Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: COCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
Methanesulphonyl chloride (1.75 ml, 22 mmol) was added to a solution of 3-methoxy-1-propanol (1.81 g, 20 mmol) and triethylamine (3.35 ml, 24 mmol) in DCM (40 ml) cooled in an ice bath and the mixture stirred at ambient temperature for 18 hours. DCM (25 ml) and water (50 ml) were added and the phases separated and the aqueous layer was extracted with DCM (25 ml). The extracts were combined, washed with water (50 ml) and brine (50 ml), dried (Chemelut column CE1010) and evaporated to give the title compound 3.25 g (97%) as a pale yellow oil. NMR 2.00 (m, 2H), 3.01 (s, 3H), 3.35 (s, 3H), 3.49 (t, 2H), 4.38 (t, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:6][CH2:5]1.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1>CO>[CH3:1][O:2][CH2:3][C@@H:4]([OH:6])[CH2:5][NH:14][CH2:13][C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: COC[C@H]1CO1
Reactant: NCc1ccncc1
Solvent: CO
Product: COC[C@@H](O)CNCc1ccncc1
Temperature: 120 °C
Yield: 17 %

Procedure:
(R)-(−)-Glycidyl methyl ether (88 mg, 1 mmol) and 4-picolylamine (108 mg, 1 mmol) in methanol (1 mL) were sealed in a reaction tube and heated at 120° C. for 30 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (17% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1>[Pt].C(O)C>[CH3:20][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1)[NH2:21]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C

Procedure:
3,5-Dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)nitrobenzene (480 mg) and 50 mg of 10% platinum on carbon in 100 ml ethanol are reduced on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate stripped. The residue is taken up in ether and acidified with gaseous hydrogen chloride. The ether solution is chilled, filtered to remove insolubles, and stripped to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-aniline hiedrochloride, m.p. 95°-100°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:61])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([C:21]2[C:31]3[O:30][CH2:29][C@H:28]([NH:32][C:33](=[O:45])[C@@H:34]([N:36](C(OC(C)(C)C)=O)[CH3:37])[CH3:35])[C:27](=[O:46])[N:26]([CH2:47][C:48]4[C:57]5[C:52](=[CH:53][C:54]([Br:58])=[CH:55][CH:56]=5)[CH:51]=[CH:50][C:49]=4[O:59][CH3:60])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:61])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]([C:21]2[C:31]3[O:30][CH2:29][C@H:28]([NH:32][C:33](=[O:45])[C@@H:34]([NH:36][CH3:37])[CH3:35])[C:27](=[O:46])[N:26]([CH2:47][C:48]4[C:57]5[C:52](=[CH:53][C:54]([Br:58])=[CH:55][CH:56]=5)[CH:51]=[CH:50][C:49]=4[O:59][CH3:60])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cccc3c2OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3Cc2c(OC)ccc3cc(Br)ccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H]1COc2c(C(=O)NCc3ccc(C(=O)OC)cc3)cccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Yield: 95.4 %

Procedure:
TFA (340 mg, 222 μl, 2.99 mmol, Eq: 200.00) was added to a solution of 4-[({(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionyl amino]-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester (12 mg, 14.9 μmol, Eq: 1.00) in DCM (300 μl) at 0° C. After 1 h the mixture was concentrated and the residue dissolved in DCM. The solution was washed with sat. NaHCO3 and the NaHCO3 solution back extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in a minimum of DCM. Et2O was added followed by pentane which resulted in a precipitate. The supernatant was decanted, the residue was washed with pentane and dried in vacuo to afford the title compound (10 mg, 95%) as a white solid. 1H NMR (DMSO-d6) δ: 8.81 (br. s., 1H), 8.22 (d, J=8.2 Hz, 1H), 8.03-8.12 (m, 2H), 7.87 (d, J=8.5 Hz, 2H), 7.79 (d, J=9.1 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.53 (dd, J=9.2, 2.0 Hz, 1H), 7.32-7.40 (m, 3H), 7.25-7.31 (m, 1H), 7.16-7.25 (m, 1H), 5.87 (d, J=14.8 Hz, 1H), 5.24 (d, J=14.8 Hz, 1H), 4.66-4.82 (m, 1H), 4.13-4.52 (m, 4H), 3.78 (s, 3H), 2.94 (d, J=6.9 Hz, 1H), 2.20 (s, 3H), 1.08 (d, J=6.9 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:31][CH2:30][C:23]3([NH:27]C(=O)N[C:24]3=[O:29])[CH2:22][CH2:21]2)=[O:19])=[C:12]([Cl:32])[C:11]=1[Cl:33].[O:34](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C(N(CC)CC)C.[OH-].[Na+]>COCCOC.CN(C1C=CN=CC=1)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:31][CH2:30][C:23]([NH2:27])([C:24]([OH:34])=[O:29])[CH2:22][CH2:21]2)=[O:19])=[C:12]([Cl:32])[C:11]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccccc1Sc1ccc(/C=C/C(=O)N2CCC3(CC2)NC(=O)NC3=O)c(Cl)c1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1Sc1ccc(/C=C/C(=O)N2CCC(N)(C(=O)O)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a suspension of Example 355 (700 mg, 1.4 mmol) in DME (10 mL) was added a solution of (BOC)2O (1.51 g, 6.9 mmol) in DME (5 mL), triethylamine (0.23 mL, 1.7 mmol) and DMAP (9 mg, 0.07 mmol). The reaction mixture was stirred at room temperature overnight. Additional triethylamine (0.23 mL) and DMAP (30 mg) were added, and the mixture was heated at 60° C. for 6 hours. After aqueous work up, the crude product was suspended in DME (5 mL) and water (5 mL) containing 200 mg of NaOH. The suspension was stirred for 5 hours at room temperature, and separated by HPLC to give the title compound (300 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 1.78 (m, 2H), 2.10 (m, 2H), 3.60 (m, 2H), 3.80 (s, 3H), 3.86 (m, 2H), 6.58 (d, 1H), 7.10 (d, 1H), 7.25 (d, 1H), 7.28 (d, 1H), 7.50 (d, 1H), 7.58 (t, 1H), 7.77 (d, 1H), 7.80 (d, 1H), 8.50 (br s, 2H). MS (ESI+) m/z 481 (M+H)+. Anal calcd for C22H22N2Cl2SO4.0.75H2O: C, 47.34; H, 4.06; N, 4.60. Found: C, 47.31; H, 4.05; N, 4.43.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[O:30]>O1CCCC1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[OH:30])=[N:8]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC1(C)COC(c2ccccc2)=N1
Agent: [Li]CCCC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2C(O)c2ccc3ccccc3c2)=N1
Temperature: -30 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
At −78° C., 104 ml of a 1.6M solution of butyl lithium were slowly added dropwise to 25 g (0.14 mol) of 4,4-dimethyl-2-phenyl-2-oxazolin and 0.1 g of triphenylmethane in 400 ml of anhydrous tetrahydrofuran. The mixture was stirred for 1 h. The mixture was then allowed to warm to −30° C. and a solution of 20.3 g (0.13 mol) of 2-naphthaldehyde in 200 ml of anhydrous tetrahydrofuran was added dropwise. Stirring was continued for about 1 h at −20 to −30° C. The reaction solution was then allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was introduced into ice-water which was then extracted with ether. The organic phase was dried and concentrated under reduced pressure. This residue was purified chromatographically (eluent: n-heptane/acetone=40/3), affording 25.3 g (54%) of the product.
Reaction SMILES: [CH3:1][CH:2]([SH:5])[CH2:3][CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH3:1][CH:2]([S:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:3][CH3:4]
Reactant: CCC(C)S
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CCC(C)SCCC#N

Procedure:
β-(1-Methyl-1-propylmercapto)propionitrile was prepared according to the procedure of Example 1 using 1-methyl-1-propanethiol (25.0 g; 0.28 moles), acrylonitrile (14.9 g; 0.28 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [CH:1]1([C:7](=[O:15])[CH2:8]P(=O)(OC)OC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[H][H].[CH:20]([CH:22]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH:23]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=O>O1CCCC1.C(O)(=O)C>[CH:1]1([C:7](=[O:15])[CH:8]=[CH:20][CH:22]2[CH2:30][CH2:29][C:24]3([O:25][CH2:26][CH2:27][O:28]3)[CH:23]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COP(=O)(CC(=O)C1CCCCC1)OC
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Reaction time: 2 h
Yield: 112 %

Procedure:
A solution of dimethyl 2-cyclohexyl-2-oxoethylphosphonate (10.1 g.) in dry tetrahydrofuran (40 ml.) was added to a stirred suspension of sodium hydride (1.04 g.) in dry tetrahydrofuran (300 ml.). The mixture was stirred at room temperature until the evolution of hydrogen had ceased, then treated dropwise with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [10.2 g; prepared as described in Example 1(iv) above] in dry tetrahydrofuran (100 ml.) and stirred for a further 2 hours. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvents were removed in vacuo, the residue was triturated with diethyl ether and the solid filtered off. The ethereal solution was washed with aqueous sodium carbonate solution, dried over magnesium sulphate, and evaporated to dryness, to give 7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (16 g.), νmax 3400 cm-1, 1680 cm-1, 1650 cm-1, 1620 cm-1, 1040 cm-1.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:26]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([CH3:20])=[CH:22][CH:23]=3)[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Product: Cc1ccc(Cn2c(C)cc3c2C(C)CN(Cc2ccccc2)C3)cc1

Procedure:
Using a procedure to analogous to Example 3, 3-acetonyl-1-benzyl-5-methyl-4-piperidone may be reacted with p-methylbenzylamine to give the title compound.
Reaction SMILES: CC(O[C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])CC1NC2C=CC=CC=2C=1)=[O:7])(C)C.[NH:23](C(OC(C)(C)C)=O)[C@H:24](C(O)=O)CC1N=CNC=1.N[C@H](C(O)=O)CCC(=O)O>>[CH2:24]([NH2:23])[C:6]([NH:8][CH2:9][C:20]([OH:22])=[O:21])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NCC(=O)NCC(=O)O

Procedure:
The synthesis of the peptide resin 15 was done according to the method described in Example 6 by building on Boc glycine resin (2.0 g, 0.3 mmol Gly/g) or by using resin 14a and adding Boc-Trp, Boc-His (Bzl) and Pyro-Glu. Amino acid analysis gave Gly2.0 Ser0.96 Pro1.05 Glu1.05 Leu1.06 Tyr1.13 Arg1.10 BzlHis0.86. A suspension of 1.1 g of 13 in absolute ethanol was photolyzed and purified as described in Example 7. The purified protected decapeptide 15 was obtained in 64% yield (0.257 g): m.p. 155°-159°; tlc Rf1 0.80, Rf2 0.11, Rf3 0.75, Rf4 0.04; UV max (MeOH) 262 mμ (t=6000); the nmr was consistent with the structure; [α]27D-22 (c 1 (CH3CO2H); the amino acid composition was Gly1.90 Ser0.92 Pro1.0 Leu1.0 Tyr0.92 Arg1.02 Glu1.02.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=C=NCC.[OH2:13].ON1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2N=N1>N1C=CC=CC=1>[CH:18]1[CH:23]=[CH:22][C:21](/[CH:4]=[CH:5]/[C:6]([NH2:7])=[O:13])=[CH:20][CH:19]=1
Reactant: On1nnc2ccccc21
Reactant: O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (40 ml) and washed with H2O (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH3OH/CH2Cl2, absorbed onto silica gel and is purified on a Biotage 12M column with SIM using 2% CH3OH (saturated with NH3) in CH2Cl2 as the eluent to afford 56.2 mg (0.096 mmol, 51%) of the desired cinnamide. 1H-NMR (DMSO) δ: 8.66, 8.48, 8.02, 7.64, 7.49, 7.40, 7.35, 6.70, 4.86, 4.22, 3.84, 3.60.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[NH2:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.[K+].C(#N)C.CO>C(OCC)(=O)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:26][CH:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NC1CCc2ccccc21
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc2c(c1)CCC2NCCCOc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 1-aminoindan potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=400.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccc(F)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-fluoro-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(4-fluoro-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[F:19]>CN(C=O)C.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Cn1ccc2c(Cl)ncnc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (398.8 mg, 2.4 mmol) and 3-chloro-4-fluoro-phenylamine (378 mg, 2.6 mmol) in DMF (6 mL) was stirred at room temperature for 2 minutes. To it was added silver triflate (672 mg, 2.6 mmol), the mixture was then stirred at 90° C. for 2 hours. The reaction was then diluted with ethyl acetate and filtered off the precipitate, washing the precipitate with 10% ammonia solution. The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was triturated with ethyl acetate and filtered to give 549.1 mg (83%) of (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-amine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) 9.48 (s, 1H, NH), 8.35 (s, 1H), 8.29 (dd, J=2.7 & 6.8Hz, 1H), 7.75-7.80 (m, 1H), 7.37 (t, J=9.3 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 3.75. (s, 3H, CH3). MS 277 [M++1].
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(CO)c1cc(C)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)cc(C(CO)C(=O)O)c1

Procedure:
A solution of ethyl 3-hydroxy-2-(3-methoxy-5-methylphenyl)-propionate (1.7 g; 7.1 mmol; from step (vi) above) and NaOH (7.0 g, 180 mmol) in 200 mL MeOH:H2O (1:1) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, washed with ether and acidified. The resulting mixture was extracted twice with ether, and the combined organic layers were washed with water, dried (Na2SO4), and evaporated to yield 1.47 g (98%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[C:18]([O:21][C:22](=O)[CH3:23])(=O)[CH3:19].CC(OCC)(OCC)OCC>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:4]1=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2](=[O:1])/[C:3]/1=[C:18](\[O:21][CH2:22][CH3:23])/[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2)n1
Agent: CCOC(C)(OCC)OCC
Product: CCO/C(C)=C1\C(=O)N(c2ccccc2)N=C1CC(=O)OC
Reaction time: 8 h
Yield: 80 %

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-phenyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 1.85 g), acetic anhydride (1.00 ml) and MeC(OEt)3 (2.50 ml) was refluxed for 1 h. and left overnight at an ambient temperature. Resulting precipitate was collected by filtration and washed with ethyl ether (10 ml) in order to obtain crude product methyl[(4Z)-4-(1-ethoxyethylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g, 80% purity) in 50% yields. 1HNMR (400 MHz, CDCl3, ppm): 1.42 (3H, t, 7.1 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.76 (2H, s), 4.31 (2H, q, 6.9 Hz), 7.16 (1H, t, 7.2 Hz), 7.37 (2H, t, 7.6 Hz), 7.97 (2H, d, 8.0 Hz). MS (ESI+): 303.3; MS (ESI−): 301.2.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9].[Na].O>C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 113.9 %

Procedure:
After adding 5 ml of trifluoroacetic acid to 340 mg of tert-butyl 4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl) amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate, the mixture was stirred at room temperature for 7minutes. Saturated sodium bicarnobate water and ethyl acetate were added to the reaction solution for extraction. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 320 mg of a light yellow solid.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=O)=[CH:30][N:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([C:31]3[CH:30]=[N:29][C:28]([OH:27])=[CH:36][CH:35]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)c1ccc(O)nc1
Product: CON=C1C[C@@H](c2noc(-c3ccc(O)nc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 50 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 6-hydroxynicotinic-acid, the title compound was obtained in 50% yield (90% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:29][C:26]2[S:25][C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)=[N:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(CNc3ccc(F)cc3)s2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
21 mg (0.19 mmol) 4-Fluoroaniline was dissolved in tetrahydrofurane (1 ml). 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde was added. The suspension was stirred at room temperature for 10 minutes. 133 mg (0.56 mmol) sodium triacetoxyborohydride and 23 mg (0.38 mmol) acetic acid were added and the reaction was stirred at room temperature over night. Since the reaction was not complete the same amount of 4-fluoroaniline, sodium triacetoxyborohydride and acetic acid were added and the reaction stirred at room temperature over night. 2N aqueous NaOH solution was added and the reaction was extracted once with methylene chloride. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with ethyl acetate yielding 22 mg (26%) [5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 410.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.63 (s, 1H), 7.28-7.16 (m, 4H), 6.95-6.87 (m, 4H), 6.66-6.60 (m, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 2.29 (s, 3H).