Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.[C:25](=O)([O:28]C)[O:26]C>C1COCC1>[C:25]([CH2:24][C:17]1[CH:16]=[C:15]([O:14][CH3:13])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([OH:28])=[O:26]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A solution of diisopropylamine (3.43 ml, 24.07 mmol) in THF (3 mL) was cooled to −78° C. and n-butyllithium (9.63 ml, 24.07 mmol) was added dropwise and allowed the solution to warm to 0° C. for 5 min and then re-cooled to −78° C. 4-methoxy-2-methylbenzoic acid (1 g, 6.02 mmol) and dimethyl carbonate (1.013 ml, 12.04 mmol) in THF (3 mL) was added dropwise. After the addition is complete, the reaction is allowed to slowly warm to RT and stir for 4 h. The reaction was quenched with 10 mL of H2O and allowed to stir for 16 h. The layers were separated, washed the organics with H2O (2×), combined all the aqueous extractions and adjusted the pH to 2-3 with 6N HCl while in an ice bath. The resulting in a white precipitate was filtered and dried under vacuum to afford the title compound (1.09 g, 86%) as a white solid. LCMS (ES+) m/z 211.05 (M+H)+.
Reaction SMILES: Br.Br.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.[O-2].[Ca+2].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[C:25]=[S:26]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:25]([NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[S:26])[CH2:18][CH2:19]1
Reactant: NCC1CCN(CC2COc3ccccc3O2)CC1
Reactant: COc1ccc(N=C=S)cc1
Agent: Br
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(NC(=S)NCC2CCN(CC3COc4ccccc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.4 parts of (1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide, 4 parts of calcium oxide and 80 parts of methanol was stirred for 3 hours at room temperature. Then there were added 5 parts of 1-isothiocyanato-4-methoxybenzene and the whole was stirred for 3 hours at room temperature. The whole was filtered and the filtrate was evaporated. The sticky residue was suspended in a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane, the latter was decanted (the residue was set aside) and allowed to crystallize, yielding a first fraction of 1 part of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91). The residue, which was set aside, yield a second fraction of 5 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91). Total yield: 6 parts (93.5%) of N-[[ 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea; mp. 147.9° C. (intermediate 91).
Reaction SMILES: C([N:9]1[C:13](=[O:14])[C:12]([CH:16]([CH3:18])[CH3:17])([CH3:15])[N:11]=[C:10]1[C:19]1[N:28]=[CH:27][C:26](C(Br)Br)=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=O)C1C=CC=CC=1.C(NCCN)C.C(N(CC)CC)C.[O:45]1CCC[CH2:46]1>>[CH:46]([C:26]1[CH:27]=[N:28][C:19]([C:10]2[NH:9][C:13](=[O:14])[C:12]([CH:16]([CH3:17])[CH3:18])([CH3:15])[N:11]=2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:45]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(C(Br)Br)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Agent: CCNCCN
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.38 g of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(dibromomethyl)nicotinic acid, methyl ester, in 35 mL tetrahydrofuran is cooled to -78° and treated with a mixture of 0.3 mL of N-ethylethylenediamine, 10 mL tetrahydrofuran, and 0.8 mL of triethylamine. After warming to room temperature, the reaction solution is treated with 0.3 mL of N-ethylethylenediamine, stirred for 2 hours, heated at reflux for 24 hours, and concentrated in vacuo. The residue is partitioned between methylene chloride and water; the aqueous phase is further extracted with methylene chloride, and the combined organic phases are dried and concentrated in vacuo. Chromatography of the residue on silica gel using hexane-ethyl acetate mixtures affords the desired product, mp 113°-117°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([NH:18][OH:19])=[NH:17])[N:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:19][N:18]=[C:16]([C:4]2[N:5]=[C:6]([N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[C:2]([NH2:1])[N:3]=2)[N:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccco3)n2)n1

Procedure:
To a suspension of 4-amino-N-hydroxy-6-(methyl-phenyl-amino)-[1,3,5]triazine-2-carboxamidine (Intermediate 1, 95 mg, 0.37 mmol) in anhydrous toluene (3 mL) and anhydrous pyridine (1 mL) was added 2-furoyl chloride (53 mg, 0.41 mmol) in a solution of anhydrous toluene (3 mL) at 0 C in a sealed tube under an atmosphere of nitrogen.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9]O.[Br:11]P(Br)Br>C1(C)C=CC=CC=1>[Br:11][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: OCc1cccc(Cl)c1Cl
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Clc1cccc(CBr)c1Cl
Yield: 233.8 %

Procedure:
To a solution of (2,3-dichlorophenyl)methanol (75 g, 0.431 mol), in toluene (800 mL), tribromophosphine (40.7 g, 0.151 mol) was added dropwise at room temperature with stirring. Then the reaction mixture was stirred at room temperature for 2 h and concentrated. The resulting residue was neutralized with aq. NaHCO3 and extracted with DCM (300 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (84.7 g, 83%), as a deep red solid.
Reaction SMILES: [C:1](=[N:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([CH2:13][CH3:14])=[C:7]([N:15]=[C:16]([CH3:18])[CH3:17])[C:6]=1[CH3:19])([CH3:3])[CH3:2].C(O)C>[Pt].C(OCC)(=O)C>[CH:16]([NH:15][C:7]1[C:8]([CH2:13][CH3:14])=[CH:9][C:10]([CH2:11][CH3:12])=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[C:6]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: CCc1cc(CC)c(N=C(C)C)c(C)c1N=C(C)C
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(CC)c(NC(C)C)c(C)c1NC(C)C
Reaction time: 1.2 h
Yield: 94 %

Procedure:
N,N′-diisopropylidene-[diethyl(methyl)-1,3-benzenediamine] (3.17 g) and Pt(S)/C (0.3 g) were added to a mixture of ethanol (20 g) and ethyl acetate (20 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The mixture was kept at 22° C. and 0-125 psi (0 to 8.62×105 Pa) of H2 for 1.2 hours, forming the corresponding N,N′-diisopropyl-[diethyl(methyl)-1,3-benzenediamine] in 94% yield. Six percent of the diimine was underhydrogenated; conversion of the diimine was 100%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH:5]=1.Br[CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH2:22][CH2:23][CH3:24])[CH:5]=1
Reactant: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1cc(Cl)ncn1)n1cc(C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60% in oil, 1.52 g) in 40 ml dimethylformamide (hereafter DMF) at ice bath temperature was added 9.0 g of 6-chloro-N-(3-methyl-1H-indol-1-yl)-4-pyrimidinamine dropwise, in 50 ml DMF. After addition was complete, the reaction was stirred for 5 minutes and then 3.45 ml of 1-bromopropane was added dropwise to the cool mixture. Reaction was allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [CH3:1][S:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][C:5]1=O)=O.C[OH:16]>Cl>[CH3:1][S:2][C:4]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH:5]=1
Reactant: CO
Reactant: CS(=O)C1Cc2ccccc2OC1=O
Agent: Cl
Product: CSc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
A mixture of 3-(methylsulfinyl)chromanone (11 g), methanol (100 ml) and 1N hydrochloric acid (100 ml) is stirred at room temperature for 20 hrs. The methanol is removed at reduced pressure, and the aqueous residue is extracted with chloroform. The chloroform extracts are combined, extracted with 1N sodium hydroxide solution, washed with water, dried over MgSO4 and evaporated to give an oil. The oil is heated at 100° C. in 5N hydrochloric acid (100 ml) for 5 hrs. The solution is cooled, and the product which precipitated is filtered off. Recrystallization from methanol gives 3-(methylthio)chromone (2) as white crystals (7.2 g, 72%), mp 103°-105° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[N:11]2C2CCCCO2)=[C:7]([NH2:22])[N:6]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[NH:11]2)=[C:7]([NH2:22])[N:6]=1
Reactant: CCC(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (199 mg) in dry MeOH (1.99 mL) was added TFA (0.199 mL). The mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to give a yellow residue. The residue was triturated with Et2O and was filtered to give the title compound as an off-white solid (111 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>ClCCl>[C:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2CC)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.06 g, 0.16 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.05 mL, 0.63 mmol) and propionyl chloride (0.03 mL, 0.3 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05, 77%), m.p. 111-112° C.;
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH2:11]([O:25][C:26]1[O:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>>[CH2:11]([O:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCN2CCOCC2)o1

Procedure:
The title compound was prepared as in Example 30 starting with 0.224 g (1.2 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid with the exception that a total of 0.730 g of cesium carbonate was added to neutralize the hydrochloride. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.40 (t, 2H), 4.10 (t, 2H), 3.70 (app t, 4H), 2.70 (t, 2H), 2.55 (app t, 4H), 1.80 (p, 2H), 1.18-1.55 (m, 22H), 0.89 (t, 3H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:41]1[CH:42]=[C:43]([S:47][C:48]2[C:53]([O:54][CH2:55][CH2:56][CH2:57][C:58]3[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=3)=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:44]=[CH:45][CH:46]=1>C1COCC1>[CH:1]1([O:6][C:45]2[CH:44]=[C:43]([S:47][C:48]3[C:53]([O:54][CH2:55][CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=4)=[CH:52][CH:51]=[CH:50][N:49]=3)[CH:42]=[CH:41][CH:46]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(Sc2ncccc2OCCCc2ccncc2)c1
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CCCC2)cc(Sc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Cyclopentanol (0.11 g, 1.3 mmol) and triphenylphosphine (0.47 g, 1.8 mmol) are dissolved in THF (15 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (0.26 g, 1.3 mmol) and 2-(3-hydroxyphenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.30 g, 0.89 mmol) obtained in Example 13. The mixture is further stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. The residue is extracted with a 10% aqueous hydrochloric acid solution (30 ml), and the aqueous layer is washed with chloroform (30 ml×2), and the pH value thereof is adjusted to pH 12 with potassium carbonate. The mixture is extracted with ethyl acetate (50 ml×2), and the organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give the title compound (0.26 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1)[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)benzaldehyde (250 mg, 1.13 mmol, synthesized at Example 278 (1)) in 2.3 mL of dry N,N-dimethylformamide was added sodium hydride (59 mg, 55%, 1.4 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methyl iodide (105 μL, 1.69 mmol) was added with additional stirring overnight. After quench with saturated NH4Cl aqueous solution, the mixture was extracted with diethyl ether. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound (210 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:26][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: O=S1(=O)CCNCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 55 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using thiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to the title compound (73 mg, 55%) which was obtained as a white solid. MS: m/e=446.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:16][CH2:15]2.[ClH:26].[CH3:27]COCC>CO>[ClH:26].[ClH:26].[CH3:27][O:24][C:23](=[O:25])[CH2:22][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]3[NH:3][CH2:4][CH2:5][CH2:6][N:1]=3)[CH:13]=2)[CH2:18]1
Reactant: O=C(O)CC1CCc2cc(OCCCNC3=NCCCN3)ccc2C1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)CC1CCc2cc(OCCCNC3=NCCCN3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of {6-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-propoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid (25 mg) in MeOH (2 mL) was added HCl in MeOH and the solution was heated to reflux for 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure to afford a tan oil. Ether was added, the contents were swirled and the solvent decanted. Lyophilization of the oily residue gave the title compound as a hygroscopic, ivory solid (29 mg). NMR (300 MHz, MeOH-d4) δ6.84 (d, J 8.20 Hz, 1H), 6.61-6.56 (m, 2H), 3.92 (t, J=5.75 Hz, 2H), 3.59 (s, 3H), 3.28-3.21 (m, 5H), 2.72-2.68 (m, 3H), 2.33-2.24 (m, 3H), 2.09-2.06 (m, 1H), 1.92 (t, J=7.09 Hz, 2H), 1.87-1.77 (m, 3H), 1.37-1.19 (m, 2H); MS (+ESI) m/z 360 (M+H)+; Calculated for C20H29N3O3.2 HCl: C, 55.56; H, 7.23; N, 9.72. Found: C, 55.15; H. 7.10; N, 9.88.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH3:39][N:35]1[C:36](=[O:38])[C:37]2[C:33](=[C:32]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:31]=[CH:30][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][CH:14]=3)[N:3]=2)[CH2:34]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 636.24 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]2[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 271. NMR (CDCl3): 1.00-1.04 (2H, m), 1.18-1.22 (2H, m), 2.27-2.33 (1H, m), 2.45 (3H, s), 2.67-2.70 (4H, m), 3.38-3.41 (4H, m), 3.86 (2H, s), 3.39-3.41 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+ 531.29 (70%)
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][C@H:31]([OH:33])[CH3:32])[C:5]=32)=[CH:10][CH:9]=1)[CH3:15]
Reactant: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A solution of 1.6 g of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.2 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.03 g (52%) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][C:16]#[N:17])=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:4]2[C:3]=1[CH:15]=[C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)[N:17]=[C:5]2[OH:6]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(C(=O)O)c(CC#N)c(Cl)c1OC
Solvent: CC(=O)O
Product: COc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 3-Chloro-2-cyanomethyl-4,5-dimethoxy-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 5-Chloro-6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 335 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH2:16](O)[CH:17]=C>>[CH2:1]([O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH:16]=[CH2:17]
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Reactant: C=CCO
Product: C=CCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and allyl alcohol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.62 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).