Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:9]([CH2:41][OH:42])([OH:40])[C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([OH:31])[C@:11]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:22])[C:12](C(=O)C1C=CC=CC=1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:43].CC(O)=O>ClCCl>[Br:43][C:12]([C@:11]([C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:41][OH:42])[OH:40])[OH:31])[OH:22])=[O:13]
Reactant: O=C(C(=O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1)c1ccccc1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Crude tetra-benzoyl-L-ribose 20 (17.0 g, 30.0 mmol) was dissolved in dichloromethane (150 mL) under an atmosphere of argon at 0° C. To this solution was added 33% HBr in AcOH (32.6 mL, 180.0 mmol of HBr) and the reaction was stirred for 30 min at 0° C. then brought to room temperature for 30 min. Dichloromethane (150 mL) was added and the reaction mixture was washed with 125 mL of cold water, dilute NaHCO3, two times with saturated NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo to give 21 as a off-white solid (13.3 g, 25.3 mmol, 84%). This material was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[OH:23][C:24]1C=CC(NC(N)=S)=CC=1.C(=O)C>C(Cl)Cl.CO>[CH3:24][O:23][C:19]1[CH:20]=[C:15]([C:12]2[S:11][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[N:14][CH:13]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Nc2ncc(-c3ccc(OC)cc3)s2)cc1
Reactant: NC(=S)Nc1ccc(O)cc1
Agent: CC=O
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(-c2cnc(Nc3ccc(O)cc3)s2)c1

Procedure:
The title compound is prepared as described in Example 4 for (4-methoxy-phenyl)-[5-(4-methoxy-phenyl)-thiazol-2-yl]-amine but using (4-hydroxy-phenyl)-thiourea and 3-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 312.9 [M−H]−; single peak at tR=6.81 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:34])[CH2:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>O1CCCC1.O>[OH:34][CH:15]([C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[CH2:16][CH2:17][C:18]1[S:22][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH3:33]
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl [2-methyl-4-(3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propanoyl)phenoxy]acetate (intermediate11, 0.28 g) in tetrahydrofuran (8 ml) and water (8 ml) at 0° C. was treated portion-wise with sodium borohydride (0.043 g) and the mixture was stirred at 0° C. for 1 hour. The solvent was evaporated and the residue partitioned between water and ethyl acetate; the aqueous layer was separated and extracted twice more with ethyl acetate. The combined organic solutions were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a colourless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:14](O)=O>>[Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[NH:12][CH:14]=[N:13][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cc(Br)c(C(F)(F)F)cc1N
Product: FC(F)(F)c1cc2[nH]cnc2cc1Br
Temperature: 120 °C
Reaction time: 6 h

Procedure:
4-Bromo-5-trifluoromethyl-benzene-1,2-diamine (200 mg, 0.785 mmol) was dissolved in formic acid (3 ml), and the mixture was stirred at 120° C. for six hours. The reaction solution was concentrated, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-bromo-6-trifluoromethyl-1H-benzimidazole (201 mg) as a crude compound.
Reaction SMILES: O[CH:2]([C:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19]OC3CCCCO3)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[S:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].C([SiH](CC)CC)C.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl.O>[F:50][C:49]([F:52])([F:51])[C:47]([O:53][CH2:19][CH2:18][CH2:17][N:13]1[C:14](=[O:16])[C:15]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:5])[CH3:6])=[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:38])([F:39])[F:37])[CH:30]=3)[S:9][C:10]=2[N:11]([CH3:28])[C:12]1=[O:27])=[O:48]
Reactant: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)CCc1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)n2C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 22, Step 3, 40 mg, 0.070 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at RT for 48 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3 (4H)-yl)propyl 2,2,2-trifluoroacetate (35 mg, 88.1% yield) as an oil. LCMS: MH+ 567 and TR=2.383 min.
Reaction SMILES: [C:1]([CH:5]1[C:10]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[CH3:20])=[CH:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][C:25]=12>>[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:10]4[CH:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:6][CH2:7][CH2:8][CH:9]=4)=[C:12]([CH3:20])[CH:13]=3)=[O:16])[CH2:26][C:25]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1C(C)(C)C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1C(C)(C)C
Yield: 95.5 %

Procedure:
4-(6-tert-Butyl-cyclohex-1-en-1-yl)-3-methyl-benzoic acid of Step B (0.104 g, 0.382 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.077 g, 0.420 mmol) were reacted in the manner of Example 15, Step D: Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from pentane afforded the title compound (0.160 g) as white crystals, m.p. 127–129° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38](O)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38]([N:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc([C@@H](CN2CC[C@H](OC3CCCCO3)C2)NOC2CCCCO2)cc1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N(OC1CCCCO1)[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Yield: 69.8 %

Procedure:
This was prepared from 1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrroidin-1-yl)ethylamine and 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brown Viscous oil according to a procedure similar to that described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20]([NH2:21])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[N:18][CH:17]=[CH:16][CH:15]=4)[C:20]=3[NH:21][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1c(C(=O)c2ccc(F)c(F)c2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)c(F)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 49 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7-[(3, 4difluorophenyl)carbonyl]-8-aminoquinoline (Intermediate 377) (100 mg, 0.35 mmol), N-methylsulfamoyl chloride (Intermediate 213) (105 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (62 mg, 47%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH3:24]>C(Cl)Cl>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:22][O:23][CH3:24])[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(C#N)cc1OC
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A solution of 4-hydroxy-3-methoxy-benzonitrile (11, 1.5 g, 10 mmol) and diisopropylethylamine (2.7 mL, 15 mmol) in CH2Cl2 (50 mL) was treated with chloromethylmethylether (0.92 mL, 12 mmol) and stirred for 3 h. After diluted with CH2Cl2, the mixture was washed with H2O, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (1:2) as eluant to give 12 as white solid (1.54 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:27][CH:26]=1)#[N:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH3:22])[C:33](=[O:35])[CH2:32][CH2:31][C:28]4[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C(=O)CCc1ccc(C#N)cc1)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-methylamino-benzimidazole (0.9 g, 3.1 mmol), 3-(p-cyanophenyl)-propionic acid (0.6 g, 3,4 mmol) and 0.5 mL of N-methylmorpholine are taken up in 10 mL of dimethylformamide. TBTU (1.2 g, 3.7 mmol) is added and the mixture is stirred for 16 h at ambient temperature. After dilution with 75 mL of ethyl acetate the mixture is washed with dilute aqueous NaOH or saturated NaHCO3 solution and with water, dried and evaporated down. The product is crystallised from ethyl acetate/diethylether.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)(C)C.[OH-].[Na+]>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27]
Reactant: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (47 mg, 125 μmol) in isopropanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) and the mixture is stirred at 70° C. for 14 h. Another portion of (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) is added and stirring is continued at 70° C. for 24 h. The solvent is removed in vacuo and the residue is separated on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (15 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.18.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClC1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:20]([C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:5])=[O:7])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:18][CH3:19])(=[O:22])[CH3:21]
Reactant: COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Temperature: 0 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
To 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (310 mg, 1.18 mmol) dissolved in 9 mL of chlorobenzene was added acetyl chloride (0.3 mL, 3.6 eq). The solution was cooled to <0° C. while titanium tetrachloride (0.61 mL, 4.8 eq) was added dropwise. The reaction mixture was stirred at 0° C. and below for 6 h and then heated in an 85° C. oil bath for 3.5 h. The reaction mixture was poured into ice/water, and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Removal of the solvents in vacuo gave 167 mg (57% yield) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[O:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution cooled to r.t. and concentrated under reduced pressure to give a white solid which was dissolved in methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to afford 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(N(CC)CC)C>ClCCl>[O:30]([C:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)Oc3ccccc3)cc1[C@@H](NC(C)=O)CC2
Yield: 79 %

Procedure:
A solution of N-acetyl colchicinol (0.35 g; 0.98 mmol), phenyl chloroformate (145 μl; 1.08 mmol) and triethylamine (150 μl; 1.08 mmol) in dichloromethane (20 ml) was stirred at ambient temperature for 1 hour. The mixture was washed with water and the organic phase evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (80/20) to give N-[(5S)-3-phenoxycarbonyloxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C1C(=O)N([Br:22])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:22][C:5]1[S:1][C:2]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
To a solution of produce tert-butyl thiophen-2-ylmethylcarbamate (1.28 g, 6 mmol, 1.0 equiv.) in DMF (4 mL) was added NBS (1.17 g, 6.6 mmol, 1.1 eq). After stirring at 20° C. for 5 h, the reaction mixture was diluted with ethyl acetate and washed with water for three times. The organic layer was dried (MgSO4) and concentrated in vacua. The residue was purified by silica gel column chromatography (PE/EtOAc=100:1 to 5:1) to afford tert-butyl (5-bromothiophen-2-yl)methylcarbamate (1.6 g, 91%). LC-MS (m/z)=235.9 [M−55]+. 1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 4.20 (d, J=6.0 Hz, 2H), 6.76 (d, J=4.0 Hz, 1H), 7.03 (d, J=3.6 Hz, 1H), 7.52 (t, J=5.6 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (50 mg, 145 μmol), 2,5-dichloropyrimidine (43 mg, 287 μmol), and DIPEA (75 mg, 431 mol) in isopropanol was stirred at 120° C. for 1 h in a microwave reactor. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H). 1H NMR (500 MHz, CDCl3) δ 8.25-6.85 (m, 7H), 5.55-2.65 (m, 8H), 1.95-0.85 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:34][CH2:35][O:36][CH:37]3[CH2:39][CH2:38]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs2CO3 (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na2SO4. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). 1H NMR (CDCl3, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52(m, 2H).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:23]C(=O)OCC1C=CC=CC=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])([O:13][CH2:14][C:15]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:7]
Reactant: CC(C)(C)OP(=O)(OCC(C)(NC(=O)OCc1ccccc1)c1ccccc1)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OP(=O)(OCC(C)(N)c1ccccc1)OC(C)(C)C

Procedure:
The product of Example 442B (0.10 g, 0.21 mmol) and 20% palladium hydroxide on carbon (0.02 g) in ethyl acetate (1 mL) and methanol (1 mL) was stirred under an atmosphere of hydrogen or 18 hours. The reaction was filtered through a bed of celite and concentrated to give the title compound, which was used without further purification (0.073 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][N:3]=1.Cl.[C:12](=[NH:17])(OCC)[CH3:13]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:10])[C:12](=[NH:17])[CH3:13])=[CH:4][N:3]=1
Reactant: CNCc1ccc(Cl)nc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CC(=N)N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 191.5 %

Procedure:
To 40 ml of ethanol was added 5.1 g of N-(2-chloro-5-pyridylmethyl)-N-Methylamine and then 4 g of ethyl acetimidate hydrochloride at 0° C. After stirring for an hour, the reaction mixture was allowed to warm to room temperature and stirred over night. The solvent was then distilled off. The obtained white residue was washed with diethyl ether to afford 7.3 g of the title compound m.p. 192°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)=[O:10].[OH:18][C@H:19]1[CH2:23][CH2:22][O:21][CH2:20]1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O[C@H]1CCOC1
Reactant: O=C(c1ccc(F)cc1)c1cc(I)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccc(O[C@H]2CCOC2)cc1)c1cc(I)ccc1Cl
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 60.56 g (2-chloro-5-iodo-phenyl)-(4-fluoro-phenyl)-methanone in 170 mL of tetrahydrofuran and 16.46 g of (S)-3-hydroxytetrahydrofuran is added 26 g of potassium tert-butoxide in 250 mL of tetrahydrofuran at 0 to 5° C. The solution is stirred at 10° C. for 0.5 hour. The reaction is quenched with 170 mL of water and 170 mL of methyl tert-butyl ether at 0 to 25° C. The product is washed with 170 mL of brine (3 weight-%). The solvent is removed upon evaporation and crystallized in 220 mL of iso-propylacetate.