Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([Br:18])=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:19]=1)(=O)C.C(=O)(O)[O-].[Na+].[OH-].[NH4+:33].C1(S(Cl)(=O)=O)C=CC=CC=1>O.C(Cl)(Cl)Cl>[NH2:33][C:10]1[C:9]2[N:19]=[C:6]([CH2:5][OH:4])[N:7]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:8]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:18])=[CH:13][C:12]=2[N:11]=1
Reactant: [NH4+]
Reactant: CC(=O)OCc1nc2cnc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2cc(Br)ccc2c2c1nc(CO)n2CC1CCOCC1
Reaction time: 18 h
Yield: 52.1 %

Procedure:
3-Chloroperoxybenozic acid (2.4 g, 50% pure, 7.0 mmol) was added to a mixture of [7-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (2.3 g, 5.4 mmol) and chloroform (27 mL) at ambient temperature. The reaction was stirred at this temperature for 18 hours. Saturated aqueous sodium bicarbonate (50 mL) and water (50 mL) were then added to the reaction and the layers were separated. The aqueous layer was extracted with additional dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to a dark oil. This oil was dissolved in methanol (27 mL) and to this solution was added 15 M ammonium hydroxide (3.6 mL, 54 mmol) and benzene sulfonyl chloride (2.9 mL, 23 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours before adding additional 15 M ammonium hydroxide (3.6 mL, 54 mmol) and benzene sulfonyl chloride (2.9 mL, 23 mmol). The reaction was stirred 18 hours. The reaction was then concentrated under reduced pressure and diluted with saturated aqueous sodium bicarbonate and chloroform. A suspension resulted that was filtered to afford a solid that was stirred with saturated aqueous sodium bicarbonate and filtered to give 1.1 g of [4-amino-7-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol as a white solid.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:8][C:7]=1[CH3:29])C.S(=O)(=O)(O)O>CO>[CH3:29][C:7]1[CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CCOCOc1ccc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(CCCc2ccc(O)c(C)c2)cc1C(=O)OC

Procedure:
In a manner similar to Example 1f, by reacting 6.9 g (17.2 mmol) of dimethyl 4-[3-(4-ethoxymethoxy-3-methylphenyl)propyl]phthalate in 100 ml of methanol with 3 ml of concentrated sulphuric acid. A colorless oil is obtained (m=5.2 g; y=88%).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]#[N:13])[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]([NH2:6])=[NH:13])[CH3:8]
Reactant: [NH4+]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C#N
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)N
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Trimethylaluminium (10 mL, 2 Molar solution in hexanes) was added dropwise to a slurry of ammonium chloride (1.07 g, 0.02 Mol) in toluene (15 mL) at 0° C. The mixture was stirred without cooling until gas evolution stopped. 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)benzonitrile (the compound of Preparation 7) (3.23 g, 0.01 Mol) was then added and was washed in with toluene (5 mL) before the reaction was stirred at 80° C. for 40 h. After cooling to room temperature silica gel (15 g) and dichloromethane (100 mL) were added. The mixture was then filtered and the solids were washed with dichloromethane/methanol mixtures. The combined filtrate and washings were evaporated and the residue was chromatographed over silica gel using dichloromethane methanol mixtures to afford 1.08 g, 28.6% of the title compound. M/Z=found 341 (M+H). 1H NMR (CD3OD) 1.28 (t, 3H) 1.49 (t, 3H) 2.97 (q, 2H) 3.14 (br, s, 4H) 3.33 (br, s, 4H) 4.32 (q, 2H) 7.45 (d, 1H) 7.96 (d, 1H) 8.05 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:33][C@H:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([NH2:42])=[O:41])[CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:40]([C@H:36]1[CH2:37][CH2:38][CH2:39][C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=2)=[O:23])[CH2:35]1)(=[O:41])[NH2:42]
Reactant: NC(=O)[C@H]1CCC[C@H](N)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C(N)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.15 g, 0.33 mmol), trans-3-aminocyclohexanecarboxamide hydrochloride (88 mg, 0.49 mmol), HBTU (155 mg, 0.41 mmol), and HOBT (49 mg, 0.41 mmol). Then added DMF (1.0 mL) followed by N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 119 mg (62%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-carbamoyl-cyclohexyl)-amide as a white solid. MS: [M+Na]+=604.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.CCOCC>COCCOCCOC>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ncc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (1.14 g), K3PO4 (1.30 g) and 5-hydroxyindazole (0.90 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>>[CH3:1][C:2]12[O:3][CH:4]([CH:5]=[CH:6]1)[CH:8]1[C:7]([O:12][C:10](=[O:11])[CH:9]21)=[O:13]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccco1
Product: CC12C=CC(O1)C1C(=O)OC(=O)C12

Procedure:
2-Methyl furan was reacted with maleic anhydride in a manner similar to the procedure described in Example 1 to yield 1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride. An amount of 28 mmol of this compound was dissolved in methanol (50 ml). To this solution, solid sodium methoxide (56 mmol) was added at 0° C. The resulting deep orange solution was stirred for 18 h at room temperature, after which the solvent was evaporated in vacuo. After drying for 1 h at 77° C. under reduced pressure, the solid was dissolved in water and heated under reflux for 5 h followed by treatment with charcoal (stirring for 30 min at reflux). Filtration and evaporation under reduced pressure yielded 3-methylphthalic acid disodium salt (4.4 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][C:14]([OH:16])=[O:15].CCOCC.Cl>C([O-])([O-])=O.[Na+].[Na+]>[C:14]([CH2:13][NH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:16])=[O:15]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)CNc1ccc(Br)cc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (2 g, 9 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was slowly added dropwise. Then, after stirred for 20 hours at 80° C., the reaction mixture was cooled down to room temperature. 50 ml of ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After evaporation, a light brown solid was obtained. The solid was purified by silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1) to obtain a white solid (2-(N-carboxymethylamino)-5-bromobenzoic acid) (1.55 g, yield: 60%; mp: 178-180° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:14]([OH:16])=[O:15])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-methyl 2-[4-(4-chlorophenyl)phenoxy]3,3,3-trifluoro-2-methylpropionate (20 g.), methanol (120 ml.) and 5.2 N-aqueous potassium hydroxide (13 ml.) is stirred at ambient temperature for 18 hours. Most of the methanol is evaporated in vacuo, and water is added. The mixture is washed with light petroleum, and concentrated hydrochloric acid added to the aqueous phase. The mixture is extracted with ether, and the extract is dried with sodium sulphate, treated with carbon and evaporated. The residue is crystallised from toluene to give (±)-2[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid, m.p. 198°-199° C. (8.35 g.).
Reaction SMILES: [CH2:1]([O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Br:31])C1C=CC=CC=1>>[BrH:31].[CH2:1]([O:13][CH:14]1[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:20])([CH3:21])[CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCc1ccccc1
Agent: CCCCCCCCCCCCOC1CC(C)(C)NC(C)(C)C1
Product: Br

Procedure:
A misture of 13.0 parts of 4-dodecyloxy-2,2,6,6-tetramethylpiperidine and 3.42 parts of benzyl bromide was heated at 100° C. for 48 hours. Petroleum ether (b.p. 40°-60° C.) was added to the cooled reaction mixture and the 4-dodecyloxy-2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction was filtered off. The petroleum ether solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-dodecyloxy-1-benzyl-2,2,6,6,-tetramethylpiperidine having a boiling point of 200° C. at 0.5 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: [F:1][C:2]([C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[CH:7][C:6]=1[F:24])([F:4])[CH3:3].N1C2C(=CC=CN=2)C=CC=1C(O)=O>>[F:4][C:2]([C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C:11]([C:15]([F:17])([F:18])[F:16])=[N:12]2)=[CH:7][C:6]=1[F:24])([F:1])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(F)c(C(C)(F)F)nc2nc1C(F)(F)F
Agent: O=C(O)c1ccc2cccnc2n1
Product: CC(F)(F)c1nc2nc(C(F)(F)F)c(C(=O)O)cc2cc1F

Procedure:
In a similar procedure to Example 1, Stage 2, ethyl 7-(1,1-difluoroethyl)-6-fluoro-2-trifluoromethyl-[1,8]-naphthyridine-3-carboxylate was hydrolysed to the required naphthyridine carboxylic acid as a colourless solid. 1H NMR (CDCl3) δ: 9.15 (1H, s), 8.80 (1H, d), 2.20 (3H, t). Molecular ion: (MH)+325.)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12](B(O)O)=[C:11]([F:19])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1>>[F:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:14]=[C:13]([F:15])[C:12]=1[C:21]1[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1
Reactant: CCc1ccc(Br)s1
Reactant: CCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Product: CCc1ccc(-c2cc(F)c(-c3ccc(CC)s3)c(F)c2)cc1

Procedure:
The compound 2-(3,5-difluoro-4′-ethylbiphenyl-4-yl)-5-ethylthiophene (PUS-2-2) is prepared analogously to Example 2 from 4′-ethyl-3,5-difluoro-4-biphenylboronic acid and 2-bromo-5-ethylthiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Nc1cncnc1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cncnc1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-pyrimidine (CAS:[591-55-9] (J. Org. Chem., 20, 829 (1955)) was performed in accordance with the general method of Example 78, step 3 to yield the tide compound as a light brown solid, MS (ISP): m/e=259.3 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[NH2:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-(1-Benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (17.8 mmol) was dissolved in 4M HCl-dioxane (67 mL) at 0° C., the solution stirred at 25° C. for 1 hour, the reaction concentrated and the residue triturated with ether. Yield, 5.0 g, 98%; PBMS 251 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>>[C:46]([C:45]1[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:47]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: N#Cc1ccccc1OCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4C#N)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.057 g of 2-(3-bromopropoxy)benzonitrile are used to prepare the title compound. Rf=0.18 (2:1 EtOAc-heptane); Rt=5.58.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:45][NH2:46]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:45][NH:46]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (235 mg, 0.538 mmol), 5 ml of EtOH, Hunig's base (0.376 ml, 2.153 mmol), and hydrazine anhydrous (0.101 mL, 3.23 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached 100° C. while heating, the solid in the mixture was all dissolved. After overnight, there were yellow suspension as well as some black colored solid formed. LCMS showed mainly product. The black solid and the yellow solid were carefully separated due to the black solid being heavier than yellow solid in the CH3OH solvent. The yellow solid in CH3OH was filtered and washed with CH3OH to remove the color and afford the title compound (157 mg) as a white solid. LC-MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.05-1.35 (m, 8H), 1.50-1.88 (m, 9H), 2.24 (s, 1H), 2.90 (s, 1H), 3.46-3.60 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16].C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:4]1[C:3]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:2]([F:1])[C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nccc2c1c(=O)n(C)c1c(F)c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc21

Procedure:
(S)-tert-butyl (1-((7-fluoro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.08 g, 0.175 mmol), prepared as described in Example 29, Part G, was subjected to chlorination using NCS to afford (S)-tert-butyl (1-((9-chloro-7-fluoro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2 yl)carbamate (80 mg, 0.104 mmol, 60% crude yield) as semi-solid. The material was carried forward without further purification. LC/MS (ESI) m/e 492.2 [(M+H)+, calcd for C25H32ClFN3O4 492.2].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)ccc1N

Procedure:
The title compound was prepared in analogy to the procedure described in Step 85.2 using 6-chloro-N-methyl-3-nitropyridin-2-amine (Step 102.1) at RT for 23 hr. The crude material was purified by silica gel column chromatography (25% EtOAc/hexane) to afford a purple solid. tR: 0.64 min (LC-MS 2); ESI-MS: 158 [M+H]+ (LC-MS 2); Rf=0.12 (25% EtOAc/Hexane).
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19]C=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: NC1CCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCCC1
Yield: 47 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (70 mg, 0.28 mmol), triethyl orthoformate (2 ml), cycloheptylamine (0.066 ml, 0.52 mmol), and acetic acid (0.1 ml) were used to give 45 mg (0.13 mmol, 47% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([O:40][CH3:41])[CH:33]=1>CN(C)C=O>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: COc1cc(F)ccc1C#N
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 474 mg of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 2.9 mL of dimethylformamide was added 60 mg of sodium hydride. The resulting mixture was stirred for 30 minutes at 0° C. then 208 mg of 4-fluoro-2-methoxybenzonitrile was added. After stirring for 30 minutes at 0° C., the temperature was allowed to warm up to room temperature and the reaction mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and dichloromethane/water was added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 95/methanol 5) to give 279 mg of 2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].C1(C)C=CC(S(O[C@H:23]2[CH2:30][CH2:29][CH2:28][C@@H:27](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][CH2:24]2)(=O)=O)=CC=1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C@H:23]2[CH2:24][CH2:25][CH2:26][C@@H:27]([N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[NH2:1])[CH2:28][CH2:29][CH2:30]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCC[C@@H](OS(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1[C@H]1CCC[C@@H](n2c(N)nc3ccccc32)CCC1
Reaction time: 0.5 h

Procedure:
To a hot (60° C.) solution of 2-aminobenzimidazole (0.22 g; 1.65 mmol) in DMF (25 ml) was added sodium hydride (70 mg; 60% dispersion in mineral oil), and the mixture was stirred for 30 minutes prior to addition of cis-1,5-bis(p-toluenesulfonyloxy)cyclooctane. The resulting mixture was stirred at 100° C. for four days, cooled and filtered. The filtrate was diluted with water and the precipitate was filtered off, washed with water and dried to yield the desired product (9 mg).