Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>ClCCl>[Cl:22][CH2:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=1
Reactant: CSc1ncc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(CCl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (0.7813 g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0° C.) was added triethylamine (0.836 mL, 8.2 mmol) followed by the addition of methanesulfonyl chloride (0.465 mL, 6.0 mmol). The reaction mixture stirred at 0° C. under a nitrogen atmosphere for 30 minutes then at room temperature for 3.5 hours. The reaction was quenched with sodium bicarbonate (5%, 100 mL)) and extracted with dichloromethane (50 mL). The organic extracts were concentrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane to afford the desired compound (0.720 g, 82%) as a white solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 175.0106 (M+H C6H7N2ClS requires 175.0091).
Reaction SMILES: [N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH2:23])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>CN(C1C=CN=CC=1)C.ClCCl>[N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH:23][S:30]([C:28]4[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=4)(=[O:32])=[O:31])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2CCC2)CC3)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-ylmethanamine (250 mg, 0.816 mmol) and N,N-dimethyl-4-aminopyridine (199 mg, 1.632 mmol) were dissolved in dichloromethane (18 mL). 1-Methyl-1H-imidazole-4-sulfonyl chloride (147 mg, 0.816 mmol) dissolved in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed successively with saturated ammonium chloride (3×15 mL) and water (2×10 mL). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 64 mg (0.142 mmol, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:21])=[CH:16][CH:15]=1.I[CH2:35][CH3:36]>>[CH2:35]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:32])([F:33])[F:31])[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:36]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C(F)(F)F)cc3)c2)o1
Product: CCN(Cc1ccccc1C(F)(F)F)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.90,(1H. d), 7.78-7.50,(9H, m), 7.38,(1H. b), 4.86-4.68,(2H, m), 3.48-3.32,(2H, b), 2.56,(3H, s), 2.33-2.23,(3H, m), 1.06,(3H, b). LCMS; retention time 3.71 min, MH+ 480.
Reaction SMILES: C([O:3][C:4](=[O:28])[C@:5]([F:27])([CH3:26])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])C.O.[OH-].[Li+]>O1CCCC1.O>[F:27][C@@:5]([CH3:26])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
A solution of 75 mg (0.2 mmol) of (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid ethyl ester in 1 ml of tetrahydrofurane was treated for 2 h at room temperature with a solution of 8 mg (0.2 mmol) of lithium hydroxide monohydrate in 0.5 ml of water. For the working-up, the tetrahydrofurane was evaporated under reduced pressure and the remaining aqueous layer was extracted twice with 10 ml of diethylether. The combined organic layers were washed with 5 ml of water and, thereafter, the combined aqueous layers were acidified with 0.025 ml of hydrochloric acid (25%). Thereupon, the aqueous layer was extracted three times with 15 ml of ethyl acetate. The organic layers were washed with 15 ml of a saturated solution of sodium chloride, then combined, dried over sodium sulphate, and evaporated under reduced pressure. There were obtained 69 mg (99% of theory) of the title compound as a white foam;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: NC1CC1
Product: Fc1ccc(-c2ccc3ncnc(NC4CC4)c3c2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclopropylamine in 80% yield, using the procedure described example 37 and was characterized by its mass spectrum as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:19](O)[CH3:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:19][CH2:20][Cl:24])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN(Cc2ccc(Cl)nc2)C(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(CCCl)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.8 grams (0.022 mole) of 2-{[(6-chloro(3-pyridyl)methyl][(4-methoxyphenyl)methyl]amino}ethan-1-ol in 200 mL of chloroform was stirred and a solution of 2.9 grams (0.024 mole) of thionyl chloride in 50 mL of chloroform was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature during one hour, and then it was warmed to reflux where it stirred for 2.5 hours. After this time the reaction mixture was cooled to room temperature and was slowly poured into a solution of 100 mL of aqueous 5% sodium carbonate. The organic layer was separated and dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using 2% diethyl ether in methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 6.4 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)(O)[CH2:9][O:10]C)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CC(c1cccc(Cl)c1)c1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 1,1-bis-(3-chlorophenyl)-2-methoxyethanol (47 g) (obtained by reaction of (3-chlorophenyl)magnesium bromide on methyl 2-methoxyacetate in tetrahydrofuran) in formic acid (44 cc) is refluxed for 5 hours, cooled and poured into a mixture of saturated sodium carbonate solution (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×250 cc) and with saturated sodium chloride solution (200 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis-(3-chlorophenyl)acetaldehyde (36.9 g) in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][NH:22][CH2:21][CH2:20]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCc2cc(CCn3ccc(OCc4ccccc4)cc3=O)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 170 mg (0.47 mmol) 4-benzyloxy-1-[2-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H-pyridin-2-one (example 27.2) in 5.0 mL THF is added 57 μL (0.71 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with 3 drops of acetic acid and then 150 mg (0.71 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 2 h at RT, poured into aqueous 10% Na2CO3-solution and the layers are separated. The aqueous phase is extracted with tert-butylmethylether, the combined organic phase is washed a few times with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[CH:4][CH:3]=1.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]([OH:25])[C:30]([F:33])([F:32])[F:31])=[CH:4][CH:3]=1
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(O)C(F)(F)F
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (51.8 mg, 0.123 mmol) and trimethyl(trifluoromethyl)silane (54.3 μL, 0.368 mmol) in tetrahydrofuran (0.6 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 12.3 μL, 0.0123 mmol) at 0° C. After 30 min, hydrochloric acid (1.0 M, 0.25 mL) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (49.0 mg, 0.0995 mmol, 81%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (13 mg, 0.1191 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 64% yield (0.031 g, 0.0592 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:27][C@H:28]([CH3:50])[CH2:29][O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:27][C@H:28]([CH3:50])[CH2:29][OH:30])[N:12]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COc1ccccc1
Solvent: CO
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-4-pyrimidinyl]-4-pyridinesulfonamide (the product from step iv). (100 mg) in MeOH (10 mL) was added p-toluenesulfonic acid (31 mg) and anisole (0.15 g). The reaction was then stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC using a TFA (0.2%)/MeCN to give the title compound as a white solid. Yield: 50 mg.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:28][C:29]1[O:33][C:32]([C:34]2([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:31][C:30]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:30]2[N:31]=[C:32]([C:34]3([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[O:33][C:29]=2[CH3:28])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 42. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, 2H, J=8.60 Hz), 7.08 (d, 2H, J=8.60 Hz), 6.89 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.16-2.08 (m, 2H), 1.62-1.32 (m, 8H), 1.42 (s, 3H), 1.32 (s, 3H); MS (ES+) calcd for C30H35NO6F3: Found m/e 562.3 (M+1, 100%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Reactant: COc1ccncc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccncc1-c1nc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[4,5-d]pyrimidine, 4-methoxypyridine-3-boronic acid hydrate, and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 100° C. for 10 minutes. Water was added and the solution was filtered to give the product 5-chloro-2-(4-methoxypyridin-3-yl)-7-morpholinothiazolo[4,5-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13]C(=O)C(F)(F)F)[CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 84 %

Procedure:
To a stirred solution of Intermediate 2 (2.97 g) in methanol (15 ml) and water (5 ml) was added potassium carbonate (5.53 g). The mixture was stirred at 22° C. for 18 h before the methanol was removed in vacuo. Water (25 ml) was added and the mixture extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with water (5 ml) and saturated aqueous sodium chloride solution (10 ml) before drying over sodium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 75:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless oil (1.85 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC([Si](C)(C)[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)(C)C.[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][OH:42])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1nc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nc(F)ccc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 16.4 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-6-fluoro-2-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D54, 53.5 mg, 0.1 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol) were dissolved in toluene (1.5 mL). Bis tritertbutylphosphine palladium (13 mg, 0.026 mmol), followed by hexadecyltrimethylammoium chloride (10 μL, 25% aq sol), and finally sodium hydroxide solution (0.13 mL, 50% aq sol). The mixture was degassed for 5 minutes before heating at 90° C. for 4.5 hours. Cooled to R.T., diluted with EtOAc, washed with sat. NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified by SCX column, washing with MeOH before eluting with NH3 in MeOH. Solvent evaporated. Residue purified by column chromatography eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated under reduced pressure to afford a colourless solid of the title compound (11 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH3:23])[CH:6]([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C)C=O>[N:24]1([CH2:2][C:3]([N:5]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[CH3:23])[CH:6]([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8])=[O:4])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: CCC(C(=O)OC)N(C(=O)CCl)c1c(C)ccc2ccccc12
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)N(C(=O)Cn1ccnc1)c1c(C)ccc2ccccc12
Yield: 60.8 %

Procedure:
12 g (0.036 mole) of methyl 2-(N-chloroacetyl-2-methylnaphth-1-ylamino)-butyrate (Example 1) were dissolved in 60 ml of dry N,N-dimethylformamide, and the solution was stirred with 7.3 g (0.108 mole) of imidazole at 70° C. for 10 hours. The mixture was concentrated under reduced pressure, and the residue was extracted by shaking with 150 ml of methylene chloride and 50 ml of water. The organic layer was separated off, washed with twice 50 ml of water, dried over sodium sulfate, and concentrated under reduced pressure. 8 g (61.6% of theory) of methyl 2-[N-(imidazol-1-ylacetyl)-2-methylnaphth-1-ylamino]-butyrate were obtained as a yellowish resin (compound No. 2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH2:13][CH2:14]Br.O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]#[N:9])[CH2:14][CH2:13]2)=[CH:3][CH:2]=1
Reactant: N#CCc1ccncc1
Reactant: BrCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g of 4-pyridylacetonitrile are added to a mixture of 2.5 g of sodium amide in 80 ml of DCM, followed by 2.6 ml of 1,2-dibromoethane, and the mixture is stirred overnight at RT. The reaction mixture is poured into water and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvents are evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/MeOH mixture from (99/1; v/v) to (95/5; v/v). 2.5 g of the expected product are obtained.