Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][S:19](=[O:38])[O:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:40].[Na+]>O.[Ru](Cl)(Cl)Cl.ClCCl.C(#N)C>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([C@H:21]2[C@H:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:18][S:19](=[O:40])(=[O:38])[O:20]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc([C@@H]2OS(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc([C@@H]2OS(=O)(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
Mixture: 33 g (63 mmol) of (4S,5S)-4,5-bis(3'-benzyloxy-4'-methoxyphenyl)-2-oxo-1,3,2-dioxathiolane, 300 ml of dichloromethane/acetonitrile 1:1, 200 ml of ice-water, 72.7 mg (0.35 mmol) of ruthenium (III) chloride hydrate, 26.83 g (125.4 mmol) of sodium metaperiodate.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH:3]=[O:4].P([O-])(O)(O)=[O:23].[Na+].CC(CC)=C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][C@@H:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[C:3]([OH:23])=[O:4]
Reactant: O=P([O-])(O)O
Reactant: C[C@H](C=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C=C(C)CC
Solvent: O
Product: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)O

Procedure:
(S)-2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionaldehyde (1.99 g; 6.6 mmol, prepared in accordance with Example 66) is suspended in a mixture of tert-butanol (48 mL) and water (12 mL); sodium dihydrogenphosphate (1.59 g; 13.3 mmol) and 2-methyl-butene (13.94 g; 199 mmol) are added and the resulting mixture is stirred until a solution is obtained. Sodium chlorite (1.12 g; 9.9 mmol) is added and the reaction is stirred at room temperature for one hour. The precipitate formed is filtered, is washed with water and is dried at 40° C. under 3 mbar. Aqueous sat ammonium chloride (50 mL) is added to the filtrate which is then extracted with dichloromethane (2×50 mL). The combined organic layers are washed with brine (50 mL) and concentrated under reduced pressure. The residue obtained is dried at 40° C. under 3 mbar. The enantiopure product is obtained as colourless solid (1.3 g; 4.1 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4]OC1.FC1C=CC(NC(=O)OC(C)(C)C)=C(NC2N=C(N[C@H:29]3[C:38]4C(=CC=C[CH:37]=4)[C:32](=[O:39])[CH2:31][CH2:30]3)C([N+]([O-])=O)=CN=2)C=1.FC1C=CC(NC(=O)OC(C)(C)C)=C(NC2N=C(SC#N)C([N+]([O-])=O)=CN=2)C=1.[NH2:71][C@H:72]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:75](=[O:82])[CH2:74][CH2:73]1>CN(C=O)C.CCOC(C)=O>[O:82]=[C:75]1[C:76]2[C:81](=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@H:72]([N:71]2[C:5](=[O:1])[C:4]3[C:31](=[CH:30][CH:29]=[CH:38][CH:37]=3)[C:32]2=[O:39])[CH2:73][CH2:74]1
Reactant: N[C@@H]1CCC(=O)c2ccccc21
Reactant: C1COCO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1
Agent: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](N2C(=O)c3ccccc3C2=O)c2ccccc21

Procedure:
1,3-Dioxolane of (R)-tert-butyl 4-fluoro-2-(5-nitro-4-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-2-ylamino)phenylcarbamate. A solution of tert-butyl 4 fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (170 mg), 1,3-Dioxolane of (R)-4-amino-3,4-dihydronaphthalen-1(2H)-one (85 mg), and TEA (0.2 mL) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by PTLC (EtOAc/hexane, 50/50) to afford 150 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CCO.[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 3-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-1H-indole (10.0 g, 39.2 mmol) and 10% Pd/C (1.0 g) in 100 mL of EtOH was placed under 40 psi of H2 and shaken at 23° C. for 3 h. The Pd/C was removed via filtration, and the solvent evaporated. Flash chromatography (CH2Cl2/MeOH) gave 8.66 g (33.7 mmol, an 86% yield) of the title compound as a white solid. MS (ES) m/z (relative intensity): 258 (M++H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)O)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:33])=O>C(Cl)(Cl)Cl>[Cl:33][CH:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(Cl)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The reaction was performed in two batches of starting material (0.250 g and 0.324 g) according to the following procedure. The crude reaction mixtures were recombined and used in the subsequent step without additional purification or characterization. To a suspension of (2-methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanol (0.324 g, 0.780 mmol) in chloroform (3.90 mL) at 0° C. was added dropwise thionyl chloride (0.153 mL, 2.090 mmol). The reaction was stirred at 0° C. for 45 min then at room temperature overnight. Additional thionyl chloride (0.05 mL) and reaction time (5 h) were necessary to drive the reaction to completion. The reaction was quenched with water and neutralized with sodium carbonate. 5-(Chloro(2-methoxypyridin-4-yl)methyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine was obtained as a yellow oil not further purified or characterized. MS (ESI): m/z 434.2 [M+1]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[CH:11]=[CH:12][C:13]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[O:14])=[CH:4][CH:3]=1.[CH3:32][I:33]>CN(C)C=O>[I-:33].[CH3:32][N+:21]1([CH2:20][C:19]2[CH:27]=[CH:28][C:16]([NH:15][C:13](=[O:14])[CH:12]=[CH:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH:9]=3)=[CH:17][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CI
Reactant: O=C(C=Cc1cccc(-c2ccc(F)cc2)c1)Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C=Cc3cccc(-c4ccc(F)cc4)c3)cc2)CCCCC1
Product: [I-]

Procedure:
A solution of Compound 83 (0.25 g) and methyl iodide (0.2 ml) in dimethylformamide (5 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol to give 1-methyl-1—(4—(3—(4-fluorophenyl)cinnamoylamino)benzyl)piperidinium iodide (Compound 87) (0.27 g) as pale brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1)[O:12][C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-5-(trifluoromethyl)phenol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[O:34][CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:34][CH3:35])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: COc1c(CBr)ccc2ccccc12
Product: COc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 3 (c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethyl-1-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[1 -methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)[OH:16]>>[C:1]([NH:4][C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[CH2:7][CH2:6][Cl:5])(=[O:16])[CH:2]=[CH2:3]
Reactant: O=S(=O)(O)O
Reactant: C=CC#N
Reactant: C=C(C)CCC(=O)CCCl
Product: C=CC(=O)NC(C)(C)CCC(=O)CCCl

Procedure:
The title compound is prepared by the Ritter reaction of acrylonitrile with 7-chloro-2-methyl-5-oxo-1-heptene in the presence of sulfuric acid. ##STR25##
Reaction SMILES: [CH:1]([CH:3]([CH2:9][N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18])[C:4]([O:6]CC)=O)=O.CCN(CC)CC.[C:26]1([CH2:32][NH:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl>C1(C)C=CC=CC=1>[CH2:32]([N:33]1[C:4](=[O:6])[CH:3]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:1]=[N:34]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCC1CC(=O)N(CC(C=O)C(=O)OCC)C1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CC2C=NN(Cc3ccccc3)C2=O)C1
Temperature: 40 °C
Yield: 14 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate x280 (0.9 g) in PhMe (10 ml) is added onto a solution of Et3N (1.6 ml) and PhCH2NHNH2.2HCl (0.75 g, 0.0039 mol.) in PhMe (30 ml) at room temperature. The mixture is heated up to 40° C. for 12 h, cooled down to room temperature, washed with NH4Cl (saturated) and the aqueous layer is acidified to pH 3 by addition of HCl (5 N). After 3 extractions with EtOAc, the organic layers are dried over MgSO4, concentrated in vacuo to afford the crude reaction mixture which is purified by chromatography on silicagel (first purification with CH2Cl2/MeOH/NH4OH 98/018/0.02; second purification with EtOAC/iPrOH 95/5; third purification by preparative reverse phase LC/MS) to afford 2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-one x281 as a red oil (0.18 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:37][C:38]([O:40][CH3:41])=[O:39])[C:8]([O:35][CH3:36])=[C:9]([NH:11][C:12](=[O:34])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](C(O)=O)[CH:26]=3)=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.CNC.[CH3:64][N:65]([CH:67]=[O:68])[CH3:66]>O>[CH3:41][O:40][C:38](=[O:39])[NH:37][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:67](=[O:68])[N:65]([CH3:66])[CH3:64])[CH:26]=3)=[CH:16][CH:15]=2)=[O:34])[C:8]=1[O:35][CH3:36]
Reactant: CN(C)C=O
Reactant: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)N(C)C)c3)c3ccccc23)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a cold solution (0° C.) of 4-{4-[3-(5-tert-butyl-2-methoxy-3-methoxycarbonylamino-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid (Example 14) (56 mg, 0.1 mmol) in DMF (1 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and triethyl amine (0.070 mL, 0.5 mmol). The solution was allowed to stir at 0° C. for 30 min, then dimethylamine (2M solution in THF, 0.25 mL, 0.5 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 12 h. Water (4 mL) was added and the product was extracted with EtOAc, dried over magnesium sulfate and concentrated via rotary evaporation. The resulting crude solid was purified by column chromatography (CH2Cl2:MeOH, 95:5) to provide the title compound as a light tan solid (45 mg, 77% yield).
Reaction SMILES: [NH2:1][C:2](=S)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][NH2:10].O.O=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O>C(O)C>[C:16]1([C:13]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:9]=[N:10][CH:14]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN
Reactant: O=CC(=O)c1ccccc1
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nncc(-c2ccccc2)n1
Reaction time: 1 h
Yield: 58.6 %

Procedure:
In a 500 mL three-neck round bottom flask, ethyl 2-amino-2-thioxoacetate (2.5 g, 18.77 mmol) was mixed with ethanol (25 mL). To this orange solution was added via addition funnel a solution of hydrazine (0.590 mL, 18.77 mmol) in Ethanol (15 mL) over 5 minutes. The reaction mixture was stirred for 1 hr. 2-oxo-2-phenylacetaldehyde hydrate (2.86 g, 18.77 mmol) was added to the above mixture and the mixture was stirred overnight at r.t. under N2. The mixture was concentrated and diluted with 10 ml CH2Cl2 and purified by BIOTAGE® with 0-20% EtOAc in CH2Cl2. The fractions containing the product were concentrated to give 2.52 g titled product. MS (ESI) m/z 229.95 (M+H)+. 1H NMR (DMSO-d6) δ ppm 9.82 (s, 1H), 8.30 (d, 2H, J=8.6), 7.7-7.6 (m, 3H), 4.65 (q, 2H, J=7.1), 1.55 (t, 3H, J=7.1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: NCCOCCO
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: OCCOCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-(2-amino-ethoxy)-ethanol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 111-119° C.; LC-MS: 460 (MH+); HPLC RT: 3.40 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10](Cl)[N:9]=1>C(O)C>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(N4CCOCC4)nc(Cl)nc32)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Morpholine (0.8 ml) and ethanol (10 ml) were added to tert-butyl(3S)-3-(2,6-dichloro-9H-purin-9-yl)pyrrolidine-1-carboxylate (1.55 g, 4.3 mmol) and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.76 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:31](=[O:32])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CNCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 101.3 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10](=[S:13])[NH:11][N:12]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10]([S:13][CH3:15])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2F)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccccc2F)n1C

Procedure:
A mixture of 5-(2-fluorophenyl)-2,4-dihydro-4-methyl-3-H1,2,4-triazole-3-thione (4.56 g, 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1.5 ml, 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated and the concentrate was treated with water. The aqueous mixture was extracted three times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a pale yellow oil which was purified by chromatography and kugel rohr distillation, affording a pale yellow oil: bp=190°-197° C. (0.3 mm).
Reaction SMILES: [I-:1].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N+](C)(C)C.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[I-:1].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1cccc1C[N+](C)(C)C
Agent: [I-]
Solvent: CC#N
Product: Cn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 80.6 %

Procedure:
(1-Methylpyrrol-2-yl)methyltrimethylammonium iodide (55.3 g, 198 mmol) was suspended in acetonitrile (400 mL) and triphenylphosphine (62.2 g, 237 mmol) was added thereto, followed by stirring of the mixture at 80° C. for 10 hours. After cooling, the mixture was concentrated to about 1/2 under reduced pressure, ethyl acetate (200 mL) was added thereto, and the precipitated crystal was collected by filtration. The crystal was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (77.1 g, yield: 81%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:8]=1[NH:15][C:16](=[O:32])[CH2:17][CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.O>C(Cl)Cl>[S:34]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:8]=1[NH:15][C:16](=[O:32])[CH2:17][CH:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[O:25][C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:33])(=[O:36])=[O:35]
Reactant: CSc1cccc(COCCCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(COCCCOS(C)(=O)=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1 h

Procedure:
212 mg (0.48 mmol) of N-[2-(3-hydroxypropoxy)methyl-6-methylthiophenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 4) were suspended in 15 ml of methylene chloride. The suspension was cooled on an ice bath, and then 102 mg (0.89 mmol) of methanesulfonyl chloride were added, followed by 94 mg (0.90 mmol) of triethylamine. The temperature of the reaction mixture was allowed to rise to room temperature, after which the mixture was stirred for an additional 1 hour. At the end of this time, the reaction was stopped by the addition of water. The mixture was then diluted with methylene chloride, after which the organic layer was washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure, to obtain 251 mg (a quantitative yield) of the title compound as crystals. These crystals were used for the next step without purification.