Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:5][CH2:6][C:7]#[N:8].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][C:4]([O:5][CH2:6][C:7]#[N:8])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CCOc1ccc(OCc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(OCC#N)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of 5.9 g of (3-amino-4-benzyloxy-phenoxy)-acetonitrile and 24 ml of pyridine was cooled in an ice bath and treated at a dropwise rate with 3.46 g of methanesulfonyl chloride and stirred for 1 hour. The mixture was treated with 5 ml of water, removed the ice bath, and stirred at room temperature for 30 minutes. The mixture was poured into ethyl acetate, ice added, acidified with concentrated hydrochloric acid, washed with brine, dried (MgSO4), and evaporated. The residue was purified on silica gel eluting with ethyl acetate/hexane (2:5) and obtained 3.57 g of N-(2-benzyloxy-5-cyanomethoxy-phenyl)-methanesulfonamide as a cream solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][C:22]=3[O:36][CH3:37])[N:11]=2)=[C:4]([C:38](=[O:41])[NH:39][CH3:40])[CH:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:51]=[N:52][N:53]([CH2:55][CH2:56][CH2:57][OH:58])[CH:54]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:8][C:7]1[C:2]([C:50]2[CH:51]=[N:52][N:53]([CH2:55][CH2:56][CH2:57][OH:58])[CH:54]=2)=[CH:3][C:4]([C:38](=[O:41])[NH:39][CH3:40])=[C:5]([NH:9][C:10]2[C:15]([C:16]([F:17])([F:19])[F:18])=[CH:14][N:13]=[C:12]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])=[CH:23][C:22]=3[O:36][CH3:37])[N:11]=2)[CH:6]=1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(Br)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(-c4cnn(CCCO)c4)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
A suspension of diethyl (4-{[4-{[4-bromo-5-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 7C, 400 mg, 0.60 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E 258 mg, 1.02 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (49.17 mg, 0.06 mmol), and potassium carbonate (252 mg, 1.82 mmol) in 1,4-Dioxane (2 mL) and H2O (0.5 mL) was evacuated and purged with nitrogen (3×). The sample was irradiated in the microwave at 100° C. for 1.5 hours. The reaction mixture was filtered. The filtrate was quenched with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→85:15) to afford the title compound as 345 mg of a yellow solid (81%). 1H NMR (DMSO-d6, 400 MHz): δ=11.84 (s, 1H), 8.94 (s, 1H), 8.80 (d, J=4.8 Hz, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 6.86 (ddd, J=1.8, 2.2, 8.4 Hz, 1H), 4.62 (t, J=5.1 Hz, 1H), 4.23 (t, J=7 Hz, 2H), 3.91-4.00 (m, 4H), 3.78 (s, 3H), 3.39-3.45 (m, 2H), 3.19-3.27 (m, 2H), 2.81 (d, J=4.6 Hz, 3H), 1.96 (quin, J=6.6 Hz, 2H), 1.16 (t, J=7.1 Hz, 6H). MS (ESI): m/z 710.22 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).
Reaction SMILES: Cl.[C:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[NH:3][NH2:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=O)[CH3:14].C(O)C>O>[N:19]1[CH:20]=[CH:21][C:16]([C:13](=[N:4][NH:3][C:2]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:5])[CH3:14])=[CH:17][CH:18]=1
Reactant: NNC(=O)Oc1ccccc1
Reactant: CC(=O)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=NNC(=O)Oc1ccccc1)c1ccncc1
Yield: 53.9 %

Procedure:
A solution of 5.66 gm (0.03 mole) of phenyl carbazate hydrochloride, 3.63 gm (0.03 mole) of 4-acetylpyridine and 50 ml of ethanol is refluxed 2 hr. The solution is cooled and evaporated to dryness in vacuo to give an oil. The oil is triturated with ethyl acetate-methanol to afford a solid. The solid is dissolved in 50 ml of water and treated with 50 ml water containing 5 gm sodium carbonate. A gummy solid separates which solidifies on standing. The crude product is collected and crystallized from ethyl acetate-Skellysolve B to yield 4.13 gm (54%) of the title compound having a melting point of 120.4° C. (decomp.).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C1C(=O)N([Cl:24])C(=O)C1>CN(C=O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[C:5]1[Cl:24])[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 145.6 %

Procedure:
To a solution of 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 31.82 mmol) in DMF (50 mL) was added NCS (5 g, 37.45 mmol) in portions at 0° C. The resulting mixture was stirred at room temperature for 5 h under nitrogen. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione (11.8 g, ˜50% pure) as light yellow oil. LCMS retention time 0.764 min; LCMS MH+ 255.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
A mixture of 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.200 g, 0.47 mmol), ethanol (6 ml), and 1M aqueous Na2S2O4 (1.8 ml) was stirred at 80° C. for 16 h. The reaction mixture was then allowed to cool to room temperature; the solvents were removed in vacuo, and the residue was absorbed on a silica gel. The free-running powder was placed on a 10 g isolute silica column, and elution of the column with a gradient of methanol (0 to 3%) in ethyl acetate gave the title compound (0.104 g, 54%); 1H-NMR (250 MHz, DMSO-d6) 2.53, 2.70, 2.81, 3.50 (4×br s, 8H, piperazine N(CH2)2), 3.35 (s, 2H, NCH2CO), 4.75 (s, 2H, NH2), 5.60 (s, 2H, NH2) 7.23 (d, J=3.46 Hz, 1H, thiazole 4-H or 5-H), 7.30 (s, 1H, 6-H), 7.48 (d, J=3.48 Hz, 1H, thiazole 4-H or 5-H);
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=1)[OH:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.54 mmol) in THF (126 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of 4-methylbenzaldehyde (1.28 g, 10.6 mmol) in THF (42 mL) was added at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.3 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cl)cc1CC(=O)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)Cc1cc(Cl)ccc1OC
Yield: 94.1 %

Procedure:
A stirred suspension of (5-chloro-2-methoxyphenyl)acetic acid (10 g, 0.05 mol), anhydrous K2CO3 (8.3 g, 0.06 mol) and dimethyl sulfate (7.6 g, 0.06 mol) in anhydrous CH3CN (60 mL) was heated to reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and the excess dimethyl sulfate was quenched with Et3N (1 mL) and then filtered. The filtrate was rotary evaporated and the residue was suspended in water and extracted with ether, washed with satd. NaHCO3, water, brine and then dried (Na2SO4). Filtration and evaporation of the ether gave a colorless oil which was distilled in vacuo to afford methyl (5-chloro-2-methoxyphenyl)acetate (10.1 g, 94%): bp 96°-98° C./0.5 torr; IR (film, cm-1) 1742, 1250, 1150, 1028; 1H NMR (300 MHz, CDCl3)δ 3.56 (2 H, s), 3.66 (3 H, s), 3.76 (3 H, s), 8.75 (16 H, d, J=8.6 Hz), 7.13 (1 H, d, J=2.5 Hz), 7.17 (1 H, dd, J=8.6 and 2.5 Hz); MS m/e 215 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55](Cl)(=[O:58])[CH2:56][CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:55](=[O:58])[CH2:56][CH3:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and propanoyl chloride as starting materials in 20% yield. LCMS for C27H31ClN7O2 (M+H)+: m/z=520.2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the title compound as a white solid, m.p. 122-123° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.O1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:12]1([N:8]=[C:1]=[N:3][CH:7]2[CH2:6][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The compounds of Formula I wherein n is two, R2 is hydrogen, R3 is phenyl or substituted phenyl, and X is a tetrazole are prepared as set forth in Chart V. Compound (32) is prepared according to the method of Paganelli (Tett. Lett. 1991; 32: 2807-2810) by a transition metal catalyzed Michael addition of benzyl cyanide to methyl acrylate. Compound (32) is then treated with (n-Bu)3SnN3 in refluxing dioxane to give the tetrazole (33), which is then alkylated with an alkyl halide, R4 halo, e.g., R4Br, wherein R4 is as defined in Formula I, in acetonitrile employing Et3N as base, giving a mixture of regioisomers (34) and (35) which are separated by flash chromatography. Hydrolysis of each ester with ethanolic NaOH at room temperature gives the respective acids (36) and (38). The acids are then coupled with an appropriate amine of the formula R1NH2 wherein R1 is as defined in Formula I employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl at 0° C. as coupling agent to give the amides (37) and (39).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](CCl)=[CH:15][N:14]=1.O>CN(C)C=O.C(#N)C>[Cl:12][C:13]1[C:18]([N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]2=[O:9])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N#Cc1ccc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cccn(-c2cccnc2Cl)c1=O
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
2.0 g (0.017 mol) of 3-cyano-2-pyridone (Brana, Rodriguez, J. Heterocycl. Chem., 1297 (1982)) are dissolved in 30 ml of absolute N,N-dimethylformamide, and 0.56 g (0.019 mol) of sodium hydride (80% suspension) are added at 0° C. After the mixture has been stirred for 20 minutes, a solution of 2.75 g (0.017 mol) of 2-chloro-5-chloromethyl pyridine in 10 ml of absolute acetonitrile is added dropwise, and the mixture is stirred for 3 hours at room temperature. The reaction mixture is then poured into 400 ml of water and extracted using ethyl acetate, and the organic phase is dried over magnesium sulphate and then distilled to dryness. The residue is stirred with a little diethyl ether and filtered off with suction. In this manner, 3.2 g of 1-(2'-chloropyridin-3-yl)-3-cyano-2-pyridone of melting point 145° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]([CH2:22][C:23](Cl)=[O:24])#[N:21]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH:19][C:23](=[O:24])[CH2:22][C:20]#[N:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=Cc2ccccc2)csc1N
Reactant: N#CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-styryl-thiophene-3-carboxylic acid ethyl ester (0.1298 g, 0.475 mmol) S was dissolved in anhydrous CH2Cl2 (2.0 mL). This was treated with cyanoacetyl chloride (0.713 mL, 0.713 mmol, 1 M in CH2Cl2) and stirred at room temperature for 1 hr. More cyanoacetyl chloride (0.238 mL, 0.238 mmol) was added and stirring was continued at room temperature for 1 hr then refluxed for 30 min. The reaction was diluted with EtOAc (25 mL). This was washed with sat. NaHCO3 (1×25 mL), H2O (1×25 mL), and brine (1×25 mL). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo to give 0.0803 g (50%) of crude 7 which was carried on to the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([CH:24]=[O:25])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:26][CH3:27])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([CH2:24][OH:25])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:26][CH3:27])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Sc1c(ccc(OC)c1CO)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude 10-benzyl-3,7-dimethoxyphenothiazine-4-carbaldehyde obtained was dissolved in 150 ml of absolute tetrahydrofuran, whereupon the solution was treated at 0° with 31.5 ml of lithium borohydride solution (1M in tetrahydrofuran). The reaction mixture was brought slowly to room temperature, stirred for 1 hour and then poured into ice-water, and the pH was adjusted to 3-4 with 0.5N hydrochloric acid solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel with ethyl acetate/hexane (1:2) 8.0 g (73.7%) of (10-benzyl-3,7-dimethoxy-phenothiazin-4-yl)-methanol were obtained as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH:11]1([C:17]2([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CC(N(C)C)=O>[CH:11]1([C:17]2([C:23]([O:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=3)=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(Cl)C1(C2CCCCC2)CCCCC1
Reactant: Cc1ncc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ncc(OC(=O)C2(C3CCCCC3)CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To an ice-cooled mixture of 2-methyl-5hydroxypyrimidine (0.9 g) and sodium hydride 80% (0.24 g) in dimethylacetamide (15 ml), a solution of 1-cyclohexylcyclohexane-1-carbonyl chloride (1.68 g) in dimethylacetamide (10 ml) was added. The mixture was then stirred at room temperature for 1 hour, then filtered and evaporated in vacuo. The residue was taken up with ethyl acetate, which was washed with water and dried. Evaporation of the solvent and column chromatography (cyclohexane/ethyl acetate 9:1) afforded 1.2 g of 2-methylpyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate. M.p. 52°-55° C. According to the procedure above described the following compound was also prepared, 2-methylpyrimidin-5-yl α-cyclopentylphenyl glicolate hydrochloride. M.p. 132°-138° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](C)([CH3:20])[CH2:11][C:12]([C:16]([F:19])([F:18])[F:17])([OH:15])[CH2:13][OH:14].ClCCl.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH3:20])[CH2:11][C:12]([OH:15])([C:16]([F:18])([F:19])[F:17])[CH:13]=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(CO)C(F)(F)F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cccc(C(C)CC(O)(C=O)C(F)(F)F)c1F
Reaction time: 8 h
Yield: 89 %

Procedure:
2.5 g (8.06 mmol) of rac-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol is introduced into a mixture that consists of 52 ml of dichloromethane, 14 ml of dimethyl sulfoxide and 4.08 g (40.29 mmol) of triethylamine. At room temperature, 2.57 g (16.11 mmol) of SO3/pyridine complex is added, and the batch is stirred overnight at this temperature. The reaction mixture is mixed with saturated ammonium chloride solution and stirred vigorously. After additional common working-up, 2.11 g (85%) of the desired aldehyde is obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:20]([C:19]1[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:6]2
Reactant: Ic1cccc2c1CNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cccc(I)c2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 4-Iodo-2,3-dihydro-1H-isoindole and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 540.0 (MH+, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].[H-].[Na+]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:30][N:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)[CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH3:29]
Reactant: CC(C)c1ccc(-c2csc(NCCc3cccs3)n2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCN(CCc1cccs1)c1nc(-c2ccc(C(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a THF solution of [4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amine (100 mg, 0.3 mmol) and ethyl bromopropionate (42 μL, 0.33 mmol) was added NaH (18 mg, 60%, 0.45 mmol). The mixture was stirred at room temperature for 30 min, and the excess NaH was quenched with brine and extracted into ethyl acetate (3×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate, concentrated and purified on silica gel column to afford 3-[[4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amino]-propionic acid ethyl ester (98 mg). LCMS m/z: 430 (M+1)+.