Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2Cl)n1
Reaction time: 96 h
Yield: 90.6 %

Procedure:
4.2 g of 6-(2-chlorophenyl)-2-methylpyridine was dissolved in 100 ml dioxane, 1.8 g of selenium dioxide (Aldrich, Gold Label) was added and the mixture was refluxed for 16 hours. The solution was decanted, fresh selenium dioxide (1.8 g) was added and refluxing was continued for a further 4 days. The solids were filtered and 250 ml ether was added. The organic solution was washed five times with 50 ml H2O, dried over magnesium sulfate. Evaporation afforded an oil which was filtered through silica gel eluting with 30% ether-hexane to afford 3.2 g of 6-(2-chlorophenyl)-2-pyridinecarboxaldehyde as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.C(N(CC)CC)C.CC(C(Cl)=O)[C:28](Cl)=[O:29].[C:34]([O:37][CH2:38]C)(=[O:36])[CH3:35]>>[CH3:18][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][C:15]=1[CH3:17])[NH:1][C:28](=[O:29])[C:35]([C:34]([O:37][CH3:38])=[O:36])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: CCOC(C)=O
Reactant: Cc1cc(N)c(C(=O)c2ccccc2C)cc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2C)c2cc(C)c(C)cc2[nH]c1=O

Procedure:
To a mixture of 2-amino-4,5,2'-trimethylbenzophenone (4.8 g), triethylamine (5.6 ml) and ethyl acetate (80 ml) was dropwise added methyl malonyl chloride (4.88 g) under ice-cooling and stirring. The mixture was stirred for an hour under ice-cooling, washed with water, dried (MgSO4) and concentrated to remove the solvent. The oily product was dissolved in toluene (60 ml), and DBU (0.3 g) was added to the solution. The solution was refluxed for 30 minutes with removal of water using Dean-Stark's apparatus. The resulting solution was washed with diluted hydrochloric acid and water, dried (MgSO4) and concentrated to obtain methyl 1,2-dihydro-6,7-dimethyl-4-(2-methylphenyl) -2-oxo-3-quinolinecarboxylate as crystals (5.3g, 82.6%}. Recrystallization from ethanol - chloroform gave colorless needles. mp 288°-289° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[CH:13]=[CH:17][CH:16]=[CH:15]1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1-n1cccc1
Yield: 96.6 %

Procedure:
1.37 g (9.9 mmol) 2-nitro-anilin and 1.3 ml (11 mmol) of 2,5-dimethoxy-tetrahydrofuran was refluxed for 1 hour in 20 ml acetic acid. The reaction mixture was evaporated and the residue was diluted in EtOAc and washed with water, NaHCO3 (sat.), water, and then dried over Na2SO4. The solvent was evaporated and 1.8 g (96%) of 1a was obtained as an oil.
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:28]=1.[F:39][C:40]1[C:45]2[CH2:46][O:47][CH2:48][O:49][C:44]=2[C:43]([O:50][CH3:51])=[CH:42][C:41]=1[CH:52]=O.C[Si]([C:58]#[N:59])(C)C>C1COCC1>[F:39][C:40]1[C:45]2[CH2:46][O:47][CH2:48][O:49][C:44]=2[C:43]([O:50][CH3:51])=[CH:42][C:41]=1[CH:52]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[CH:33][CH:34]=1)[C:58]#[N:59]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: COc1cc(C=O)c(F)c2c1OCOC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c(F)c2c1OCOC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 45 mg of Yb(OTf)3 in 3 ml of THF there were added 126 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 153 mg of 5-fluoro-8-methoxy-4H-benzo[1,3]dioxine-6-carbaldehyde, 0.2 g of MS3A and 192 μl of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with THF. The organic layer was concentrated under reduced pressure to give (5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).
Reaction SMILES: CS[C:3]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:12])(=[O:11])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)[CH3:15]>C(O)C>[CH3:15][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]2[C:7]3=[CH:8][S:9][CH:10]=[C:6]3[S:5](=[O:11])(=[O:12])[N:4]=2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC1=NS(=O)(=O)c2cscc21
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)c3cscc32)o1
Reaction time: 1.5 h

Procedure:
To a suspension of 1.8 g. (0.0082 m.) of 3-(methylthio)thieno[3,4-d]isothiazole-1,1-dioxide in 10 ml. of ethanol is added 1.76 g. (0.0082 m.) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine with stirring at room temperature. The reaction mixture is heated to reflux and heating is continued for 1.5 hours. At this time the reaction mixture is filtered to remove insoluble material and then evaporated to dryness. The product is purified using a silica gel column with methanol as the eluant. The desired fraction was evaporated to dryness and then triturated with ether to give 120 mg. a white solid with a m.p. 100°-103° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 103.9 %

Procedure:
A mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (7), 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulphuric acid is heated under reflux for 1.5 hours. Thereafter, the hot suspension is poured onto ice, and the precipitate is filtered off under suction, rinsed thoroughly with water and dried in vacuo at 100° C. In this manner, 88.9 g of pure 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid II of melting point 228°-230° C. (decomposition) are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC([NH:69][CH2:70][C:71](O)=[O:72])=O)(C)(C)C>C(Cl)Cl.CC(=O)OCC>[NH2:69][CH2:70][C:71]([NH:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)=[CH:8][C:7]=1[CH3:29])=[O:72]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(O)CNC(=O)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
A solution of 3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (70 mg, 0.164 mmol, Example 99) in DCM (3 mL) is treated with DIPEA (85 mg, 0.655 mmol), TBTU (74 mg, 0.23 mmol) and tert. butoxycarbonyl glycine (43 mg, 0.246 mmol) and the reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 and brine. The organic extract is dried over MgSO4, filtered and evaporated. The residue is dissolved in DCM (2 mL) and TFA (0.1 mL) is added. The mixture is stirred at rt for 3 h before another portion of TFA (0.02 mL) is added. Stirring is continued for 1 h. The mixture is diluted with EA, washed twice with a sat. aq. NaHCO3 solution, dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM:methanol 9:1 to give 2-amino-N-(3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-2-hydroxy-propyl)-acetamide (3 mg) as a colourless resin; LC-MS: tR=0.86 min, [M+1]+=485.33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:39])=[C:15]([C:19]2[N:20]=[C:21]([C:35]([CH3:38])([CH3:37])[CH3:36])[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>CN(C)C=O>[CH3:38][C:35]([C:21]1[S:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[O:33])[N:25]=2)=[C:19]([C:15]2[C:14]([F:39])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=2)[N:20]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)O)n2)s1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)N3CCOCC3)n2)s1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoic acid (200 mg, 0.347 mmol) was taken up in N,N-dimethylformamide (DMF) (2 ml). HATU (0.158 g, 0.416), DIEA (0.134 g, 1.041 mmol), and morpholine (0.060 g, 0.694) were added. After 30 min, the reaction mixture was concentrated and residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column) to obtain the title compound (147 mg, 53%) as white solid. MS (ESI): 646 [M+H]+.
Reaction SMILES: C[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]([Li])(C)(C)C.CCCCC.[CH2:21]([C:28]1([N:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([C:28]1([N:35]([CH3:36])[CH3:37])[CH2:29][CH2:30][C:31]([C:2]2[N:3]([CH3:11])[C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:34])[CH2:32][CH2:33]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: [Li]C(C)(C)C
Reactant: Cc1cc2ccccc2[nH]1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of 2-methylindole (500 mg, 3.81 mmol) in dry THF (20 ml) is cooled to −5° C. under a stream of argon. Thereafter, tert-butyllithium (4.19 mmol, 2.47 ml of a 1.7 M pentane solution) is cautiously added dropwise such that a reaction temperature of 0° C. is not thereby exceeded. When the addition has ended, the reaction mixture is stirred at 0° C. for 2 h. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (Ket-3, 880 mg, 3.81 mmol) in dry THF (7 ml) is added dropwise at 0° C. The mixture is stirred at 0° C. for 15 min and then at room temperature for 4 h. The reaction mixture is quenched with saturated ammonium chloride solution (20 ml), the organic phase is separated off and the aqueous phase is extracted four times with methylene chloride (20 ml). The combined organic phases are dried over sodium sulfate and thereafter the solvent is removed in vacuo. Purification is carried out by means of flash chromatography (silica gel, cyclohexane/EtOAc 8:2). 456 mg (33%) of the desired cyclohexanol with a melting point of m.p.=105-107° C. are obtained. Only 1 of 2 possible diastereoisomers is formed.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.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>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
A 250-mL 3-necked round-bottom flask was charged with a solution of 4-bromo-3-nitrobenzaldehyde (11.5 g, 50.00 mmol, 1.00 equiv) in toluene (80 mL). To this was added phenylboronic acid (6.7 g, 54.92 mmol, 1.10 equiv), followed by the addition of a solution of K2CO3 (13.8 g, 100.00 mmol, 2.00 equiv) in water (50 mL). To the mixture was added Pd(PPh3)4 (1.2 g, 1.04 mmol, 0.02 equiv) in one portion. The resulting solution was stirred at 110° C. for 15 hours. Upon completion, the reaction mixture was cooled down to room temperature. The resulting solution was diluted with 1000 mL of Et2O. The solids were filtered out. The resulting organic layers were washed with water (3×300 mL), dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50) to afford 2-nitrobiphenyl-4-carbaldehyde as yellow solid (6.7 g, 59%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:4]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32].CCN(C(C)C)C(C)C>CN(C=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][N:5]1[C:6]2=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[C:3]([CH2:2][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:4]1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCO
Product: COCCOCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OC)cc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (4 mL, 0.197M in CH2Cl2, 0.788 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (10 mL) was added 2-(methoxyethoxy)-ethanol (0.47 g, 3.94 mmol, 0.43 mL, 5 eq.) followed by i-Pr2NEt (0.407 g, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed and eluted with CH2Cl2-EtOAc 70:30 v/v, 0.4 L, CH2Cl2-EtOAc-MeOH 80:18:2 1.0 L, and CH2Cl2-EtOAc-MeOH 80:17.5:2.5 1.0 L, 25 mL fractions) using the flash technique. Fractions 42-80 were combined to afford 0.339 g (78%) of methyl 1-(2,4-difluorobenzyl)-3-{[2-(2-methoxyethoxy)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate: 2-(methoxyethoxy)-ethanol (1:1) as a clear, colorless, viscous oil.
Reaction SMILES: [Na].[H][H].Cl[C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([CH3:22])[N:9]2[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1.[CH3:23][OH:24]>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[C:8]([CH3:22])=[N:7][C:6]3[C:10]2=[N:11][CH:12]=[N:13][C:5]=3[O:24][CH3:23])=[CH:15][CH:16]=1)#[N:21]
Reactant: CO
Reactant: [H][H]
Reactant: Cc1nc2c(Cl)ncnc2n1-c1ccc(C#N)cc1
Agent: [Na]
Product: COc1ncnc2c1nc(C)n2-c1ccc(C#N)cc1
Yield: 83 %

Procedure:
Sodium metal (160 mg, 6.96 mmol) was allowed to react with dry methanol (5 ml) under nitrogen until evolution of hydrogen had ceased. 6-Chloro-9-(4-cyanophenyl)-8-methylpurine (1.03 g, 3.82 mmol) was added in one portion and the resulting slurry was heated under reflux for 90 minutes. The solvent was removed under reduced pressure and the residual gum was dissolved in dichloromethane (50 ml). The solution was washed with brine (20 ml), dried (MgSO4) and concentrated under reduced pressure to give the title compound, (840 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N.S(=O)(=O)(O)O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:10]([NH2:29])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(N)=O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A suspension of (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid (11.9 g, 33.2 mmol, >99.9% ee) in acetonitrile (36 ml) is admixed at −15° C. with a solution of 1,1′-carbonyldiimidazole (8.36 g, 51.6 mmol) in acetonitrile (125 ml), and the reaction mixture is stirred for 2 h at this temperature. Ammonia (4.0 g, 222 mmol) is then introduced, and the mixture is stirred for further 1 h and then adjusted to pH 4.5 using 2N sulfuric acid. Acetonitrile is distilled off, and the precipitated solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (11.3 g, 95%, >99.9% ee) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.Cl[CH2:18]SC.O>CS(C)=O>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH2:18]1
Reactant: Clc1ccccc1CNCCc1cccs1
Reactant: CSCCl
Solvent: CS(C)=O
Solvent: O
Product: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 60 °C
Yield: 142.2 %

Procedure:
To 52 g (0.2 M) N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine dissolved in 60 ml dimethylsulfoxide and heated at 60° C. are added, over 30 minutes, 51 g (0.3 M) crude chloromethylmethylthioether prepared in step (a) above. The temperature of the reaction medium increases gradually and it is maintained at 80°-85° C, throughout the addition step, by cooling with water. When addition of chloromethyl methylthioether is completed, the medium is cooled to 6° C. The desired product precipitates out readily. After filtration and washing with 2×70 ml acetone, there are obtained 44.1 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride (Yield: 73.5%). Treatment of the filtrates provides another 10 g of the desired product (Yield: 90% M.p.=190° C.). The resulting crude product contains 1-2% impurities and may be made analytically pure by recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Cl:9][C:3]1[C:2]2[N:1]=[C:19]([NH:18][C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:20][C:7]=2[N:6]=[CH:5][N:4]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CC(C)=O
Product: O=C(Nc1nc2c(Cl)ncnc2s1)c1ccccc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A mixture of 5-amino-4,6-dichloro-pyrimidine (5.0 g, 30.49 mmol) in acetone (30 mL) at 25° C. was treated with benzoyl isothiocyanate (5.5 g, 33.54 mmol). The mixture was stirred at reflux for 6 h and then was cooled to 25° C. The resulting solids were collected by filtration, washed with acetone and petroleum ether and dried in vacuo to afford N-(7-chloro-thiazolo[5,4-d]pyrimidin-2-yl)-benzamide (7.87 g, 79%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:15]=[C:16]([C:24]2O[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:24]2[C:2]3[CH2:3][CH2:4][CH2:5][C:1]=3[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:22])([F:23])[F:21]
Reactant: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Reactant: C1=CCCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Temperature: 230 °C
Yield: 50.1 %

Procedure:
The reaction was performed on a custom-made flow system consisting of a Dionex P580 pump and a HP 6890 Series Gas Chromatography oven used as a heating source. The GC oven was equipped with a stainless steel coil reactor (53 mL volume) made from Supelco stainless steel tube (ID=2.1 mm). After heating to 230° C. using toluene as a system solvent, a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL), a mixture of 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (0.30 g, 1.30 mmol), cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) and finally a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) were injected onto the stainless steel coil reactor in sequential order. The system was run at a flow rate of 0.35 mL/min equaling to a nominal residence time of tR=150 min and an effective residence time of tR,eff=120 min taking the 25% volume expansion of toluene at 230° C. into account (R. E. Martin et al., Eur. J. Org. Chem. 2012, 47-52). A 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool) was used at the exit of the reactor to maintain system pressure. The reaction mixture was collected in a round bottom flask, triethylamine (5 mL) was added and the solvent mixture removed under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (183 mg, 50%) as a slightly brown solid. MS: 282.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][CH:15]=[CH:16][C:11]3=[CH:10][C:9]=2[C@@H:17]([NH2:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][CH:15]=[CH:16][C:11]3=[CH:10][C:9]=2[C@@H:17]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2ccsc2nc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccsc2nc1-c1cccc(F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
In a reaction flask was combined (1S)-1-(6-(3-fluorophenyl)thieno[2,3-b]pyridin-5-yl)ethanamine (39 mg, 143 μmol), 6-chloropurine (24 mg, 158 μmol), Hunig's Base (38 μL, 215 μmol) and n-butanol (1.5 mL). The solution was heated to 110° C. After 24 h, the solvent was removed and the residue purified by column chromatography using a 0-70% gradient of (90:9:1 CH2Cl2:MeOH:NH4OH) in CH2Cl2 to afford N—((S)-1-(6-(3-fluorophenyl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 12.90 (br s, 1H), 8.51 (br s, 1H), 8.34 (br s, 1H), 8.10 (m, 2H), 7.88 (d, J=5.9 Hz, 1H), 7.59 (m, 3H), 7.45 (d, J=5.9 hz, 1H), 7.30 (br t, J=6.3 Hz, 1H), 5.60 (br s, 1H), 1.44 (br d, J=5.1 Hz, 3H) ppm. LC/MS (M+1, found=391.1).