Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Product: O=C(O)c1c(N2CCCC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and pyrrolidine. Yellow solid. MS (ESI): 387.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]4[N:6]([CH2:9][CH2:10][N:11]5[CH2:15][CH2:14][CH2:13][CH2:12]5)[CH:7]=[N:8][C:4]=4[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2c(c1)ncn2CCN1CCCC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)ncn4CCN3CCCC3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole (150 mg, 0.44 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (94 mg, 0.44 mmol).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][OH:15].CCCCCC>O1CCCC1>[CH2:16]([C:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])([CH2:14][OH:15])[CH2:18][CH3:19])[CH3:17]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCC(N)(CC)CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(CO)NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Benzoyl isothiocyanate (4.28 mL, 31.8 mmol) was added under nitrogen to a solution of 2-amino-2-ethylbutan-1-ol (3.7315 g, 31.8 mmol), prepared in the previous step, in 100 mL of anhydrous tetrahydrofuran (exotherm on addition). After the addition, the reaction was refluxed for 2.5 h. After cooling to room temperature, 100 mL of hexane was added. The solid that formed was collected by filtration and dried under reduced pressure to give N-({[1-ethyl-1-(hydroxymethyl)propyl]amino}carbonothioyl)benzamide (7.1406 g, 80%) as a white solid. mp 161-163° C.; MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[Cl:29])=[C:14]([Cl:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[Cl:29])=[C:14]([Cl:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)c(Cl)c2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
Powdered potassium hydroxide (0.045 g, 0.81 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-dichlorobiphenyl-4-yl)acetate (Intermediate 22-1; 0.12 g, 0.27 mmol) in tert-butanol (2.00 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 20 minutes. A thick precipitate formed so the reaction was quenched with HCl (1.620 mL, 1.62 mmol) in ethanol (20.0 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was partitioned between water (5 mL) and EtOAc (15 mL). The aqueous layer showed a pH=4˜5. The organic layer was separated and the aqueous re-extracted with EtOAc (2×5 mL). The combined organics were washed with brine (15 mL), dried over MgSO4 and evaporated in vacuo to give product. This was washed with ether (5 mL) and dried under vacuum at room temperature to give an off white solid. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% ammonia) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-dichlorobiphenyl-4-yl)acetic acid (0.063 g, 51.7%) as a colourless solid.
Reaction SMILES: C[O:2][CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:14]2[C:19]1[CH:20]=[CH:21]C(=O)NC=1.[H-].[Na+].IC.O.N>CN(C)C=O.[Cl-].[NH4+].C(OCC)(=O)C>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:14]2[C:19]1[CH:20]=[CH:21][C:3](=[O:2])[N:4]([CH3:6])[CH:5]=1
Reactant: Nc1ncnc2c1nc(-c1cccc(F)c1)n2-c1ccc(=O)[nH]c1
Reactant: COC(OC)N(C)C
Agent: N
Agent: [Cl-]
Agent: [H-]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-n2c(-c3cccc(F)c3)nc3c(N)ncnc32)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide dimethylacetal (0.5 ml, 3.76 mmol) was added to a suspension of 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1,2-dihydro-2-pyridinone (1.0 g, 3.10 mmol) in Example 2 in N,N-dimethylformamide (10 ml) and stirred in a nitrogen atmosphere at room temperature. After 1 hour, N,N-dimethylformamide dimethyl acetal (0.5 ml, 3.76 mmol) was further added thereto and stirred for additionall 5 hours. The reaction solution was ice-cooled, and 60 to 70% sodium hydride (136 mg, 3.40 mmol) was added thereto at 0 to 6° C. and stirred. After 30 minutes, iodomethane (0.29 ml, 4.66 mmol) was added dropwise thereto and stirred. After 20 minutes, conc. ammonia water (10 ml) was added thereto and stirred at room temperature. After 16 hours, the reaction solution was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate (×4), and the combined organic layers were washed with 1 N aqueous sodium hydroxide solution (×1) and a saturated aqueous ammonium chloride solution (×1), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in ethyl acetate, and the solid was collected by filtration and washed with ethyl acetate, to give the title compound in free form (703 mg). This free compound was dissolved in methanol-4N hydrochloric acid/ethyl acetate (1.5 ml) and concentrated. The residue was crystallized from methanol/ethyl acetate/diethyl ether, and the solid was collected by filtration and washed with diethyl ether, to give the title compound (697 mg, 60%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:36][CH3:37])([CH2:34][OH:35])[CH2:32][CH3:33])[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[CH2:45][O:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([CH2:45][OH:44])[CH2:48][CH2:49][NH:50][C:38]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:41])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH2:36][CH3:37])([CH2:34][OH:35])[CH2:32][CH3:33])[NH:17]1)=[O:39]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CCC(CC)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(CC)(CO)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 10.2 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 111c (1.1 g, 1.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.78 g, 5 mmol), HATU (1.2 g, 3 mmol) and iPr2NEt (1.6 mL, 9 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 10%).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CO>[Si:1]([O:8][C@H:9]([CH3:10])[C@H:11]([CH2:17][NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(C(=O)OCC)C(C)O[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-[1-(t-butyldimethylsilyloxy)ethyl]acrylate (5 g) in methanol (50 ml) was added 4-methoxybenzylamine (2.65 g) at room temperature. After stirring for 2 days, the solvent was removed from the reaction mixture. The residue was column-chromatographed on silica gel in a usual manner (eluent : a mixture of hexane and ethyl acetate, 2:1 to 1:1) to give ethyl (2S*,3R*)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (6.435 g).
Reaction SMILES: Br[CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(P(N(C)C)(N(C)C)=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC>[C:23]1([NH:22][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOC(=O)C(Nc1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of ethyl 2-bromo-3-hydroxybutanoate (10 g) and 15 ml of HMPT is added 13.2 g of aniline. The reaction is stirred at RT for 3 days and then taken up in ether followed by washing with dilute sulfuric acid, pH 3, and water. The ether phase is dried over magnesium sulfate and evaporated to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is saponified using 1.6 g of sodium hydoxide, 40 ml of methanol and 20 ml of water with stirring overnight at RT. The acid 2-phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium carbonate (2.12 g) at 35° for a few hours and worked up using ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([CH:15]([CH3:17])[CH3:16])([CH2:13][O:14][C:4]=2[CH:3]=1)[CH2:11][N:10]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O)[N:9]=3.P(Cl)(Cl)(Cl)(Cl)[Cl:32].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([CH:15]([CH3:17])[CH3:16])([CH2:13][O:14][C:4]=2[CH:3]=1)[CH2:11][N:10]([C:18]([Cl:32])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[N:9]=3
Reactant: CC(C)C12COc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)C12COc3cc(Cl)ccc3C1=NN(C(Cl)=Nc1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Yield: 7.3 %

Procedure:
To 0.50 g (0.0012 mol) of the product obtained in Step C in 20 mL of benzene was added 0.25 g (0.0012 mol) of phosphorous pentachloride. The reaction mixture was refluxed for 42 hours, cooled to room temperature, poured into a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford an off-white solid. The solid was chromatographed on silica gel using ethyl acetate (15%) and hexanes (85%) as eluents which yielded 0.04 g of a white solid, mp 148° C. to 149° C.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]=[CH:6][CH2:5]2)[CH2:3][O:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[O:2]1[CH2:3][C:4]2([CH2:8][CH:7]3[CH:6]([CH:11]3[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5]2)[CH2:1]1
Reactant: C1=CCC2(C1)COC2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2CC3(COC3)CC21
Yield: 83.1 %

Procedure:
To a solution of 2-oxaspiro[3.4]oct-6-ene (1.0 g, 9.2 mmol) and copper sulfate (145 mg, 0.907 mmol) in toluene (5 mL) was added a solution of ethyl 2-diazoacetate (2.64 g, 22.7 mmol) in toluene (20 mL) at 100° C. over 16 h. The reaction mixture was concentrated, and the resulting residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to afford product as a brown oil (1.5 g, 84% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=CC=CC=1.[Cl:28][C:29]1[N:34]=[C:33]([CH:35]=O)[C:32]([NH:37]C(=O)OC(C)(C)C)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:28][C:29]1[N:34]=[C:33]2[C:32](=[CH:31][CH:30]=1)[N:37]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=1)[C:7]([C:1]1[CH:8]=[CH:7][CH:1]=[CH:6][CH:6]=1)=[CH:35]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nc4cc3-c3ccccc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (1-3) (2.7 g, 6.1 mmol), tert-butyl (6-chloro-2-formylpyridin-3-yl)carbamate (1-4) (1.6 g, 6.1 mmol), potassium carbonate (5.0 g, 6.0 mmol), and DMF (20 mL). The reaction mixture was heated to 80° C. while stirring in a hot oil bath under an atmosphere of nitrogen for 15 hours. Then the reaction mixture was warmed to 120° C. for 1 hour. The reaction mixture was permitted to cool to room temperature, added water, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-50% EtOAc/5% DCM/Hexane) to give tert-butyl {1-[4-(6-chloro-3-phenyl-1,5-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) as an off-white solid. HRMS (M+H)+: observed=486.1954, calculated=486.1943.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C[C:36]#[N:37])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:36]#[N:37])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CCC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc3ccccc3c2)CCCC1
Product: N#CCC1(c2ccc3ccccc3c2)CCCC1
Yield: 72.67 %

Procedure:
(1-Naphthalen-2-yl-cyclopentyl)-acetonitrile (215) (9.0 g, 72.67%) was synthesized as a brown solid from methanesulfonic acid 1-naphthalen-2-yl-cyclopentylmethyl ester 214) (16.0 g, 52.63 mmol) following the procedure described for [1-(2,5-dichlorophenyl)-cyclopentyl]-acetonitrile (202).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:14][CH2:15][O:16][CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)OC)c(O)c1
Temperature: 57.5 °C

Procedure:
A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol), 1-bromo-2-methoxyethane (3.1 mL, 33 mmol), potassium carbonate (4.55 g, 33 mmol) and sodium iodide (1 g) in DMF (20 mL) was heated overnight at 55-60° C. before it was poured into brine (300 mL). The resulting mixture was extracted with ethyl acetate; and the ethyl acetate solution was washed with brine, dried (MgSO4) and evaporated to a residue (6.17 g), which was subjected to preparative HPLC over silica gel, eluting with a gradient of 0-30% ethyl acetate in hexane over 30 min (at 100 mL/min), to afford the ether (2.72 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]12[CH2:15]C3C[CH:12]([CH2:14][CH:8](C3)[C:7]1=O)[CH2:13]2.CC(C)=O.[PH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.CCCCCC>[CH2:4]=[C:3]1[CH:12]2[CH2:13][CH:6]3[CH2:7][CH:8]([CH2:1][CH:2]1[CH2:15]3)[CH2:14]2
Reactant: [Li]CCCC
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (14 g; 39.17 mmol) in 100 ml of ether cooled to 0° C. under argon was added dropwise n-butyllithium (2.51 g; 39.17 mmol) in hexane (15.7 mml). An ice-bath was removed and the mixture was allowed to react at room temperature for 2 hours. After cooling the reaction mixture to 0° C., a suspension of 5.35 g (35.61 mmol) of 2-adamantanone in ether (25 ml) was added and the mixture was stirred at room temperature for 2 hours. Acetone was added to decompose the phosphonium salt, the reaction mixture was filtered and the residue was washed with ether. The combined organic layer was distilled in vacuo and the residue was redissolved in ether and cooled to 0° C. to yield 3.5 g (66.4%) of 2-methylene-adamantane (see J. Org. Chem. 1985, 54, 1375) (Formula III: R2 =R3 =H; R4 and R5 together are adamantanyl), as a low melting solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1ccc(-c2cnc(Nc3cccc4c3CC(O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 9C for the product of Example 1I. 1H NMR (DMSO-d6) δ 9.05 (s, 1H), 7.58 (m, 1H), 7.44 (m, 2H), 7.29 (s, 1H), 7.19 (m, 2H), 7.06 (t, 1H, J=7.5 Hz), 6.83 (d, 1H, J=7.0 Hz), 4.80 (d, 1H, J=4.0 Hz), 3.92 (m, 1H), 2.72-2.96 (m, 4H), 2.31 (s, 3H), 1.84 (m, 1H), 1.63 (m, 1H); MS (ESI+) m/z 321 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OC1C=[CH:15][C:11]([C:12](O)=[S:13])=[CH:10]C=1C.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[OH:21][CH2:20][C:19]1[CH:18]=[CH:22][C:12]([SH:13])=[C:11]([CH3:15])[CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C(O)=S)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CO)ccc1S
Temperature: 60 °C
Reaction time: 21 h

Procedure:
95% LiAlH4 (0.55 g, 14 mmol) is introduced in absolute THF (10 ml) into a three-necked flask which is heated and flushed with argon. A solution of 4-hydroxy-3-methylthiobenzoic acid (1.37 g; 7.4 mmol) in absolute THF (15 ml) is added dropwise to this initial mixture with ice-cooling in the course of 5 min such that only moderate evolution of gas takes place. After addition is complete, the cooling is removed and the reaction mixture is stirred at RT for 30 min and at 55-65° C. for a further 21 h. After the reaction mixture has cooled to RT, it is treated carefully with ice water with ice-cooling. The basic Al(OH)3 precipitate is dissolved by addition of 10% strength sulfuric acid and the aqueous, acidic solution (pH=1) is extracted with diethyl ether (150 ml). The phenolic product is extracted from the combined ethereal extract using 2 portions of sodium hydroxide solution (10%, 50 ml). The alkaline sodium hydroxide extract is adjusted to pH=7 using hydrochloric acid (20% strength), the precipitate is taken up using diethyl ether (50 ml), and the neutral aqueous solution is extracted with diethyl ether (100 ml). The combined, ethereal extract is washed with saturated NaCl solution, dried over Na2SO4 and concentrated: a crystalline, white residue remains.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.CO[CH:14]([N:17]([CH3:19])[CH3:18])OC>>[CH3:14][N:17]([CH3:19])/[CH:18]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]=[CH:14][N:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 96 h
Yield: 101 %

Procedure:
4-Methyl-5-nitro-pyridin-2-ylamine (Aldrich, 4.80 g, 31.4 mmol) was suspended in dimethoxymethyl-dimethylamine (50 mL) and the mixture was heated at about 120° C. in a sealed vessel with stirring for about 4 days. The reaction was cooled and concentrated to afford N′-[4-((E)-2-Dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-N,N-dimethyl-formamidine (8.36 g, 101%) as a dark solid, RP HPLC (Table 1, Method e) Rt=1.62, m/z: (MH)+ 264. The crude product was then used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][C:26]([OH:29])([CH3:28])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C=O)C>[OH:29][C:26]1([CH3:28])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[N:20]=2)[CH2:27]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Solvent: CN(C)C=O
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (200 mg, 0.41 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (473 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with brine, and extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl(±)-6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (183 mg, 78%). MS (ESI) m/z=573 [M+H]+, which was separated by chiral preparative HPLC to afford (R)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (51 mg) and (S)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (48 mg).