Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=1)([O-:3])=[O:2].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>CS(C)=O>[CH3:14][O:13][C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: COc1c(C(=O)O)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
4-Nitro-2-methoxybenzoic acid, 3.09 g, was added to 20 mL Nitric acid:Sulfuric acid 1:1, at 0° C. After addition was complete the reaction mixture was heated at 100 ° C. for 30 minutes. Cooled to room temperature and poured into 200 mL ice water. The aqueous layer was extracted with ethyl acetate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. This material was purified by chromatography on silica using ethyl acetate/hexane/methanol/acetic acid 5/5/1/0.1. The yellow solid obtained was used for the next step. EIMS M+ 242 (Exp. 242). NMR, d6 DMSO: s (1H) 8.5, s (1H) 7.95, s (3H) 4.05.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[S:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[N:7]=2)=[CH:35]1
Reactant: OB(O)c1ccsc1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1nc(-c2ccsc2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 85 °C
Reaction time: 4 h

Procedure:
44 mg of 6-chloro-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one, 14 mg of thiophene-3-boronic acid and 36 mg of potassium carbonate are dissolved 1.5 ml of a 1:2 mixture of water and dimethoxyethane, and argon is passed through the solution for degassing. Addition of 7 mg of (1,1′-bis(diphenylphosphine) -ferrocene)palladium(II) chloride-dichloromethane complex is followed by stirring at 85° C. for 4 hours. For workup, it is diluted with water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by silica gel chromatography (n-heptane/ethyl acetate).
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].CCN(C(C)C)C(C)C.O=S(Cl)[Cl:45]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[Cl:45])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: COC(=O)c1ccc(Oc2ccc(C(O)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(C(Cl)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of alcohol (535 mg, 1.14 mmol) from step 2 and i-Pr2NEt (436 mL, 2.5 mmol) in 10 mL of anhydrous toluene, was slowly added SOCl2 (145 mnL, 2.0 mmol). The resulting yellow solution was stirred 30 minutes at 0° C., 10 minutes at room temperature, quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28].ON1C2C=CC=CC=2N=N1.N=C=N.[N-]=C=O>CN(C)C=O.C(N(CC)CC)C>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH:28][C:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)[C:8]([CH3:20])=[C:9]2[CH3:19])=[O:18]
Reactant: CN(C)CCCN
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)O)cc12
Agent: N=C=N
Agent: On1nnc2ccccc21
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NCCCN(C)C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 8.9 mg portion of 1-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, 3.1 mg of N,N-dimethylpropane-1,3-diamine, 4.1 mg of 1-hydroxybenzotriazole (HOBt) and 0.0083 ml of triethylamine were dissolved in 1.0 ml of N,N-dimethylformamide, and 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc., USA) was added, followed by overnight stirring at room temperature. Then, 50 mg of MP-Carbodiimide (Argonaut Technologies, Inc., USA) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc., USA) was added to the reaction liquid at room temperature, followed by stirring for 4 hours. Then, the reaction liquid was filtered. By concentrating the filtrate under a reduced pressure, 9.5 mg of N-[3-(dimethylamino)propyl]-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:20]>C(O)C>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Reaction time: 3 h
Yield: 66 %

Procedure:
To a suspension of 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)-pyrone (40 g, 153 mmol) in ethanol (105 mL) was added concentrated aqueous ammonia (295 mL) and refluxed for 18 hours. The mixture was cooled, then refrigerated for 3 hours, and cooled in an ice-bath for 45 minutes. The solid was filtered off, washed with cold ethanol, followed by cold petroleum ether and dried in vacuo to afford the product as brown solid (26.21 g, 66%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH3:27])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CC1CCCN1c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Sodium triacetoxyborohydride (2.09 g) was added to a solution of 3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazine-2-carbaldehyde (1.49 g), N-benzylethanolamine (1.19 g) and acetic acid (1.13 mL) in acetonitrile (12 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (1.82 g, 76%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[N:25]1([C:30]2([C:33](O)=[O:34])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:33]([C:30]2([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:32][CH2:31]2)=[O:34])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C(O)C1(N2CCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCCC3)CC2)CC1
Yield: 41 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(pyrrolidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16D carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(pyrrolidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow solid (41%). MS ISP (m/e): 491.2 (100) [(M+H)]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[C:29](=O)[CH2:28][CH2:27][CH2:26]2>CCOCC.C1COCC1>[CH3:34][O:33][C:32]1[CH:31]=[C:30]2[C:25](=[CH:24][C:23]=1[O:22][CH3:21])[C:26]([C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1)=[CH:27][CH2:28][CH2:29]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(c1ccc(OCCN3CCCC3)cc1)=CCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 6.75 g (0.025 moles) of 1-(2-(4-bromophenoxy)ethyl)pyrrolidine in 250 ml of ether was cooled to −78° C. under N2. Several ml of THF were added to maintain a clear solution. 16.7 ml of 1.6 M n-butyllithium was added dropwise keeping the temperature below −70° C. After stirring at −78° C. for 1 hour, a solution of 5 g (0.024 moles) of 6,7-dimethoxy-1-tetralone in 25 ml of THF was added dropwise during 1 hour keeping the temperature below −70° C. After stirring for 2.5 hours at −78° C., the reaction was quenched by addition of 100 ml of 2N HCl. The reaction was allowed to warm to room temperature and the pH was adjusted to 7 by addition of 5N NaOH. The Et2O layer was separated and the aqueous layer was extracted 2 times with EtOAc. The combined Et2O/EtOAc layers were dried over Na2SO4 and evaporated to give 9 g of crude product, which was purified on 400 g of silica gel eluting with 95/5 CH2Cl2/MeOH to remove starting tetralone then with 85/15 CH2Cl2/MeOH to give 3.3 g of product.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([C:26]([F:28])([F:27])[F:25])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (25 mg, 0.056 mmol), prepared using procedures described in Example 6, was taken into DMF (0.5 mL) followed by addition of (trifluoromethyl)trimethylsilane (40 μL, 0.28 mmol) and cesium carbonate (22 mg, 0.067 mmol) and the mixture was stirred for one hour at room temperature. The mixture was partitioned with ethyl ether and water and the organic phase washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:2 as eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol (19.8 mg, 69% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 8.31-8.26 (br, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.13-7.10 (m, 1H), 6.86-6.80 (m, 1H), 6.65-6.60 (m, 1H), 4.42 (br s, 2H), 4.18 (br s, 2H). MS (EI) for C17H11F61N2O2: 517 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:34])[C:19]([S:22]([CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]2)(=[O:24])=[O:23])([CH3:21])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:34])[C:19]([S:22]([CH2:25][CH:26]2[CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]2)(=[O:24])=[O:23])([CH3:21])[CH3:20])[O:14][N:13]=1)([CH3:1])[CH3:11]
Reactant: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)COC3CCCCO3)no2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO)no2)CC1
Yield: 37.9 %

Procedure:
A solution of 1.3 g (2.6 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in DCM/methanol (1/1, 20 mL) is treated with 1.58 g (5.2 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 36 h. The resin is removed by filtration and washed alternating with DCM (10 mL) and methanol (10 mL) twice. The combined filtrates are concentrated under reduced pressure and the resulting residue is purified by column chromatography (Isolute SCX-2, eluent: DCM, 10% ethyl acetate) to yield 0.41 g of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide. Yield 38%; ES-MS: m/z 417 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(N)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Sulfamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4-hydroxybenzenesulfonamide (available from TCI America, Portland, Oreg., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.94-3.04 (m, 2H), 4.02-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.45 (s, 2H), 7.53-7.55 (m, 2H), 7.93-7.95 (m, 2H), 8.34 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].[NH2:16][C:17]1[N:22]=[C:21](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1>C(#N)CC>[NH2:16][C:17]1[N:22]=[C:21]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1
Reactant: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CCC[C@H](N)CCO
Solvent: CCC#N
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Temperature: 120 °C
Yield: 78.8 %

Procedure:
Trifluoroacetic acid (0.066 mL) was added to a mixture of (S)-3-aminohexan-1-ol (300 mg) and the product from step (vii) (490 mg) in propionitrile (5 mL). The mixture was heated at 120° C. for 16 h and cooled to RT. The solvent was removed by evaporation. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (330 mg) as a colourless gum; 1H NMR (CDCl3); 6.94 (1H, s), 6.88 (1H, d), 6.79 (1H, d), 4.66 (1H, d), 4.58 (2H, br s), 4.13 (2H, q), 4.11-4.06 (1H, m), 3.88 (3H, s), 3.70 (2H, s), 3.66 (2H, s), 3.42 (1H, ddd), 3.28-3.20 (3H, m), 2.65 (2H, q), 2.34 (3H, s), 1.82-1.74 (1H, m), 1.45-1.33 (1H, m), 1.26-1.21 (5H, m), 1.07-1.02 (5H, m), 0.73 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].[C:30](ON1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[CH:28][CH:29]=1)#[N:2]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CNCc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN(Cc1ccc(C#N)cc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (2S,3R)-4-(4-cyanobenzylamino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (600 mg, 1.5 mmol) in CH2Cl2 (30 mL) was treated with Teoc-OSu (762 mg, 3.0 mmol, 2.0 equiv) and Et3N (304 mg, 3.0 mmol, 2.0 equiv). The mixture was allowed to stir overnight at rt. LC-MS analysis showed that all of the free amine had been consumed. The solution was washed with water, 1.0 M aq HCl, and brine, then over dried over Na2SO4, filtered and evaporated to leave tert-butyl (2S,3R)-4-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate. NMR analysis showed that the compound was of sufficient purity to use in the next step.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:5]#[N:6])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [O-][n+]1ccccc1Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
Trimethylsilyl cyanide (14.56 g, 19.6 ml, 0.147 moles) was added dropwise to a solution of 2-benzylpyridine-N-oxide (10.86 g, 0.059 moles) and triethylamine (8.91 g, 12.3 ml, 0.088 moles) in acetonitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 20 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-benzyl-6-cyanopyridine (1.84 g, 16%) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1.[ClH:28]>C(O)C>[ClH:28].[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:6]2[O:5][C:4]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])=[CH:18]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCCC2)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of ethyl 4-oxo-2-pyrrolidinyl-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.038 g, y. 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][C:13]([O:15]CC)=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Li+].O1CCOCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=C(C)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C=Cc1ccc(Cl)c(Cl)c1)=CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.4 %

Procedure:
A solution of ehtyl 5-(3,4-dichlorophenyl)-3-methyl-pentadienoate (0.120 g, 0.418 mmol) in tetrahydrofuran (0.5 mL) is treated with aqueous 1 M lithium hydroxide (0.5 mL, 0.5 mmol). The cloudy reaction mixture is treated with dioxane (1 mL). After stirring at room temperature for two days, the mixture is concentrated in vacuo. The residue is diluted with 1 M aqueous HCl and extracted several times with chloroform. The organic layers are combined, dried (sodium sulfate), and concentrated in vacuo to yield 0.110 g of a white solid, mp, 212-214° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=2)=[CH:6][N:7]=1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([F:31])[CH:30]=1)[C@@H:27]([NH2:32])[CH2:26][CH2:25]2.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:32][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([F:21])=[CH:30][C:29]=4[F:31])[CH2:25][CH2:26]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: N[C@H]1CCc2cc(F)cc(F)c21
Reactant: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1nc(-c2cccc(CNC3CCc4cc(F)cc(F)c43)c2)cnc1N
Reaction time: 8 h

Procedure:
The 3-Amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (100 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with [(1S)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl]amine (151 mg, 3.0 eq), diisopropylethylamine (62 mg, 1.6 eq) at ambient temperature. After being stirred for 8 h, the white suspension was concentrated in vacuo and purified by flash column chromatography to give the title compound as colorless oil, which was dissolved in ethyl acetate (10 mL) and treated 1M HCl in ether. The resulting precipitate was filtered, washed with ether (2×2mL), and dried to afford 42mg (12% yield) of 3-amino-6-(3-{[(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide hydrochloride as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 8.71 (s, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.57 (t, 1H), 7.51 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 5.08 (m, 1H), 4.38 (q, 2H), 3.45 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H); MS (FI) for C23H23NSOF2: 424.16 (MH+).