Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.[OH-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH2:23][NH2:24])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(CN)cc(OC)c21
Yield: 59.4 %

Procedure:
To a solution of 100 mg (0.286 mmol) 2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile in 4 ml THF, LiAlH4 (54 mg, 1.43 mmol) is added. The reaction mixture is stirred at reflux temperature for 2 h. After that methanol (0.5 ml) and 5 ml 15% NaOH-solution is added. This mixture is filtered and the filtrate is extracted (3×) with EtOAc. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 60 mg of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][CH:23]=1>CN(C=O)C.O.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][CH:23]=2)[N:3]=1
Reactant: Cc1ncc(CBr)s1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (441 mg, 1.53 mmol) in anhydrous DMF (3 mL) were added potassium carbonate (422 mg, 3.05 mmol), and 5-(bromomethyl)-2-methylthiazole (440 mg, 2.30 mmol) at ambient temperature and under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature overnight (about 18 hours). The reaction mixture was diluted with water (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic extracts were concentrated, and the residue subjected to flash liquid chromatography on silica with Hexanes:EtOAc (10:1) as the eluent to afford the desired product (611 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]1([C:21]2[N:22]=[C:23]([SH:32])[O:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:32][C:23]2[O:24][C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: O=C(CSc1nc(-c2ccccc2)c(-c2ccccc2)o1)N1CCCc2ccccc21
Yield: 40 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4,5-diphenyloxazole-2-thiol as the nucleophile to yield 20 as an off-white solid (40%): MS m/z: 427 (M+H)+. Anal. Calcd. For, C26H22N2O2S: C, 73.21; H, 5.20; N, 6.57; S, 7.52. Found: C, 73.49; H, 5.13; N, 6.57; S, 7.42.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Br:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Nc1ccc(F)c(Br)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-bromo-4-fluoroaniline [Oakwood Products, Inc., product #013091] as the starting materials. LCMS for C12H15BrFN6O4S (M+H)+: m/z=437.0, 439.0. 1H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.90 (s, 1H), 7.17 (m, 2H), 7.09 (dd, J=6.3, 2.5 Hz, 1H), 6.26 (t, J=6.1 Hz, 1H), 3.33 (m, 2H), 3.13 (q, J=6.0 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: C(OC(=O)C(N)(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)C)C.C(O)(C(F)(F)F)=O.[CH2:37]([O:39][C:40](=[O:71])[C:41]([C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:60][C@H:61]3[CH2:66][CH2:65][C@H:64]([C:67]([CH3:70])([CH3:69])[CH3:68])[CH2:63][CH2:62]3)[C:52]=2[C:56]([F:59])([F:58])[F:57])[N:47]=1)([N+:43]([O-])=O)[CH3:42])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:71])[C:41]([NH2:43])([C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:60][C@H:61]3[CH2:62][CH2:63][C@H:64]([C:67]([CH3:70])([CH3:69])[CH3:68])[CH2:65][CH2:66]3)[C:52]=2[C:56]([F:57])([F:59])[F:58])[N:47]=1)[CH3:42])[CH3:38]
Reactant: CCOC(=O)C(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1)[N+](=O)[O-]
Agent: CCOC(=O)C(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(N)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propionic acid ethyl ester was synthesized as per 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propionic acid ethyl ester (Example 17) in 20% yield (TFA salt) using 2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-nitro-propionic acid ethyl ester as starting material.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24](Cl)[CH:23]=[N:22]1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:28][C:25]1[C:26](=[O:27])[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][C:24]=1[NH:14][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: CC(C)n1ncc(Cl)c(Cl)c1=O
Reactant: NCc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1ncc(NCc2cccc(OCc3ccccc3)c2)c(Cl)c1=O
Reaction time: 4.5 h

Procedure:
A mixture comprising 8.24 g of 3-benzyloxybenzylamine hydrochloride prepared in Reference Example 2A, 3.11 g of 2-i-propyl-4,5-dichloro-3(2H)pyridazinone, 7.26 g of potassium carbonate, 30 ml of 1,4-dioxane and 90 ml of water was refluxed under stirring for 4.5 hours. The majority of 1,4-dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, and then treated with cerite to remove the precipitate. The organic layer was separated, and washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. Then, the solvent was distilled off. The pale yellow oily substance thereby obtained was crystallized from ether-n-hexane to obtain 2.51 g of the above identified compound having a melting point of from 106° to 108° C. as colorless crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[NH:17]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16]1
Reactant: OC1(c2c[nH]c3ncccc23)CCCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OC1(c2c[nH]c3ncccc23)CCCNC1
Yield: 88.5 %

Procedure:
Compound 3 (2.4 g, 7.8 mmol), 1.5 g ammonium formate (23.8 mmol) and 20% Pd(OH)2/C (240 mg) were combined in MeOH (50 ml) and warmed to reflux for 2 hours. The mixture was cooled, filtered, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1 N NH3/MeOH) gave the title compound (1.5 g, 6.9 mmol, 88%) as amorphous material. 1H-NMR (400 MHz, D6DMSO): δ 11.3 (bs, 1H), 8.17-8.13 (m, 2H), 7.24 (s, 1H), 7.0-6.95 (m, 1H), 3.0-2.89 (m, 2H), 2.85 (d, J=13 Hz, 1H), 2.6-2.51 (m, 1H), 2.06-1.8 (m, 3H), 1.5-1.42 (m, 1H). (TLC MeOH/triethylamine (97/3 Rf 0.16).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reactant: C1CCNCC1
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCCCC2)CC1

Procedure:
Reaction of 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole described in Example 2 with piperidine under conditions described in Example 1 gives 2-tert-butyl-6-[(piperidin-1-yl)thiocarbonylamino]-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 202°-206°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](O)=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:23])[O:4][N:3]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([Cl:26])=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)ccc2c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)ccc2c1Cl
Yield: 95 %

Procedure:
Ethyl 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-3-quinolinecarboxylate (for a preparation see Intermediate 7, 20 g, 64.04 mmol) was reacted with thionyl chloride (326 ml) and heated to reflux overnight. Excess thionyl chloride was co-evaporated with toluene. The crude product was triturated with iPr2O and filtered to give the title compound as a brown powder (20.15 g, 95%).
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32]([Br:34])[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.[OH-].[Na+]>C1COCC1>[Br:34][C:32]1[CH:33]=[C:28]2[C:27]([C@@H:35]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=3[Cl:45])[CH3:36])=[CH:26][NH:25][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12

Procedure:
To a solution of ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (722 mg, 1.00 mmol) in THF (20 mL) was added NaOH (5N in H2O, 1 mL) at 0° C. with stirring. After stirring for 1 h at that temperature, solvents were removed under reduced pressure to give a residue which was then purified by flash chromatography (eluent: Hexane/ethyl acetate: 75/25, v/v) to give the title compound. 1H NMR and LCMS data match with the data for the racemic compound. Optical rotation: [α]25D=−112.8° (c=1.0, MeOH); [α]25D=−152.6° (c=1.0, CH2Cl2). HPLC (Chiralcel OD-RH, solvent 60:40 acetonitrile/water isocratic, flow rate 0.5 mL/min, column temperature 30° C., UV detection at 220 nm): tR=28.0 min. C15H10BrCl2FN2 (388.07): Calculated: C, 46.43; H, 2.60; Br, 20.59; Cl, 18.27; F, 4.90; N, 7.22. found C, 46.36; H, 2.49; Br, 20.38; Cl, 18.31; F, 4.79; N, 7.09. A crystal structure of Example 85, prepared using this material, bound to cMet confirmed the absolute configuration as shown.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:44][C:40]5[CH:41]=[CH:42][CH:43]=[C:38]([S:35]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)(=[O:37])=[O:36])[CH:39]=5)[N:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc(Nc3ccnc(Nc4cccc(S(=O)(=O)N5CCOCC5)c4)n3)ccc21

Procedure:
The title compound was prepared following the procedure of Example I with N2-(5-tert-Butyl-isoxazol-3-yl)-N5-(2-chloro-pyrimidin-4-yl)-1-methyl-1H benzoimidazole-2,5-diamine (35 mg, 0.09 mmol) and 3-(Morpholine-4-sulfonyl)-phenylamine (23 mg, 0.10 mmol) to afford an off white solid (32 mg, 005. mmol). MS (ESI) m/z=605 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:20]=1)[CH2:8][N:9]([CH3:19])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[F:21][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)=[CH:20][C:7]=1[CH2:8][N:9]([CH3:19])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CCC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 63 (268.44 mg; 0.83 mmol) and Intermediate 28 (192.22 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.25-8.22 (m, 1H), 8.17 (dd, J=7.8, 1.9 Hz, 1H), 8.12-8.07 (m, 1H), 7.36-7.23 (m, 4H), 7.20-7.12 (m, 2H), 4.23 (s, 2H), 3.65 (s, 2H), 3.33 (s, 3H), 2.80 (t, J=7.3 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.27 (s, 3H), 2.08 (s, 3H), 1.45 (s, 9H). 19F NMR (CDCl3) δ-113.6 ppm. LC/MS (Method B): 546.4 (M+H)+. HPLC (Method A) Rt 5 min (Purity: 97.8%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:26]([O:28][CH3:29])=[O:27])([N:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[CH3:29][O:28][C:26]([C:11]1([N:14]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:27]
Reactant: [H][H]
Reactant: COC(=O)C1(N(OCc2ccccc2)C(C)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1(N(OCc2ccccc2)C(C)=O)CCNCC1

Procedure:
A mixture of 12.45 g of 1-benzyl-4-methoxycarbonyl-4-(N-phenylmethoxyacetamido)piperidine and 250 ml of acetic acid is hydrogenated at room temperature and pressure with 1.5 g of 10% palladium-on-charcoal catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off. The acetic acid is flash evaporated, the residue is dissolved in toulene and stirred with 10 g of anhydrous sodium carbonate. The solid is filtered and the filtrate is flash evaporated to obtain 4-methoxycarbonyl-4-(N-phenylmethoxyacetamido)piperidine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.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>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:16]=[C:15]([OH:17])[C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Oc1cc(O)c2ccccc2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12

Procedure:
4-Hydroxy-2-naphthyl trifluoromethanesulfonate (100 mg, 0.34 mmol), 4-(trifluoromethoxy)phenyl boronic acid (0.14 g, 0.68 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) in DME/2M K2CO3 (1/1) were heated at reflux under an argon atmosphere. After approximately 2 hours the solution was cooled and partitioned between aqueous 1N hydrochloric acid and ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 3.94 min. (M+H)=305
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.[NH4+].[OH-]>CCOC(C)=O.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:31])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:23]([CH3:27])([CH3:28])[C:24]3([CH3:25])[CH3:26])=[O:21])=[CH:9]2)[CH2:5][CH2:6]1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(N)=O)cc23)C1(C)C
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and concentrated aqueous NH4OH (2 mL) in 5 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (20 mg, 0.052 mmol, 20% yield). 1H NMR (CDCl3, 300 MHz) δ ppm 1.32 (s, 6H), 1.36 (s, 6H), 1.39-1.58 (m, 4H), 1.92 (s, 1H), 2.08-2.23 (m, 1H), 3.34 (dt, J=11.4, 2.5 Hz, 2H), 3.94-4.04 (m, 2H), 4.08 (d, J=7.1 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 383 (M+H)+; Anal. Calculated for C23H30N2O3.0.4H2O: C, 70.89; H, 7.97; N, 7.19. Found: C, 70.77; H, 7.91; N, 7.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:11][C:4]1[CH:5]=[N:6][C:7]([CH:8]2[CH2:9][CH2:10]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]#[N:17]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
5-chloro-6-cyclopropylpyridin-3-ol (250 mg, 1.47 mmol), 3-bromo-4-fluorobenzonitrile (Preparation 37, 295 mg, 1.47 mmol) and potassium carbonate (611 mg, 4.42 mmol) were suspended in dimethylsulfoxide (6 mL). The reaction mixture was stirred at 5 hours at 50° C. then water (60 mL) was added and the suspension was extracted by ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a clear oil which solidified on standing (485 mg, 94%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:10][CH2:9]2)[N:7]=1.[C:13]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH2:28])[CH3:27])=[CH:21][CH:20]=1)([O:15][CH3:16])=[O:14].CS(C)=O.CCOCC>C(Cl)Cl.CO>[C:13]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:28][CH2:9][CH:8]([OH:10])[C:6]2[N:7]=[C:3]([C:2]([F:12])([F:11])[F:1])[S:4][CH:5]=2)[CH3:27])=[CH:21][CH:20]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: FC(F)(F)c1nc(C2CO2)cs1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared by analogy to Example 104 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)ethylene oxide with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine and dimethyl sulfoxide at 90° C. for 16 hours. The base is obtained by extraction by shaking with ether and purification on a silica gel column using methylene chloride/methanol 20:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]([CH:12]2[CH2:14][CH2:13]2)[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)C1CC1
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(Nc1cccc(Cl)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
To a solution of 3-chloroaniline (1.27 g, 10 mmol) in 1,2-dichloroethane (20 ml) were added molecular sieves (4 g, size 0.4 nM) and cyclopropyl methyl ketone (0.84 g, 10 mmol). After stirring the mixture for 5 min at room temperature sodium triacetoxyborohydride (3.18 g, 15 mmol) and acetic acid (0.6 g, 10 mmol) were added. The reaction mixture was stirred at room temperature overnight. For workup dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=9:1) to yield a colourless liquid (0.083 g, 4.5%); MS (ISP): 196.3 (M+H)+.).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[CH2:34](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]3)=[CH:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOCC
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1

Procedure:
To a solution of 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.17 mmol, 0.08 g) and aqueous formaldehyde (37%, 0.83 mmol, 0.07 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.0 mmol, 0.42 g). The mixture was shaken for 12 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 0-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 423 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.26-7.47 (3 H, m), 7.02-7.11 (2 H, m), 5.35-5.60 (1 H, m), 4.37-4.48 (1 H, m), 3.97-4.13 (1 H, m), 3.67 (1 H, d), 3.23-3.53 (2 H, m), 2.92 (3 H, s), 1.95-2.62 (12 H, m), 1.75-1.92 (3 H, m), 1.29-1.68 (6 H, m).