Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:25]([C:26](=[O:28])[CH3:27])=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:35])[CH:22]=3)[C:17]2=[O:36])=[CH:11][CH:10]=1)(C)(C)C.C(OC(=O)C)C.[ClH:44]>>[ClH:44].[C:26]([C:25]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][NH2:7])=[CH:14][CH:13]=2)[C:17](=[O:36])[C:18]2[C:23]([C:24]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:22][C:21]([Br:35])=[CH:20][CH:19]=2)(=[O:28])[CH3:27]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To [4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzyl]carbamic acid tert-butyl ester (561 mg) was added 4N hydrochloric acid ethyl acetate solution (5 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated again under reduced pressure. To the obtained residue was added diisopropyl ether and the mixture was crystallized to give the title compound (410 mg, 82%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>ClCCl.CCCCCC.C(OCC)(=O)C>[CH:33]1([C:39]([N:4]([CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH2:3]/[C:2](/[CH3:1])=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C/C(=C\c1ccccc1)CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
To a solution of 4-(N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.44 g, 4.18 mmol) and triethylamine (0.80 g, 7.9 mmol) in dichloromethane (60 mL) stirring at 0° C. under argon, was added cyclohexanecarbonyl chloride (0.75 g, 5.1 mmol) in a single portion. After 5 min the mixture was allowed to warm to room temperature. Water (0.2 mL) was added, and the mixture was evaporated under vacuum. Column chromatography (loaded as a slurry in dichloromethane, silica gel, step-wise gradient of 10% to 38% ethyl acetate in hexane) provided 4-(N-cyclohexylcarbonyl-N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.67 g, 88% yield) as a colorless gum. TLC Rf=0.19, 25% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1)[C:13]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)=[C:12]2[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:26][CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][C:19]([CH2:18][N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[C:12]([CH3:43])=[C:13]2[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:34]=2)=[CH:20][CH:21]=1)(=[O:54])=[O:53]
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCO)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCOS(C)(=O)=O)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol (546 mg, 0.96 mmol) in DCM (10 mL) was cooled to 0° C. Triethylamine (0.2 mL, 1.43 mmol) and methanesulfonyl chloride (0.1 mL, 1.29 mmol) were added and the reaction was stirred at 0° C. for 1 h. The reaction was diluted with DCM (30 mL) and then washed with 1M HCl (20 mL), washed with water (20 mL), dried (MgSO4), filtered and concentrated under vacuum to give 597 mg of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethyl methanesulfonate as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 4H), 7.44-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.83-6.74 (m, 5H), 5.20-5.10 (m, 6H), 4.50-4.45 (m, 2H), 4.17-4.11 (m, 2H), 2.16 (s, 3H). LCMS: 648.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:14][O:15][C:16](Cl)=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S-:19][C:20]#[N:21].[K+]>>[C:1]1([CH2:14][O:15][C:16]([N:21]=[C:20]=[S:19])=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: [K+]
Product: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2

Procedure:
The title compound was prepared from Fluorenylmethyloxycarbonyl chloride and potassium thiocyanate according to the procedure of Kearney et al. J. Org. Chem. 1998, 63, 199; 1H NMR (CDCl3) δ7.75 (d, J=7.5 Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 4.44 (d, J=7.4 Hz, 2H), 4.23 (t, J=7.4 Hz, 1H).
Reaction SMILES: O([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>O>[NH2:40][C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Temperature: 140 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture of 4.40 g of tert-butyl 4-[2-(4-phenoxy-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 34.5 g of ammonium acetate was stirred at 140° C. for 3 hours. The reaction mixture was added with water, adjusted to pH 9 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with saturated brine, and dried, and then the solvent was evaporated. The resulting residue was purified by alumina column chromatography using methylene chloride—methanol (100:1 to 20:1) as eluting solvents, and washed with diisopropyl ether to give 1.88 g of colorless crystals. Recrystallization from ethyl acetate gave colorless crystals having the melting point of from 193 to 193.5° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[S:36][CH:37]=[C:38]([C:40]([N:6]3[CH2:7][CH2:8][N:9]([C:11](=[O:24])[C:12]4[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=4)[CH2:10][CH:5]3[CH2:4][O:3][CH3:2])=[O:41])[N:39]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1ccc(-c2nc(C(=O)O)cs2)cc1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl) piperazine hydrochloride obtained in Reference Example 6 (0.50 g), 2-(3,4-dimethoxyphenyl)thiazol-4-carboxylic acid (0.37 g), triethylamine (0.42 g) and N,N-dimethylformamide (5 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.46 g). The reaction mixture is stirred at 0° C. for one hour and there poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent: AcOEt) to give 1-[2(3,4-dimethoxyphenyl) thiazol-4-ylcarbonyl]-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine. Recrystallization from EtOH gives colorless needles, m.p. 149-151° C.
Reaction SMILES: [NH2:1][CH:2]([P:7]([OH:10])(=[O:9])[OH:8])[P:3]([OH:6])(=[O:5])[OH:4].[OH-].[Na+].[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].Cl>O>[C:13]([CH2:14][CH2:15][NH:1][CH:2]([P:7]([OH:10])(=[O:8])[OH:9])[P:3]([OH:6])(=[O:4])[OH:5])([OH:17])=[O:16]
Reactant: C=CC(=O)O
Reactant: NC(P(=O)(O)O)P(=O)(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNC(P(=O)(O)O)P(=O)(O)O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
47.8 g. of aminomethane diphosphonic acid and 50 g. of sodium hydroxide are dissolved in 200 cc. of water. 19 g. Of acrylic acid dissolved in 50 cc. of water are added drop by drop thereto at a temperature between 20° C. and 40° C. while stirring vigorously. After the acrylic acid solution has been added, the reaction mixture is kept at a temperature of 90° C. for 30 minutes and is then neutralized with dilute hydrochloric acid. The neutralized solution is passed through a cation exchange agent and the resulting solution is concentrated by evaporation. After allowing the concentrated solution to stand for several days, N-(2-carboxy ethyl) amino methane diphosphonic acid is obtained in the form of crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pt]>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 34.9 g of 1-benzyloxy-2-fluoro-4-nitrobenzene (WO 03 064413) (MW: 247.28, 141 mmol) and 340 mg of platinum (5% on activated carbon) in 350 ml of ethyl acetate was stirred at RT and normal pressure under a hydrogen atmosphere. The course of the reaction was monitored by HPLC and the reaction was terminated after 20 h. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure using a rotary evaporator. The oily residue was dissolved in 500 ml of acetone and 250 ml of a saturated sodium hydrogen carbonate solution and 17.5 g of sodium hydrogen carbonate (MW: 84.01, 208 mmol) were added. The mixture was cooled to 5° C. and 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol) were added dropwise. The mixture was then stirred for 2 h at RT and the course of the reaction was monitored by TLC (hexane/ethyl acetate 3:1). The acetone was removed under reduced pressure, 500 ml of water were added to the residue, and the solid material was filtered off. The crystals were washed with 500 ml of water and dried.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:4]2[N:3]=1.[Si]([C:30]#[N:31])(C)(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[OH:9][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[C:6]=1[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:30]#[N:31]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(-c2c(C=O)c(C)nc3cc(-c4ccccc4)nn23)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ccc(-c2c(C(O)C#N)c(C)nc3cc(-c4ccccc4)nn23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a solution of 5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (30 mg, 0.092 mmol) in CH2Cl2 (2 mL) at 0° C. was added zinc iodide (14.63 mg, 0.046 mmol) followed by TMS-CN (0.049 mL, 0.367 mmol). The reaction mixture was stirred at room temperature for 4 h and diluted with CH2Cl2 (100 ml), washed with water, and dried over Na2SO4. The solvent was evaporated and the residue was purified by preparative HPLC to give the title compound (15 mg, 46.2%) as TFA salt. Preparative HPLC condition: Phenomenex Luna C18 30×100 mm S10, 40 to 100% B over 22 minute gradient, 7 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA. Flow rate: 40 ml/min. 1H-NMR (500 MHz, CDCl3) δ ppm 2.46 (3H, s), 2.89 (3H, s), 5.39 (1H, s), 6.85 (1H, s), 7.16-7.25 (3H, m), 7.30-7.44 (4H, m), 7.63-7.76 (2H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH2:26][CH2:27][C:28](=[O:29])[NH2:30])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NCCC(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(CCC(N)=O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3-(tert-butylamino)propanamide (289656-97-9) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=411.6 [MH+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:30]=2)=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C#N)c(F)c4)ccc3o2)CC1
Yield: 47.5 %

Procedure:
Following the General Procedure-2, the titled compound (70 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluorobenzonitrile (70 mg, 0.35 mmol) as a white solid. M.P.: 138-142° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (d, J 1.6, 1H), 7.72-7.68 (m, 1H), 7.59 (d, J 8.5, 1H), 7.53-7.42 (m, 3H), 4.15 (d, J 10.6, 2H), 3.20-3.11 (m, 1H), 3.00 (t, J 11.8, 2H), 2.2-2.12 (m, 2H), 1.98-1.86 (m, 2H), 1.56 (S, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20](#[N:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[C:20]([CH2:21][CH2:22][C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])#[N:23]
Reactant: C=CC#N
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 52.4 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.4 g, 1.47 mmol) and acrylonitrile (0.11 mL, 1.62 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Dimethyl 2-(2-cyanoethyl)-2-(2-fluoro-4-nitrophenyl)malonate (73) (0.25 g, 52%): 1H NMR δ 8.07 (dd, 1H, J=8.7, 2.3 Hz), 7.99 (dd, 1H, J=10.9, 2.3 Hz), 7.47 (dd, 1H, J=8.7, 7.3 Hz), 3.85 (s, 6H), 2.65-2.70 (m, 2H), 2.47-2.51 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C=O)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:65]=[CH:64][C:63]([NH:66][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([Br:1])[N:10]4[N:9]=3)=[CH:62][CH:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: Oc1ncc2ccc(Br)n2n1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Temperature: 25 °C

Procedure:
To a round bottom flask, 7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.593 g, 0.00277 mol), DIEA (1.50 mL, 0.0086 mol) and DMF (25 mL, 0.32 mol) were added. The mixture was stirred at room temperature and N-Phenylbis(trifluoromethanesulfonimide) (1.14 g, 0.00320 mol) was added. The mixture was stirred at room temperature for 1 h then 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert butyl ester (0.995 g, 0.00361 mol) was added and the mixture stirred at 60° C. for 4 h. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with a 2:1 Hexane/DCM and Methanol as eluant (0 to 10% Methanol). The collected fractions gave 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester as a pale solid (˜2:1 P: SM by NMR). LCMS (E/I+) 472 (M+H). ii) To a round bottom flask, Palladium Acetate (0.083 g, 0.000368 mol) and Triphenylphosphine (0.144 g, 0.000551 mol) and THF (6 mL, 0.070 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. A solution of 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester (70% pure, 1.24 g, 0.00184 mol) in THF (4 mL, 0.050 mol) was added and the reaction was stirred for a further 10 minutes. 4-(Methylsulfonylphenyl)boronic acid (0.735 g, 0.00368 mol), Ethanol (10 mL, 0.20 mol) and 0.90 M Sodium carbonate in Water (6.12 mL, 0.00551 mol) were added and the mixture was heated at 80° C. overnight. The reaction was partitioned with aqueous Sodium Carbonate and EtOAc. The organic was separated, washed with Brine, and dried over Sodium Sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and MeOH as eluant (0 to 10%). The collected fractions afforded 4-{4-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl}-piperidine-1-carboxylic acid tert butyl ester as a yellow solid (0.762 g, 75% pure by NMR). LCMS (E/I+) 570 (M+Na).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li:13])CCC>>[CH2:1]([O:8][Li:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: OCc1ccccc1
Product: [Li]OCc1ccccc1
Temperature: 25 °C

Procedure:
Into a solution of benzyl alcohol (1.51 ml) in tetrahydrofran (57 ml) was added n-butyl lithium (1.6 M in hexane) (7.25 ml) at -60° C., and the mixture was warmed to 25° C. Into the solution of benzyloxy lithium thus obtained was added the product of Example 4-(1) (6.0 g) at -78° C., and the mixture was stirred at 3° C. for 17 hr. The mixture was diluted with water and ethyl acetate. The organic layer was washed, dried and evaporated. The residue was purified by silica-gel column chromatography (chloroform:n-hexane:ethylacetate=10:1:0.1) to afford 2.57 g of (2S)-phthalimido-2-[(1R)-1-tert-butyldimethylsilyloxyethyl]-propionic acid benzyl ester in colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:23]C)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1nc2c(N)nc(OCCCO)nc2n1Cc1ccccc1
Agent: Cl
Agent: N
Product: Nc1nc(OCCCO)nc2c1nc(O)n2Cc1ccccc1
Yield: 50.7 %

Procedure:
6-Amino-9-benzyl-2-(3-hydroxypropoxy)-8-methoxypurine (83 mg, 0.25 mmol) in concentrated hydrochloric acid (5 ml) was stirred at room temperature for 4 hours. The reaction mixture was neutralized with 28% aqueous ammonia and the resulting crystals were filtered and washed with water to give the subject compound (40 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([N+:23]([O-])=O)[CH:3]=1>CN(C=O)C.[Ni]>[NH2:23][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:13])(=[O:14])[CH2:12][C:6]=2[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc([N+](=O)[O-])cc1CS2(=O)=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Yield: 76 %

Procedure:
To a solution of the methyl ester of Example 32j (0.280 g, 0.7 mmols) in DMF (10 mL) was added activated Raney-Nickel (100 mg) and the reaction mixture was subjected to reduction in a Parr hydrogenator (20 psi, 2 h). The reaction mixture was filtered (celite bed), and the filtrate was poured onto crushed ice to obtain a solid which was subjected to hydrolysis as described in the synthesis of Example 1i to obtain the title compound. Yield: 76%; 1H NMR (DMSO-d6): δ 2.60 (s, 3H, CH3), 5.10 (s, 2H, CH2), 5.40 (s, 2H, NH2), 6.80 (d, 2H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 354 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[OH:22][C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24](O)=[O:25]>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:24](=[O:25])[C@H:23]([OH:22])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)[C@@H](O)C(=O)O
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
The title compound was prepared from N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (hydrochloride salt, Example 26, Step B, 55 mg, 0.16mmol) and (2R)-hydroxy-3,3-dimethylbutyric acid (22 mg, 0.16 mmol) essentially according to the EDC coupling procedure described in Example 27, Step C (without the deprotection step). The mixture was stirred for 18 h at ambient temperature and was then concentrated in vacuo. The residue was purified directly by semi-preparative HPLC using a Waters Xterra RP8 column (1.9 cm×30 cm) using a 30 minute gradient of 95/5-water/MeCN to 100% MeCN with 0.1% TFA as the mobile phase at a flow rate of 20 mL/min. The product-containing fractions were concentrated in vacuo to afford the title compound as a white crystalline solid (62 mg). HPLC RT=2.86 min (Method A); LCMS m/z=421.3; 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.51 (br m, 1H), 7.44 (dd, J=2.2, 8.4 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 4.5 (dd, J=3.8, 8.6 Hz, 1H) 4.25 (d, J=5.3 Hz, 1H), 4.2 (m, 1H), 4.15 (s, 1H) 3.69 (m, 1H), 3.57 (m, 1H), 2.73 (br s, 1H), 1.8–2.1 (m, 4H), 1.0 (s, 9H)).