Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[NH2:10][C:11]1[N:12]=[C:13]([NH2:34])[C:14]2[C:20]([CH3:21])=[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:18](=O)[NH:17][C:15]=2[N:16]=1.C(O)C>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:12]=[C:13]([NH2:34])[C:14]2[C:20]([CH3:21])=[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:18]([Cl:8])=[N:17][C:15]=2[N:16]=1
Reactant: COc1ccc(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(Cc2c(Cl)nc3nc(N)nc(N)c3c2C)cc1OC
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of dimethylformamide (17.5 g) in chloroform (75 ml) was added thionyl chloride (28.6 g) in chloroform (25 ml) at 0°-5° C. The reaction mixture was allowed to heat to 55°-60° for about 5 minutes and cooled to 0° C. To the reaction mixture was added over a 20 minute period at 0° C. 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidine (8.2 g). Chloroform (50 ml) was added, and the mixture was heated at reflux for 2.5 hours and cooled. Ethanol in base (50 ml) was added. The resulting brown product was collected by filtration, treated with 2N sodium hydroxide and recrystallized from ethanol to give 7.6 g of crude product. Additional recrystallization from ethanol-water gave 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-chloropyrido[2,3-d]pyrimidine (2 g), m.p. 224°-225° C. (dec.). This was added to ethanol (250 ml) containing potassium hydroxide (0.2 g), 5% palladium on charcoal catalyst (Pd/C, 0.1 g) was added and hydrogenation commenced. Reduction was complete after 4 hours in a Parr low-pressure apparatus at 35-40 psi and gave 2,4-diamino-6-(3,4-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (0.1 g), m.p. 265°-268° C. (dec.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:26]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:22])([CH3:23])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:12]=[O:26])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: C=CC(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Yield: 76 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-enyl (3-chloropropyl]sulfonate (12a) (10.0 g, 27.7 mmol) dissolved in 150 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 4.0 mL (3.4 g, 55 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 7.6 g (76% yield) of the title compound (12b) as a colorless oil. The analytical data was consistent with the proposed structure and the data obtained for the enantiopure compound (11b).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.C(=O)(O)[O-].[Na+]>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][C:23]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:24][CH:25]=1
Reactant: Brc1ccc2ncnc(-c3cccs3)c2c1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 60 °C

Procedure:
14.4 mL chlorosulfonic acid and 14.42 mL thionyl chloride were added to 7.78 g of 6-bromo-4-(2-thienyl)quinazoline (compound in Production Example 96) under ice-cooling in a stream of nitrogen, and the mixture was heated at 60° C. for 16 hours, then poured into iced water, neutralized by adding a sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The residue was recrystallized from ether/hexane, to give 2.47 g of the title compound (pale skin-colored crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[N:49]=[C:50]=[S:51].NC(N)=S>>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[NH:49][C:50]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[S:51]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Fc1cccc(F)c1N=C=S
Agent: NC(N)=S
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3c(F)cccc3F)cn2)cc1
Yield: 102.7 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and 2,6-difluorophenyl isothiocyanate (57.0 μl, 0.441 mmol) instead of o-tolyl isothiocyanate, thiourea was formed in the same manner as Example 1-D-210, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid (2,6-difluoro-phenyl)-amide as a yellow solid (108 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-225) as a yellow powder (59.4 mg, 85%).
Reaction SMILES: [BH4-].[Na+].O.[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[CH:12][NH:13][C:14](=[NH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([O-])=O>[Pd].CO>[NH2:4][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[CH:12][NH:13][C:14](=[NH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: N=C(NC=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(NC=Cc1ccc(N)cc1)c1ccccc1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A nitrogen atmosphere is employed throughout the reaction. A solution of sodium borohydride (3.8 g., 0.1 mole) in 10 ml. of water is added to a suspension of about 200 mg. of 10% palladium on carbon in 10 ml. of water. After 5 min., 200 ml. of methanol is added followed by portion-wise addition of finely powdered N-(4-nitrostyryl)benzamidine (8.0 g., 0.03 mole) over a period of 5 min. During the addition, the mixture refluxes and continues to boil for about 5-10 min. thereafter. The reaction mixture is stirred without external heating for 0.5 hr., filtered through celite, concentrated under reduced pressure and the residue stirred with 25 ml. of water and filtered. The filter cake washed with cold water, dried, and triturated with isopropyl alcohol provides 6.8 g. (86% yield) of N-(4-aminostyryl)benzamidine free base, m.p. 166°-168° C. Treating the free base in methanol with ethanolic hydrogen chloride and evaporating the solvent under reduced pressure provides the crude hydrochloride. Analytically pure N-(4-AMINOSTYRYL)BENZAMIDINE DIHYDROCHLORIDE, m.p. 217.5°-219.5° C. (dec.)(corr.), (60% yield) is obtained by first triturating the crude hydrochloride with acetone and then recrystallizing from methanol-isopropyl ether.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C

Procedure:
90 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-phenylpiperazine (0.034 mL, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)(=[O:25])[CH3:24]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH2:29][CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1c(O)c2cc(O)ccc2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCCCCCOc1c(O)c2cc(OCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-octyloxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-octyloxy-4-hydroxy-6-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:9]([CH3:15])[CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1>Cl>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:9]([CH3:15])[CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CC(C)n1cnc2cc(N)ccc21
Agent: Cl
Product: CC(CC(=O)O)n1cnc2cc(N)ccc21

Procedure:
A solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)butanoate (91 mg, 390 μmol) in hydrochloric acid (5 mL of a 5N solution) was stirred at room temperature for 163 hours. The solution was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=1.54 min, MH+ 220].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](C)=[CH:9][C:8](Br)=[C:7]([Cl:13])[N:6]=1)=[O:4].Cl.[F:15][C:16]1([F:20])[CH2:19][NH:18][CH2:17]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:18]2[CH2:19][C:16]([F:20])([F:15])[CH2:17]2)=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: FC1(F)CNC1
Reactant: COC(=O)c1nc(Cl)c(Br)cc1C
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC(F)(F)C2)c(Cl)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
Under a nitrogen atmosphere a mixture of methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 3 a, 2 g, 8 mmol), 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 1 g, 8 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 0.16 g, 0.16 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 0.19 g, 0.32 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (50 mL) was stirred at 110° C. overnight. After concentration, the residue was partitioned between water (50 mL) and ethyl acetate (40 mL), the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.44 g, 21%) as light-yellow solid; MS (EI): m/e=263.0 [MH+].
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](F)=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: Cc1cc2c(s1)C(O)CNC2
Product: Cc1cc2c(s1)C(Oc1ccc(C#N)c3ccccc13)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=3)[CH2:27][CH2:26]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(Oc3cccc(C(F)(F)F)c3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-[3-(trifluoromethyl)phenoxy]piperidine. MS (+ESI) m/z 437 (MH+).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[ClH:32]>O>[Cl:32][C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1
Reactant: Cl
Reactant: COC(=O)c1sc(N)nc1-c1nccc(N2CCCCC2)n1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(Cl)nc1-c1nccc(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of methyl 2-amino-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 62, 0.070 g, 0.219 mmol) in concentrated HCl (1 mL), sodium nitrite (0.045 g, 0.658 mmol) in water (1 mL) was added drop wise at 0° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 5-10° C. and basified with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with brine solution, dried and concentrated under reduced pressure to obtain methyl 2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate 0.040 g (54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:31])[C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:20]([NH:19][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[NH:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)=[O:31]
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 266 mg, 1.46 mmol), N-[(1S,2S)-2-aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 400 mg, 1.33 mmol), DIPEA (0.70 ml, 3.99 mmol) and DMSO (4.8 ml) was subjected to microwave irradiation at 140° C. for 2 hours. Upon cooling, the resulting mixture was partitioned between ethyl acetate (10 ml) and water (10 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was further purified by trituration with di-isopropylether to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([CH3:9])=[C:6]([C:14]2[CH:13]=[C:12]([Cl:11])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[N:7]=1
Reactant: Cc1c(Cl)nc(N)nc1Cl
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1nc(N)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
To a mixture of 2-amino-4,6-dichloro-5-methyl-pyrimidine (0.18 g, 1.0 mmol), 5-chloro-2-methoxy-phenyl boronic acid (0.19 g, 1.0 mmol), palladium (II) acetate (0.034 g, 0.15 mmol) and triphenylphosphine (0.079 g, 0.30 mmol) was added a solution of sodium carbonate (0.64 g, 6.0 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere at room temperature for 72 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide 2-amino-4-chloro-6-(5-chloro-2-methoxyphenyl)-5-methyl-pyrimidine (0.06 g, 21% yield) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)([CH3:18])[CH2:5][CH2:6][N:7]1[CH2:15][CH2:14][N:13]2[CH:9]([CH2:10][CH2:11][S:12]2(=[O:17])=[O:16])[CH2:8]1.O[Li].O>O.C1COCC1>[Cl:26][C:21]1[CH:20]=[C:19]([C:4]([CH3:18])([CH2:5][CH2:6][N:7]2[CH2:15][CH2:14][N:13]3[CH:9]([CH2:10][CH2:11][S:12]3(=[O:16])=[O:17])[CH2:8]2)[C:3]([OH:27])=[O:2])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)C(C)(CCN1CCN2C(CCS2(=O)=O)C1)c1ccc(Cl)c(Cl)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(CCN1CCN2C(CCS2(=O)=O)C1)(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.16 g (2.6 mmol) 2-(3,4-dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ6-thia-5,7a-diaza-inden-5-yl)-2-methyl-butyric acid methyl ester and 0.123 g (2.9 mmol) LiOH.H2O in 40 mL water and 40 mL THF was stirred at room temperature for 48 h. After evaporation of THF the pH was adjusted to pH=2 with 2N HCl aq., evaporated to dryness, taken up in acetonitrile and evaporated (3×), The residue was dried at 60° C. under high vacuum and used without further purification in the consecutive amide coupling step. MS(m/e): 421.0 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]1[C:27]([C:28]([OH:30])=O)=[CH:26][N:25]=[CH:24]1.FC(F)(F)C(O)=O.[CH3:38][O:39][C:40]1[CH:60]=[CH:59][C:43]([O:44][C:45]2[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]([C:53]3([NH2:56])[CH2:55][CH2:54]3)=[O:52])=[CH:47][CH:46]=2)=[C:42]([C:61]([F:64])([F:63])[F:62])[CH:41]=1>CN(C=O)C>[CH3:38][O:39][C:40]1[CH:60]=[CH:59][C:43]([O:44][C:45]2[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]([C:53]3([NH:56][C:28]([C:27]4[O:23][CH:24]=[N:25][CH:26]=4)=[O:30])[CH2:54][CH2:55]3)=[O:52])=[CH:47][CH:46]=2)=[C:42]([C:61]([F:62])([F:63])[F:64])[CH:41]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: O=C(O)c1cnco1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnco4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
57.5 μL (0.41 mmol) of TEA and 48 mg (0.15 mmol) of TBTU were added to a solution of 15.4 mg (0.14 mmol) of oxazole-5-carboxylic acid in 1.5 mL DMF and the mixture was stirred for 5 min at RT. Then 67.5 mg (0.14 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.Cl.CN(C)CCCl>>[CH3:18][N:3]([CH3:1])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: CN(C)CCCl
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN(C)C)cc1
Yield: 81 %

Procedure:
The title compound was prepared using a similar procedure as described for the preparation of 21 except that 2-(dimethylamino)ethyl chloride hydrochloride was used instead of 2-(diethylamino)ethyl chloride hydrochloride. This produced a crude oil, which was purified by flash silica gel column chromatography (gradient elution from 1:1 hexanes/ethyl acetate to ethyl acetate) to give 22 (580 mg, 81%) as a light yellow oil: MS (ES+) m/z 236.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]I>[Ag]=O.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 80 °C
Reaction time: 13 h
Yield: 89.9 %

Procedure:
1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (1.40 g, 3.89 mmol), N,N′-dimethylformamide (7 ml), silver oxide (9.0 g, 39 mmol) and methyl iodide (24 ml, 389 mmol) were placed in a shaded and sealed tube, and this mixture was stirred for 13 hours in an oil bath of 80° C. The reaction solution was then filtered through cellite (ethyl acetate washing) and the filtrate was then diluted with ethyl acetate (100 ml). The organic layer was then washed with water (50 ml×3) and saturated saline solution (50 ml) in that order, and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 1.31 g (89%) of the title compound was obtained in the form of a pale-yellow syrup an n-hexane:ethyl acetate=2:1 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])[CH:7]=1.[CH3:17][C@@H:18](O)[CH2:19][CH:20]=[CH2:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([O:15][C@H:20]([CH2:19][CH:18]=[CH2:17])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])[CH:7]=1
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cccc(F)c1-c1cc(Br)ccc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cccc(F)c1-c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 77.8 %

Procedure:
5′-Bromo-2′,6-difluoro-[1,1′-biphenyl]-2-ol (520 mg, 1.82 mmol., 1.0 equiv) were mixed with (R)-pent-4-en-2-ol (314 mg, 3.65 mmol, 2.0 equiv) and Ph3P (957 mg, 3.65 mmol, 2.0 equiv) in THF (6 mL). To this solution was added DEAD (1661 μl, 3.65 mmol, 2.0 equiv) dropwise and stirred overnight. The solution was mixed with silica gel and concentrated and purified by 40 g ISCO column with 0-10% EtOAc/hexane to afford 5-bromo-2,2′-difluoro-6′-((S)-pent-4-en-2-yloxy)-1,1′-biphenyl (500 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.42 (m, 2H), 7.34-7.28 (m, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.81-6.74 (m, 2H), 5.81-5.62 (m, 1H), 5.12-4.96 (m, 2H), 4.41 (dq, J=11.7, 5.9 Hz, 1H), 2.44-2.18 (m, 2H), 1.23 (dd, J=7.3, 6.3 Hz, 3H). LCMS (M+1)=353.1.