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:3])C.[N:5]1[C:6]([CH:14]([O:17][Si](C)(C)C)[C:15]#N)=[CH:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12.C[OH:23]>>[OH:17][CH:14]([C:6]1[N:5]=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[CH:7]=1)[C:15]([O:3][CH3:1])=[O:23]
Reactant: C[Si](C)(C)OC(C#N)c1cn2ccccc2n1
Reactant: CO
Reactant: CC(=O)Cl
Product: COC(=O)C(O)c1cn2ccccc2n1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Acetyl chloride (0.79 mL, 11.1 mmol) was added to anhydrous methanol (7 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for 10 minutes before adding 2-{imidazo[1,2-a]pyridin-2-yl}-2-[(trimethylsilyl)oxy]acetonitrile (25a) (227 mg, 0.93 mmol). The mixture was stirred 45 minutes at reflux then 1 hour at room temperature. The solution was concentrated in vacuo. The saturated solution of sodium hydrogencarbonate (10 mL) was added to the residue. The aqueous layer was extracted with dichloromethane (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired ester (25b) (153 mg, 0.74 mmol, 80%) as a yellow solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O>>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:12][C:11]([CH3:13])=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2ccc(Br)c(C)c2)o1
Product: Cc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1

Procedure:
5-(4-Bromo-3-methylphenyl)-2-methylfuran (D118) (600 mg, 2.39 mmol) and 4-boronobenzoic acid (397 mg, 2.39 mmol) were converted to the title compound using a method similar to that of Description 11, as a pale yellow solid (207 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]O)=[CH:7]2.O=S(Cl)[Cl:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][Cl:23])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1

Procedure:
Prepared according to Procedure C using (8-chloro-2-phenoxyquinolin-3-yl)-methanol (1.0 eq) and SOCl2 (5 eq) in CHCl3 (0.25 M) at rt. 8-chloro-3-(chloromethyl)-2-phenoxyquinoline was obtained after purification as a yellow oil.
Reaction SMILES: [Li:1]CCCC.[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[CH2:13]=[O:14]>C1COCC1>[Li+:1].[CH3:7][CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])[CH3:8].[CH2:13]=[O:14]
Reactant: [Li]CCCC
Reactant: CC(C)NC(C)C
Agent: C=O
Solvent: C1CCOC1
Product: CC(C)[N-]C(C)C
Product: [Li+]
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A solution of LDA (280 mmol) was prepared by addition of n-BuLi (1.6 M in THF, 175 mL, 280 mmol) to a solution of diisopropylamine (39.3 mL, 280 mmol) in THF (400 mL) at −40° C. and stirring the resulting solution at −15° C. for 30 min. Subsequently the solution was cooled down to −78° C. and a solution of the starting material (50.0 g, 233 mmol) in THF (400 mL) was added dropwisely. After 1 h, gaseous formaldehyde (1.05 mol), which was prepared by heating paraformaldehyde (31.5 g, 1.05 mol) in a separate flask connected by a polyethylene tube to the reaction flask, was passed at −78° C. through this solution over a period of 1 h. After being stirred at −78° C. for additional 30 min and allowed to reach 25° C. over 3 h, the reaction was quenched (saturated aqueous NH4Cl) and extracted (3×EtOAc). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography (SiO2, 30-60% EtOAc/hexanes, gradient elution) gave the product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:27]CC4C=CC(OC)=CC=4)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=3)=[CH:14][C:13]=2[F:37])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](=[O:27])[NH:20][CH:19]=3)=[CH:14][C:13]=2[F:37])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(Cl)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(Cl)c3)c(F)c2)c[nH]c1=O
Yield: 31.5 %

Procedure:
A solution of N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (60 mg, 0.108 mmol) in HCl (MeOH, 27.0 μl, 0.108 mmol) was stirred at 20° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The crude product was purified by preparative HPLC to give pure product N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (14.72 mg, 0.034 mmol, 31.3% yield): 1H NMR: (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.45 (s, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.38-7.32 (m, 3H), 7.28-7.25 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.14 (m, 2H), 3.79 (s, 2H), 1.47 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 435.0 (M+H).
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16]C(C#N)=[CH:12][C:11]=2[C:18]([F:21])([F:20])[F:19])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.[OH-:22].[Na+].[CH2:24]([OH:26])[CH3:25]>>[N:1]1([C:10]2[CH:17]=[CH:16][C:25]([C:24]([OH:22])=[O:26])=[CH:12][C:11]=2[C:18]([F:21])([F:20])[F:19])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: [OH-]
Reactant: N#Cc1ccc(-n2cnc3c2CCCC3)c(C(F)(F)F)c1
Reactant: CCO
Agent: [Na+]
Product: O=C(O)c1ccc(-n2cnc3c2CCCC3)c(C(F)(F)F)c1
Yield: 94 %

Procedure:
Prepared analogously to Example 1f from 4-(4,5,6,7-tetrahydrobenzimidazol-1-yl)-3-trifluoromethylbenzonitrile and sodium hydroxide solution in ethanol. Yield: 94%; C15H13F3N2O2 (310.28); mass spectrum: (M+H)+=311 and (M−H)−=309
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:19]([CH2:21][CH3:22])[CH3:20])=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:21]([N:19]([CH3:20])[C:7]1[C:6]([C:4]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[O:5])=[C:11]([CH3:12])[CH:10]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:8]=1)[CH3:22]
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1N(C)CC
Reactant: NCc1ccc(F)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(C)c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 120 °C
Yield: 40.7 %

Procedure:
A solution of 249 mg (0.81 mmol) 2-(ethyl(methyl)amino)-4-methyl-6-morpholino-pyridine-3-carboxylic acid ethylester and 924 μl (8.1 mmol) 4-fluoro-benzylamine in toluene (17 ml) was treated with 2.85 ml (2M in toluene, 5.7 mmol) AlMe3 and was subsequently heated to 120° C. for 4 d. Then the solution was diluted with water, a 1M aq. NaOH sol. and EtOAc. The organic layer was separated, washed with a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 127 mg (0.33 mmol, 40%) 2-(Ethyl-methyl-amino)-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 174). [M+H]+387.2
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][OH:27])[CH:20]=1>ClCCl>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([S:15]([O:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
6.62 mL (47.26 mmol) of triethylamine and 8.26 g (43.32 mmol) of 4-methylbenzenesulfonyl chloride are added at 0° C. to a solution of 5 g (39.38 mmol) of 2-pyrid-3-ylethanol in 300 mL of dichloromethane. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 4/6 heptane/EtOAc), 8 g of 2-pyrid-3-ylethyl toluene-4-sulfonate were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (200 mg, 0.33 mmol, 1.00 equiv, 50%) in DMF (5 mL) was added potassium carbonate (91.1 mg, 0.66 mmol, 2.00 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (73.5 mg, 0.50 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH3HCO3 and CH3CN (5.0% CH3CN up to 50.0% in 11 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The fractions containing product were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(pyrrolidin-1-yl)ethan-1-one (40 mg) as a white solid. MS (ES, m/z): 414 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 5.97 (d, 1H), 4.02-4.04 (m, 1H), 3.49 (t, 2H), 3.35 (t, 2H), 3.21 (s, 2H), 3.09 (t, 2H), 2.95 (t, 2H), 2.39-2.51 (m, 3H), 2.25 (s, 3H), 1.95-2.03 (m, 2H), 1.69-1.88 (m, 6H), 1.33-1.51 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[NH:5][C:6](=O)[NH:7]C(=O)[C:9]=2[N:10]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O.[CH2:27]([Cl:29])Cl>>[Cl:24][C:6]1[N:7]=[C:27]([Cl:29])[C:9]2[N:10]=[C:2]([CH3:1])[S:3][C:4]=2[N:5]=1
Reactant: Cc1nc2c(=O)[nH]c(=O)[nH]c2s1
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc2c(Cl)nc(Cl)nc2s1
Temperature: 130 °C
Yield: 54 %

Procedure:
To a mixture of 2-methyl-4H-thiazolo[5,4-d]pyrimidine-5,7-dione (7.5 g, 0.041 mol) in N,N-dimethylaniline (3.7 mL, 0.029 mol) was added phosphorous oxychloride (38.0 mL, 0.410 mol) and the mixture heated at 130° C. for 4 h. The resulting black solution was cooled to RT, then carefully quenched with crushed ice and H2O, before being extracted with EtOAc. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo to give a yellow solid. The solid was dissolved in DCM, then washed with an aqueous solution of NaHCO3 followed by brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale yellow solid (4.90 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:19][NH2:20])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5 g, 20 mmol) in 1-butanol (75 mL) was added hydrazine hydrate (2.0 ml, 40 mmol) at room temperature. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. LCMS calculated for C10H14ClN6O (M+H): 269.1. found: 269.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:10]=[CH:11][CH:12]=[CH:13]4)=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 110 °C

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (1.67 g, 12 mmol), 2-(quinolin-6-yl)acetic acid (1.65 g, 8.8 mmol), and HCl (2000 μl, 24 mmol) was heated in an oil bath at 110° C. for 20 min before it was heated in a microwave (Personal Chemistry) at 180° C.&15 min. The mixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly until the suspension is ˜neutral in pH. The mixture was filtered and washed with H2O (2×5 mL). A brown solid was obtained (2.2 g). The solid was treated with aqueous Na2CO3 (3 g, 20 mL, pH ˜11) and heated at 50° C. for 30 min. The blue mixture was cooled to room temperature, and filtered. The black solid was washed with H2O and lyophilized to give the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([Sn])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9].[C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Sn]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccccc2)cc1
Yield: 5 %
Yield: 85 %

Procedure:
A preparative reaction was conducted with 0.40 g of p-bromonitrobenzene (2 mmol) and 2.97 g of phenyltin reactant 1a (2.4 mmol) in 10 mL 1/1 DMF/THF at 80° C. for approximately 22 hours. Both reactants were consumed according to TLC analysis. After azeotropic evaporation with toluene at 75° C. (to remove some of the solvent), a three-phase extraction was conducted as described above. The methylene chloride phase was then washed three more times with water and FC-72 (together) to remove DMF and fluorous products. The crude organic product was purified by flash chromatography to provide 337 mg (85%) of 4-nitrobiphenyl and 17 mg (5%) of biphenyl. The crude fluorous tin chloride (99%) from the FC-72 phase was reacted with phenyl magnesium bromide to provide 2.85 g (96% overall) of the original tin reactant la after purification by passing through a short column of neutral alumina.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:29][C:30]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CN1CCCC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and pyrrolidin-1-yl-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(pyrrolidin-1-yl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 425; RT=4.954 min; LCMS Method III
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]([S:31](Cl)(=[O:33])=[O:32])=[CH:16]2.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:17]([S:31]([N:9]1[CH2:8][CH2:7][NH:6][CH:5]([CH2:4][CH:3]([CH3:11])[CH3:2])[CH2:10]1)(=[O:33])=[O:32])=[CH:16]2
Reactant: CC(C)CC1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a methylene chloride solution (150 ml) of 2-(2-methylpropyl)piperazine hydrochloride (1.50 g) were added 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (2.72 g) and triethylamine (2.91 ml). The resulting mixture was stirred at room temperature for 13 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:20), whereby the title compound (2.69 g) was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:14]([CH3:22])([CH2:16][CH2:17][C:18](Cl)([CH3:20])[CH3:19])[CH3:15]>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]2[C:14]([CH3:22])([CH3:15])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:6]=2[CH:7]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Reaction time: 10 h
Yield: 68 %

Procedure:
60 g (347 mmol) of 3-bromophenol are dissolved in 600 mL of dichloromethane. This solution is added to a solution of 46 g (347 mmol) of aluminum chloride in 200 mL of dichloromethane. 127 g (694 mmol) of 2,5-dichloro-2,5-dimethylhexane are added in 10 g portions every 40 minutes. The medium is then stirred for 10 hours, after which it is poured onto ice and extracted with dichloromethane. The residue obtained is dissolved in ethyl ether and this organic phase is then washed with 1N sodium hydroxide solution, and then with water. The residue obtained is purified by chromatography (eluent:heptane and then 1/1 heptane/dichloromethane). A thick oil is obtained (67 g; yield=68%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: OCCCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCOCc1ccccc1

Procedure:
The 5-benzyloxypentanol (Aldrich, 0.32 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.