Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccsc1CN
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1ccsc1CNC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Yield: 52 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (3-methylthiophen-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.30 (m, 5H), 7.24 (d, J=5.1 Hz, 1H), 6.79 (d, J=5.1 Hz, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.45-4.43 (m, 2H), 2.53 (s, 3H), 2.17 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[NH2:17][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH2:21])=[O:20]>>[C:19]([C@@H:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:5]([CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:6])=[O:7])[N:13]=1)=[O:16])[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:20])[NH2:21]
Reactant: CC(C)CS(=O)(=O)c1cccc(C(=O)O)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cccc(S(=O)(=O)CC(C)C)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylsulfonyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=356.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:20]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: C1CNCCNC1
Product: Fc1ccc(C(OCCN2CCCNCC2)c2ccc(F)cc2)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 2-[bis(4-fluorophenyl)methoxy]ethyl chloride and homopiperazine, the title compound was obtained in a yield of 88%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Yield: 72.6 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (260.2 g, 2.0 mol), methyl isobutyl ketone (300 g) and 1-bromo-5-chloropentane [V-1] (311.0 g, 1.68 mol) is heated to 80°-90° C. Thereto is added anhydrous potassium carbonate (300 g), and the mixture is reacted at 80°-90° C. for 12 hours. To the reaction mixture is further added potassium carbonate (341.4 g), and the mixture is reacted for additional 6 hours. After completion of the reaction, the mixture is filtered, and the methyl isobutyl ketone layer is washed with water and concentrated under reduced pressure. The residue (398.6 g) contains ethyl 7-chloro-2-(1-oxoethyl)heptanoate (content; 70.8%, yield; 72.6%), which is purified by column chromatography to give pure ethyl 7-chloro-2-(1-oxoethyl)heptanoate [II-1].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][NH:39][CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.Cl>CN(C=O)C.C(OCC)(=O)C.O>[ClH:1].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][N:39]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCN(C)Cc2ccc(NC(=O)/C=C/c3cccc(-c4ccc(C)cc4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 2-(3,4-dimethoxyphenyl)ethylmethyl-amine (132 μl) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 12 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give colorless amorphous, which was dissolved in ethyl acetate (50 ml), and to the mixture was added 4N hydrochloric acid ethyl acetate solution (0.5 ml). The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give (E)-N-[4-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-aminomethyl]phenyl]-3-(4-methylphenyl)cinnamamide hydrochloride (Compound 63) (245 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=O)[N:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O.[F:24][C:25]1[C:30]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:29][CH:28]=[CH:27][C:26]=1[NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[NH:40]1)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:24][C:25]1[C:30]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:26]=1[NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:14](=[O:16])[CH2:13][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:5]1)=[O:38]
Reactant: NC(=O)c1nn(CC(=O)O)c2ccccc12
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2F)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-indazol-1-yl)-acetic acid (73.4 mg, 0.335 mmol, prepared as described in Scheme A25) in DMF (2 mL) were successively added (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)-amide trifluoroacetate (140 mg, 0.335 mmol), DIPEA (0.234 mL, 1.34 mmol) and HBTU (152 mg, 0.402 mmol). The reaction mixture was stirred at 25° C. for 2 h, concentrated and the residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined, CH3CN was evaporated under reduced pressure and the resulting aqueous solution was lyophilized. White powder: MS: 506 [M+H]+; tR (HPLC conditions k): 3.40 min.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:15]([CH2:23][CH3:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=1[CH2:19][CH3:20])C1C=CC=CC=1.[Na].N>>[CH2:21]([N:17]1[C:18]([CH2:19][CH3:20])=[C:14]([CH2:13][C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[C:15]([CH2:23][CH3:24])=[N:16]1)[CH3:22]
Reactant: CCc1nn(CC)c(CC)c1Cc1nccn1Cc1ccccc1
Agent: N
Agent: [Na]
Product: CCc1nn(CC)c(CC)c1Cc1ncc[nH]1

Procedure:
1,3,5-Triethyl-4-(1H-imidazol-2-ylmethyl)-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-1,3,5-triethyl-1H-pyrazole by debenzylation with sodium in liquid ammonia for 10 min. The blue reaction mixture was quenched by addition of solid ammonium chloride, the ammonia evaporated and the residue distributed between water and t-butyl methyl ether. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. 1,3,5-Triethyl-4-(1H-imidazol-2-ylmethyl)-1H-pyrazole was obtained as light yellow viscous oil; MS (ISP): 233.0 ((M+H)+.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH3:12])[CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1c(C)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnn(C)c1C(=O)O
Yield: 55.4 %

Procedure:
Using ethyl 1,4-dimethyl-1H-pyrazole-5-carboxylate (565 mg, 3.36 mmol), 1N aqueous sodium hydroxide solution (4 mL, 4 mmol) and ethanol (4 mL), and by a reaction in the same manner as in Reference Example 20, the title compound (261 mg, 55%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].S1C=CN=C1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)=[O:19]
Reactant: CSc1nc(-c2ccccc2)cs1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1cscn1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccccc2)cs1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (ice/water) solution of 8.9 g. of 2-methylthio-4-phenyl-thiazole pre-dissolved in 90 ml. of methylene chloride is added in portions over 5 minutes, 8.7 g. of m-chloro-peroxybenzoic acid. Examination by TLC after 90 minutes indicates the presence of essentially all of the sulfinyl compound (reaction complete) with a faint trace of sulfone and an even fainter trace of remaining thiazole starting material. The precipitated m-chloro-benzoic acid is filtered off and the methylene chloride solution is washed successively with a 10% solution of sodium sulfite and with saturated sodium bicarbonate solution, dried, evaporated in vacuo to dryness and the residue further dried overnight in vacuo, to yield 2-methylsulfinyl-4-phenyl-thiazole, m.p. 104°-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:37](O)[CH3:38]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:12]1[O:23][CH2:37][CH3:38])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(OCc1ccccc1)N1CCC(NC(=O)C(F)(F)F)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCOC1C(NC(=O)C(F)(F)F)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To Intermediate 4 (34 g) in ethanol (1070 ml) at −5° C. was added sodium borohydride (9.86 g). A solution of 4M hydrogen chloride in 1,4-dioxan (20 ml) was then added dropwise. Periodically further portions of 4M hydrogen chloride in 1,4-dioxan (2×5 ml, 1×10 ml) and sodium borohydride (2 g) were added. After 3 h, concentrated sulphuric acid (11 ml) was added and the mixture warmed to room temperature for 2 h. Saturated aqueous sodium bicarbonate (300 ml) was then added and the ethanol and dioxan removed in vacuo. The residue was diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel 9385 eluting with ether, to give the title compound (21 g). Mass spec. MNH4+ (found) 378 MNH4+ (calculated) 378
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH2:29](I)[CH2:30][CH3:31].O>CN(C=O)C>[CH2:29]([N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ncc(C(=O)OCC)cn1
Yield: 63 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]-pyrimidine-5-carboxylate (165 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (130 mg) in DMF (2 ml). Then, the mixture was added with n-propyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain ethyl 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (116.5 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH:18]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([NH:17][CH:18]([P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:16])[N:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)n1cnc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(NC(=O)Cc1cn(C(=O)OC(C)(C)C)cn1)P(=O)(OCC)OCC
Yield: 65.9 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)imidazol-4-yl]acetic acid (45 mg) and tetraethyl (aminomethylene)bis(phosphonate) (91 mg) in N,N-dimethylformamide (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg) with stirring on ice-sodium chloride bath under nitrogen atmosphere. After stirring for 36 hours at 5° C., the mixture was diluted with chloroform (10 ml) and washed with cold 1N aqueous solution of citric acid (10 ml). The aqueous layer was extracted with chloroform (10 ml) twice and the combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and the solution was washed with water (10 ml), dried over sodium sulfate and evaporated in vacuo to give a colorless syrup of tetraethyl [[2-{1-(tert-butoxycarbonyl)imidazol-4-yl}acetamido]methylene]bis(phosphonate) (67 mg).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]([CH:24]=[O:25])=[N:13][CH:14]=[C:15]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[N:16]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[C:12]([CH2:24][OH:25])=[N:13][CH:14]=[C:15]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[N:16]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc(C)n(-c2cnc(C=O)c(Nc3ccc(Cl)cc3)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)n(-c2cnc(CO)c(Nc3ccc(Cl)cc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added to an ice cooled solution of 3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl) -pyrazine-2-carbaldehyde (80 mg, 0.22 mmol) in methanol (5 mL) and stirred at room temperature for 30 minutes. The reaction was quenched with aqueous sodium hydrogen carbonate and diluted with ethyl acetate. The organic solvents were evaporated and the remaining aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated to give [3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-methanol (58 mg, 80%) as the crude product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Pd+2].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Temperature: 85 °C

Procedure:
A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6-bromothiochroman (Compound 66) 314 mg (3.2 mmol) of trimethylsilyl acetylene, 40 mg (0.21 mmol) of cuprous iodide, 80 mg (0.11 mmol) of bis (triphenylphosphin) palladium (II) chloride and 1 ml of triethylamine was degassed under nitrogen and heated in a sealed tube at 85 degrees C for 15 h. The mixture was then treated with a further 20 mg (0.11 mmol) of cuprous iodide and 40 mg (0.06 mmol) of the palladium (II) catalyst. The mixture was then heated under a nitrogen atmosphere in the sealed tube at 100 degrees C for a further 64 h. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 0.28 (9H, s), 1.30 (6H, s), 1.88-1.97 (2H, m), 2.33 (3H, s), 2.97-3.05 (2H, m), 6.92 (1H, s), 7.43 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:60])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:51]([C:53]1[N:54]=[C:55]([CH3:59])[O:56][C:57]=1[CH3:58])=[O:52])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.CO.[Li+].[OH-]>C1COCC1>[Cl:50][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][CH:47]=1)[O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:60])=[O:2])=[O:22])[N:24]([C:51]([C:53]5[N:54]=[C:55]([CH3:59])[O:56][C:57]=5[CH3:58])=[O:52])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(Oc2cccc(Cl)c2)cc1)CO3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(Oc3cccc(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
(S)-2-{[(3S,8S)-3-[4-(3-Chloro-phenoxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.020 g) dissolved in THF (0.3 mL) and MeOH (0.3 mL) and 0.3 mL of 2.0 N LiOH was added at 0° C. and stirred at that temperature for 30 minutes. The pH was adjusted to 6-7, and the mixture was extracted with EtOAc, dried with (Na2SO4), and evaporated and dried under vacuum to get the title compound (0.015 g). LCMS (m/z): 814.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:17][NH:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([C:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:15][NH:16][CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(C2(Cc3ccccc3)CNC2=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2(Cc3ccccc3)CNC2)c1

Procedure:
A 1M lithium aluminium hydride solution in tetrahydrofuran (14 ml, 14 mmol) was added to a stirred solution of 3-benzyl-3-(3-methoxyphenyl)azetidin-2-one (1.7 g, 6.36 mmol) in tetrahydrofuran and heated to reflux for 4 h. The solution was cooled and quenched by careful addition of a 2M sodium hydroxide solution and then extracted with ether. The organic phase was dried over sodium bicarbonate and purified on 12 g SiO2 using 20% methanol in dichloromethane (clear colourless oil). m=520 mg (32%)
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:20])(=[O:19])[CH2:16][CH2:17][CH3:18]>>[ClH:20].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: CCCC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 72 %

Procedure:
5.0 g (24.1 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of butyryl chloride were refluxed for 15 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from isopropanol. 4.8 g (72% of theory) of 4-butyrylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as pale beige crystals of melting point 205°-208° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of 2-tert-butoxycarbonylaminoethanol (32.7 g, 203 mmol), triethylamine (34 ml), p-toluenesulfonyl chloride (38.7 g, 203 mmol), 4-dimethylaminopyridine (0.10 g) and dichloromethane (500 ml) was stirred at 0° C. for 4 hours. The reaction mixture was washed successively with water, 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane =1/5) to obtain 48.2 g of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Temperature: 120 °C
Reaction time: 27 h
Yield: 11.3 %

Procedure:
A mixture of 3.5 g of 3-trifluoromethyl-1H-1,2,4-triazole, 3.8 g of 2,3-dichloropyridine, 6.0 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred at 120° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine of the formula: