Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].CO>C1COCC1>[Cl:13][CH2:14][CH2:15][NH:16][C:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:18]
Reactant: O=C=NCCCl
Reactant: Cc1cc(N)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 4-amino-2-methylquinoline (12.6 g, 80 mmol) in THF (480 mL) is added 2-chloroethylisocyanate (10.2 mL, 120 mmol) at rt. The reaction mixture is stirred for 40 h at rt. MeOH (100 mL) is added, and stirring is continued an additional hour. The reaction mixture is evaporated and the residue is taken up in CH2Cl2. The organic layer is shaken with 1 N HCl (250 mL), and the resulting precipitate is collected by filtration. The solid is washed with CH2Cl2 (100 mL), saturated NaHCO3 (2×100 mL), and with water (4×100 mL). The resulting solid is dried under HV at rt for 14 h to provide the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:11]1[C:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH:19]=2)[NH:14][C:13](=O)[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8].P(Cl)(OCC)(OCC)=O.[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH2:37][N+:38]#[C-:39])=[CH:35][CH:34]=1>C1COCC1>[C:7]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:39]=[N:38][C:37]([C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)=[C:13]2[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N1C(=O)C(=O)NC2CCCC=C21
Reactant: [C-]#[N+]Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0M in THF, 24.1 ml) is added to a mixture of 1-(tert-butyl)tetrahydroquinoxalin-2,3-dione (XXXI, 5.00 g) and THF (54.0 ml) at -20°. The mixture is allowed to warm to 0° over 30 min. After cooling to -40°, diethyl chlorophosphate (3.53 ml) is added and the solution is allowed to warm to 20°-25° over 40 min. After cooling to -78°, a solution of 4-fluorobenzyl isocyanide (3.62 g) and THF (5.0 ml) is added. Potassium tert-butoxide (24.1 ml) is then added dropwise over several min. The mixture is stirred at -78° for 30 min and is allowed to warm slowly to 20°-25° over 2 hr. Aqueous workup (ethyl acetate, magnesium sulfate) and purification by flash chromatography eluting with ethyl acetate/hexane (1/2), pooling the appropriate fractions and concentration gives the title compound, mp 135°-137°; IR (mineral oil) 2953, 2925, 2855, 1668, 1498, 1299 and 751 cm-1 ; NMR (CDCl3) 8.31, 8.22, 7.63, 7.55, 7.05-7.35 and 1.76 δ; MS (m/z) 335, 279.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4CCNCC4)c3F)s2)c1
Yield: 45.5 %

Procedure:
A solution of tert-butyl 4-((3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamido)methyl)piperidine-1-carboxylate (0.78 g, 1.40 mmol, described in Example 3) in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred at 23° C. for 1 hour. The reaction was then concentrated to dryness and diluted with 10% water in acetonitrile+0.05% trifluoroacetic acid. This was purified on Preparative HPLC (acetonitrile/water/ammonium acetate) to give the title material (0.292 g, 45%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.12-1.23 (2H, m), 1.69 (2H, d, J=11.9 Hz), 2.31 (3H, s), 2.56-2.65 (2H, m), 3.08 (2H, d, J=12.4 Hz), 3.15 (2H, t, J=6.19 Hz), 6.86 (1H, d, J=5.31 Hz), 6.92 (1H, s), 7.06 (1H, t, J=5.31 Hz), 7.82 (1H, s), 8.17 (1H, d, J=5.30 Hz), 8.26 (1H, d, J=5.05 Hz), 8.74 (1H, t, J=6.06 Hz). LC/MS (M+H)+: 459. HPLC ret. time (Condition C): 3.333 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15](Br)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15]([C:32]#[C:31][CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1
Reactant: C#CCc1ccccc1
Reactant: COC(=O)c1cccc(Cn2cc3nc(Br)ccc3cc2=O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Cn2cc3nc(C#CCc4ccccc4)ccc3cc2=O)c1

Procedure:
The coupling of 3-(7-bromo-3-oxo-2H-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester (1.20 g, 3.22 mmol) with 3-phenyl-1-propyne (1.00 mL, 8.06 mmol) using triethylamine (0.92 mL, 6.60 mmol), CuI (0.044 g, 0.23 mmol), and Pd(Ph3P)4 (0.15 g, 0.13 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). A portion of the resulting red oil is purified on the preparatory HPLC using 80:20 acetonitrile/water (0.1% TFA), evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated to dryness. Drying will afford the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[NH4+].[Cl-]>C1CCCCC1.C1COCC1>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]3=[O:14])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: BrCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc3c(c2)OCO3)CCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-piperidin-2-one (4.8 g, 25.4 mmol) in abs. THF (200 ml) is cooled to −70° C.; sec.-BuLi (23.4 ml of a 1.3 M solution in cyclohexane; 30.4 mmol) is added dropwise under an Ar atmosphere and the mixture is stirred at −70° C. for 30 min. A solution of 5-bromomethyl-benzo[1,3]dioxole (see Harrowven et al., Tetrahedron (2001), 57(29), 4447) (8.0 g, 37.2 mmol) in abs. THF (80 ml) is added dropwise, stirring is continued at −70° C. for 3 h, then at rt for 15 h. sat. aq. NH4Cl solution is added, the organic layer is separated, dried over Na2SO4 and evaporated. The oily residue is purified by MPLC (140 g silica gel, eluent cyclohexane, then cyclohexane:AcOEt 7:3) to give 3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one as a yellow oil. Preparative resolution using a Chiralpak AD 5×50 cm/20 μm column (Daicel Chiral Technologies, Inc., Exton USA; a chiral stationary phase); eluent hexane: isopropanol 90:10; flow 80 ml/min; UV detection (210 nM) gives (−)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one ([α]Drt=−61.1° (c=0.5, EtOH)).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6].CO>O.[OH-].[Na+]>[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(=O)c1cc(C)nc(CC(C)C)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc(C)nc(CC(C)C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of hydroxylamine hydrochloride (120 mg, 1.732 mmol) in water (0.5 mL) and 1 N aq. NaOH (1.2 mL) is added to 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (276 mg, 1.44 mmol). The solution is stirred at 80° C. for 2 h and MeOH is added to maintain homogeneity of the mixture. The mixture is cooled to rt and the precipitate that forms is collected, washed with water and dried in vacuo to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone oxime (258 mg) as a white solid; 1H NMR (D6-DMSO): δ 0.88 (d, J=6.5 Hz, 6H), 1.98-2.10 (m, 1H), 2.13 (s, 3H), 2.45 (s, 3H), 2.56 (d, J=7.0 Hz, 2H), 7.22 (s, 1H), 7.27 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC(C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (2 mL, 2 M, 4.0 mmol) was added to a solution of methyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}pyrrolidine-3-carboxylate (570 mg, 1.22 mmol) in a 1:1 mixture of MeOH:H2O (30 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (100 mL). The solvent was concentrated to 100 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 480 mg (87%); MS (ESI) (M+H)+=450.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=3[CH:18]=2)(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:12][CH2:13][C:14]1[O:15][C:16]2[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=2[CH:18]=1)=[N+:26]=[N-:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 70 °C
Yield: 74.6 %

Procedure:
To a solution of the product of step C (2.3 g, 5.35 mmol) in dimethylformamide (11 mL) was added sodium azide (1.2 g, 18.73 mmol) at ambient temperature. The reaction mixture was heated at 70° C. for 2 h, cooled and quenched with water then extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(2-azidoethyl)-5-bromo-7-chlorobenzofuran (1.2 g, 75%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.52-7.49 (m, 1H), 7.37-7.35 (m, 1H), 6.50 (s, 1H), 3.67 (t, J=6.8 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:33](Cl)(Cl)=[O:34]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:33]2=[O:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2O)c1
Reactant: O=C(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2Cn2c(=O)oc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {2′-[(2-hydroxy-phenylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:4][CH2:3]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:21]2=[C:22]([CH:25]=1)[O:23][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][N:9]3[C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[N:6]=[C:5]3[C:2]3([CH3:1])[CH2:4][CH2:3]3)[CH:35]=[CH:34][C:19]=1/[C:20]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: CC1(c2nc3ccccc3[nH]2)CC1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4(C)CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 39.8 %

Procedure:
Using 2-(1-methylcyclopropyl)-1H-benzo[d]imidazole (58 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (60 mg, 40%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 44 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 21-b, (2 g, 5 mmol), ethyl methylphosphite (1.08 g, 10 mmol) and Et3N (1.25 g, 12.5 mmol) in THF (20 ml) was added PdCl2(dppf) (360 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (dichloromethane:methanol=50/1) to provide the product, 21-c, (950 mg, 44%).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH2:28])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CC(C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH:28][C:11]([NH2:12])=[S:10])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1CNC(N)=S
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Benzoyl chloride (1.2 ml) was added dropwise to sodium thiocyanate (0.90 g) in acetone (50 ml). When the addition was complete the mixture was refluxed for 15 minutes, cooled to room temperature and (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) in acetone (5 ml) added. The mixture was refluxed for 2 hours, cooled to room temperature and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title product (1.95 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 2-dimethylaminoethanol (6.67 mL, 64.8 mmol) in anhydrous THF (100 mL), at 0° C., potassium tert-butoxide (6.66 g, 59.4 mmol) was added. The mixture was stirred at 0° C. for 1 h, then 4-fluoro-2-nitro-benzoic acid tert-butyl ester (10 g, 41.5 mmol) in anhydrous THF (50 mL) was added dropwise. After 2 hours at 0° C., the mixture was poured into water (1 L) and extracted with ethyl acetate (4×200 mL). The organic phase was washed with water, brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash chromatography, using dichloromethane-EtOH-33% NH4OH 9:1:0.01 as eluant, to give the title compound (4.53 g) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:23])CC)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][F:23])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CF)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of (6-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (prepared as illustrated in example 135) (0.20 g, 0.90 mmol) in dichloromethane (20.00 ml) was cooled under argon to 0° C. and (diethylamino)sulfur trifluoride (DAST) (0.20 g, 1.25 mmol) was added dropwise. The resulting solution was stirred at room temperature for 30 min, then quenched by pouring the reaction mixture onto saturated sodium bicarbonate. The organic phase was separated, dried over sodium sulphate and evaporated to a orange oil, which was purified by flash chromatography (dichloromethane/ether) to yield (6-fluoromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.10 g, 51%) as a colorless oil, MS (ISP): m/e=211.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][N:14]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)c1ccnc(N)c1
Reactant: S=C=NCCC1=CCCCC1
Solvent: CN(C)C=O
Product: CC(C)c1ccnc(NC(=S)NCCC2=CCCCC2)c1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (0.36 g, 2.2 mmol) and 2-amino-4-isopropylpyridine (0.36 g, 2.2 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 96 h. The reaction was cooled to room temperature, solvents removed under reduced pressure, taken up in ethyl acetate, washed with 1N aqueous HCl. The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 169 mg (5.6%) of the titled product: mp 105°-106° C.; IR (KBr, cm-1) 3215, 2931, 1614 1556, 1534, 1487, 1199; 1H NMR (300 MHz, DMSO-d6) δ 11.65 (t, 1H), 10.40 (S, 1H), 8.30 (d, 1H), 7.20 (S, 1H), 6.93 (d, 1H), 5.52 (s, 1H), 3.63 (q, 2H), 2.80 (m, 1H), 2.22 (t, 2H), 1.95 (m, 4H), 1.62-1.42 (m, 4H), 1.18 (d, 6H); MS (FD) m/e 303 (M+); UV (EtOH) 290 nm (ε=17565), 266 nm (ε=18863), 247 nm (ε=15125), 203 nm (ε=23091). Anal. Calcd for C17H25N3S: C, 67.28;H, 8.30; N, 13.85. Found: C, 67.55; H, 8.48; N, 13.94.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O.[Cu]=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1
Temperature: 150 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester (0.100 g, 0.3 mmol), 4-bromo-1-methyl-1H-pyrazole (0.0966 mL, 0.9 mmol), copper(II) oxide (0.048 g, 0.6 mmol) and potassium carbonate (0.054 g, 0.39 mmol) were combined in pyridine (1 mL) in a sealed vial. The reaction was heated to 150° C. overnight then cooled, then diluted with EtOAc. The mixture was washed with HCl (1 M aq.) and brine, and the organic portion was dried and concentrated to yield the title compound as a crude mixture that was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=[O:28])=[O:27])[C:7]([C:37]#[N:38])=[C:6]([CH3:39])[NH:5][C:4]=1[CH3:40])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:37]([C:7]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)(=[O:27])=[O:28])[C:3]([C:1]#[N:2])=[C:4]([CH3:40])[NH:5][C:6]=1[CH3:39])#[N:38]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NS(=O)(=O)Cc2ccc(F)cc2)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)Cc4ccc(F)cc4)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28 mg (0.05 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-{[(4-fluoro-benzyl)sulfonyl]amino}-1H-indazole-1-carboxylate (Example 13A), dissolved in dichloromethane (1 ml), were treated with 0.042 ml (0.55 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 10 mg (41% of th.) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:42])([CH2:40][OH:41])[C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][OH:41])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)(C)CO)CC2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.2 %

Procedure:
A solution of N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2,2-dimethyl-3-hydroxy propanoic acid (86 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.73 mmol) and 1-hydroxybenzotriazole (114 mg, 0.73 mmol). The reaction mixture was stirred under nitrogen at room temperature for 36 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. Trituration of the residue with diethylether (5 ml) gave the title compound (270 mg) as a white solid.