Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1C(O)=[C:4]([N+:10]([O-:12])=[O:11])[C:5](O)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:16])=O.[CH2:19]([Cl:21])Cl>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:16][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[C:19]([Cl:21])[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Yield: 75 %

Procedure:
5,6-Dimethyl-3-nitro-pyridin-2,4-diol (3.9 g, 21 mmol) was dissolved in acetonitrile (150 mL) and firstly tetraethylammonium chloride (7.1 g, 42 mmol) and then phosphorus oxychloride (19.9 mL, 210 mmol) were added and the whole heated at 70C for 16 h. The reaction mixture was poured into crushed ice and extracted with DCM (2×30 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a brown solid. This solid was taken up in 2 mL DCM and filtered through a short plug of silica gel eluting with 2:1 pentane:EtOAc. The filtrate was then evaporated to afford the title compound as a light brown solid (3.5 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@@H:8]1[CH2:20][CH3:21].C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@@H:8]1[CH2:20][CH3:21])=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Product: CC[C@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Yield: 19 %

Procedure:
Following the procedure for Example 112, reacting (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 113 as a white solid (27 mg, 19% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.91 (s, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.03 (t, J=9.2 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.24-3.14 (m, 2H), 3.12-2.93 (m, 4H), 2.60 (t, J=10.8 Hz, 1H), 1.48-1.28 (m, 1H), 1.28-1.16 (m, 1H), 0.79 (t, J=7.6 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]([NH:10][NH:9][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NNC(=O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of nicotinic acid hydrazide (35 mg, 0.25 mmol) in DMF (5 mL) was added triethylamine (88 μL, 0.64 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 50 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and EDCI (50 mg, 0.28 mmol). The mixture was allowed to stir at rt for 16 h. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil, which was purified by flash chromatography on silica gel (dichloromethane/methanol, 9/1) to give the title compound. m/z (ES+)=316 [M+H]+; RT=2.62 min.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][O:13][C:14]([C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:19])=[O:18])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:23]1([S+:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1CCCC1.[CH3:48][C:49]([C:51](Cl)=[O:52])=[CH2:50].COC(C)(C)C>C(Cl)(Cl)Cl>[C:51]([O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][O:13][C:14]([C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:18])=[O:19])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)(=[O:52])[C:49]([CH3:50])=[CH2:48].[C:36]1([S+:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OCC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)S(=O)(=O)[O-]
Reactant: C=C(C)C(=O)Cl
Agent: CN1CCCC1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Product: C=C(C)C(=O)OC12CC3CC(CC(COC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.8 parts of triphenylsulfonium 1-((3-hydroxyadamantyl)methoxycarbonyl)difluoromethanesulfonate and 1.0 part of 1-methylpyrrolidine were dissolved in 30 parts of chloroform. A solution of 0.7 Part of methacryl chloride and 2.2 parts of chloroform was added dropwise to the solution at room temperature and then the resultant mixture was stirred at room temperature for about 3 days and at 40° C. for 7.5 hours. After cooling to room temperature, 1.0 part of 1-methylpyrrolidine was added to the reaction mixture and a solution of 0.7 part of methacryl chloride and 2.2 parts of chloroform was added thereto at room temperature. After reacting at room temperature for 14 hours, the reaction mixture was diluted with 30 parts of chloroform and quenched with 36 parts of ion-exchanged water in an ice bath. A chloroform layer was separated and repeatedly washed with ion-exchanged water. To the chloroform layer, 1.1 parts of active carbon was added and the mixture was stirred for 1 hour. The mixture was filtered and chloroform layer obtained was concentrated to obtain pale yellow oily matters. To the oily matters, tert-butyl methyl ether was added to stir and the mixture was filtered to obtain 2.8 parts of triphenylsulfonium 1-((3-methacryloyloxyadamantyl)methoxycarbonyl)difluoromethansulfonate in the form of white solid, which is called as TPS-4.
Reaction SMILES: [P:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])[O:2]C(C)C.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>>[N+:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][P:1](=[O:2])([O:6][CH:7]([CH3:8])[CH3:9])[O:10][CH:11]([CH3:12])[CH3:13])([O-:24])=[O:23]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: CC(C)OP(=O)(Cc1cccc([N+](=O)[O-])c1)OC(C)C
Temperature: 100 °C

Procedure:
A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl (3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl (3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6 H), 1.28 (d, J=6.1 Hz, 6 H), 3.06-3.12 (m, 4 H), 3.12-3.19 (m, 4 H), 4.51-4.63 (m, 2 H), 4.96 (s, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.21-7.28 (m, 1 H), 7.29-7.33 (m, 1 H), 7.35-7.43 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 8.21 (s, 1 H), 8.45 (dd, J=4.8, 1.8 Hz, 1 H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: Fc1ccccc1CCl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccccc1F
Reaction time: 1.8 h
Yield: 86 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 125 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 36.3 g (0.25 mole) of 2-fluorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured into 1.51 of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 42 g (86%) of a light yellow oil. The crude product was washed with 100 ml of ether to give 10 g (20%) of a white solid m.p. 72°-76°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH2:19][CH:20]=[CH2:21])[CH3:3].[OH-:22].[Na+].OO.Cl>O1CCCC1.CCOCC.C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH2:19][CH2:20][CH2:21][OH:22])[CH3:3]
Reactant: C=CCc1cc(OCCCC)ccc1OCCCN(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1ccc(OCCCN(C)C)c(CCCO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of N,N-dimethyl-3-(2-allyl-4-butoxyphenoxy)propylamine (1.8 g) in tetrahydrofuran (3 ml) was added dropwise over a period of 3 minutes to a solution of borane tetrahydrofuran complex (1M, 12.4 ml) at a temperature of 0° C. and under an atmosphere of argon. The reaction mixture was stirred at 0° C. for 3 hours. Ethanol (10 ml) was added to the reaction mixture, followed by aqueous 6N aqueous sodium hydroxide and hydrogen peroxide solution (30%, 12 ml). The mixture was then heated at 50° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, extracted with ethyl acetate, the ethyl acetate extracts dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 40:60:0.2 mixture of ethyl acetate, hexane and triethylamine as eluent to give an oil. The oil was dissolved in ether and excess ethereal hydrogen chloride added until crystallisation began. The solid was collected by filtration and dried to give N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine as a white solid (60 mg), m.p. 118° C.; microanalysis, found: C, 62.4; H, 9.6; N, 4.0% C18H32NO3Cl requires: C, 62.5; H, 9.32; N, 4.05%; NMR ([CD3 ]2SO+CD3COOD): 0.95(3H,t), 1.45(2H,m), 1.7(4H,m), 2.2(2H,m), 2.58(2H,t), 2.89(6H,s), 3.35(2H,t), 3.55(2H,t), 3.9(2H,t), 4.02(2H,t), 6.72(2H,m) and 6.82(1H,s); m/z 310(M+H).
Reaction SMILES: [N:1]1([C:6]2C=CN=[C:8]([CH3:12])[CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Br:14][C:15]1[CH:26]=[CH:25][C:18]([CH:19]=[N+:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:17]([F:27])[CH:16]=1.BrC1C=CC(C=O)=C(F)C=1.[NH:38]1CC[CH2:40][CH2:39]1>>[Br:14][C:15]1[CH:26]=[CH:25][C:18]([CH:19]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:5]2[N:1]([CH2:6][C:7]3[CH:8]=[CH:12][CH:40]=[CH:39][N:38]=3)[CH:2]=[CH:3][CH:4]=2)=[C:17]([F:27])[CH:16]=1
Reactant: C1CCNC1
Reactant: Cc1cc(-n2cccc2)ccn1
Reactant: Fc1cc(Br)ccc1C=[N+]1CCCC1
Agent: O=Cc1ccc(Br)cc1F
Agent: [Cl-]
Product: Fc1cc(Br)ccc1C(c1cccn1Cc1ccccn1)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-pyrrol-1-yl-methyl-pyridine and 1-(4-bromo-2-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 4-bromo-2-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2].[C:18](=O)(OC(Cl)(Cl)Cl)[O:19]C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH2:37]1[O:45][C:44]2[C:39](=[C:40]([C@@H:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][NH2:48])[CH:41]=[CH:42][CH:43]=2)[O:38]1>C(Cl)Cl>[CH2:37]1[O:45][C:44]2[C:39](=[C:40]([C@@H:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][NH:48][C:18]([NH:11][C:10]3[N:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:8]=[CH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:19])[CH:41]=[CH:42][CH:43]=2)[O:38]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Reactant: CCCCC[C@@H](CN)c1cccc2c1OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@@H](CNC(=O)Nc1c(C(=O)OCC)cnn1-c1ccccc1)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 220.5 %

Procedure:
To a mixture of 1.16 g of 5-amino-1-phenylpyrazole-4-carboxylic acid ethyl ester and 10 ml of methylene chloride were dropwise added 0.53 g of bis (trichloromethyl) carbonate and 1.11 g of triethylamine in order with ice cooling and stirring, and the resultant mixture was refluxed with heating for 4 hours. The reaction mixture was allowed to cool to room temperature, mixed with a solution of 1.18 g of (r)-2-(2, 3-methylenedioxyphenyl) heptylamine in 3 ml of methylene chloride, stirred at room temperature for 2 hours and the solvent evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was chromatographed on a column of silica gel, eluting with ethyl acetate and n-hexane (2:5) to give 1.94 g of the titled compound as amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccc2[nH]ccc2c1
Product: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Yield: 93.9 %

Procedure:
Beginning with 1.00 gm (7.4 mMol) 5-fluoro-1H-indole and 1.82 mL (14.8 mmol) 1-methyl-4-piperidone, 1.60 gm (94%) of the title compound were recovered as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](Cl)=[C:5]2[S:4][CH:3]=1.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C1(OC)C=CC=CC=1>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[C:5]2[S:4][CH:3]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnc2c(C)csc2c1Cl
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2c(C)csc2c1Nc1ccccc1C

Procedure:
Ethyl 3-methyl-7-chlorothieno[3,2-b]pyridine-6-carboxylate (3.0 g, 0.0117 mol) and o-toluidine (2.51 g, 0.0234 mol) in anisole (30 ml) were heated under reflux for three hours. The solvent was evaporated under reduced pressure, taken up in chloroform and washed in turn with 2NHCl, H2O, aqNa2CO3, H2O and brine, dried and evaporated to give an oil. This oil was purified by flash chromatography (silica, 40-60 mesh) using dichloromethane as eluant to give a buff coloured solid. This was crystallised from methanol to give the title compound, 2.3 g, m.p. 132°-134°.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20]3[N:37]=[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[CH2:34][O:35][CH3:36])[N:22]4[N:21]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:36][O:35][CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[N:22]2[N:21]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:11]4[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=4[CH:15]=3)[N:37]=[C:23]2[CH:24]=[CH:25][CH:26]=1
Reactant: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCNCC4)nn12
Yield: 94.2 %

Procedure:
7-[5-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (105.0 mg, 0.210 mmol) was stirred in 3M trifluoroacetic acid in dichloromethane (10 mL) for 30 minutes. The volatiles were evaporated and the residue was dissolved in ethyl acetate and washed with sodium carbonate solution (2×) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Product isolated as a foam (0.079 g, 89%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.64 (d, J=7.7 Hz, 1H), 7.58-7.41 (m, 5H), 7.25-7.21 (m, 1H), 7.16-7.04 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.91-6.87 (m, 1H), 4.35 (br s, 2H), 3.20 (s, 3H), 2.98-2.81 (m, 8H), 2.02 (br s, 1H). MS=400 (MH)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[C:26]([C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCC
Product: CCCCC#Cc1nc(N)c2nc(NCCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-butylaminoadenosine (10, 200 mg, 0.43 mmol) and 1-hexyn (2.08 mmol). The mixture was purified by column chromatography (5% MeOH in CH2Cl2). Yield 111 mg (0.26 mmol, 62%), mp 182–184÷C; 1H NMR (DMSO-d6) δ 6.95 (t, 1H, J=5.49 Hz, NH), 6.55 (bs, 2H, NH2), 5.87 (d, 1H, J=7.90 Hz, H-1′), 5.77–5.72 (m, 1H, OH-2′), 5.26 (d, 1H, J=6.52 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.54 (q, 1H, J=5.84 Hz, H-2′), 4.09–4.04 (m, 1H, H-3′), 3.95–3.93 (m, 1H, H-4′), 3.64–3.59 (m, 2H, H-5′), 3.09 (m, 2H, NHCH2), 2.36 (m, 2H, ≡CCH2), 1.51–1.30 (m, 8H, 2×CH2CH2), 0.89 (t, 6H, J=,7.55 Hz, 2×CH3); MS m/z 419 (M+H)+; Anal. (C20H30N6O4) C, H, N.
Reaction SMILES: Br[C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6].[NH3:22]>>[NH2:22][C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6]
Reactant: N
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(Br)nc2c(N)ncnc21
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(N)nc2c(N)ncnc21

Procedure:
A solution of the compound from Step A (38 mg, 0.11 mmol) in liquid ammonia (10 mL) was heated in a stainless steel autoclave at 105° C. for 1 d, then cooled and evaporated. The residue was purified by HPLC [C-18 Phenomenex Luna (10 μ; 250×21.2 mm) RP-column; solvents:(A) water, (B) acetonitrile; Linear gradient: 2-35% B in 76 min.] to yield the title compound (12 mg) as a white fluffy material after freeze-drying.
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Add ethyl 1-aminocyclopropanecarboxylate (89.2 g, 0.54 mol) to diisopropylethylamine (187.86 mL, 1.08 mol) in dichloromethane (900 mL) Immerse the flask in a cold water bath and slowly add 4-chlorobenzoic acid chloride (75.46 mL, 0.59 moles). After addition is complete, remove the bath, allow the reaction to equilibrate to 20° C., and stir for approximately 2 hours. Wash with 1N hydrochloric acid (HCl), followed by saturated sodium bicarbonate (NaHCO3), water, and then brine. Dry the organic layer over sodium sulfate (Na2SO4), filter, and concentrate under reduced pressure. Slurry the residue with heptane, filter, and rinse with heptane to give the title compound (142 g, 98%) as a white powder: MS (m/z): 268 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[Mg+2].[Br-].[Br-].CCOCC.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([CH:47]=[O:48])=[N:42][CH:43]=[C:44]([Cl:46])[CH:45]=2)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:49]([F:52])([F:51])[F:50]>C1COCC1>[Cl:46][C:44]1[CH:45]=[C:40]([NH:39][S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[C:31]([C:49]([F:50])([F:52])[F:51])[CH:32]=2)(=[O:37])=[O:38])[C:41]([CH:47]([OH:48])[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:42][CH:43]=1
Reactant: O=Cc1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)C(C)(C)C)c1C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-(3-methoxy-phenyl)-2,2-dimethyl-propionamide (1.11 g, 4.8 mmol) in anhydrous THF at 0° C. was added a solution of n-BuLi (3.65 mL, 9.1 mmol) in hexanes. After 45 minutes, anhydrous MgBr2-Et2O (1.23 g, 4.8 mmol) was added in one portion and stirring was continued at the same temperature for 1 h. The mixture was then cooled to −78° C. and solid 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (300 mg, 0.75 mmol) was added in one portion and slowly warmed to room temperature over 4 h. The mixture was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-(2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-hydroxy-methyl}-3-methoxy-phenyl)-2,2-dimethyl-propionamide: MS m/z 606.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18].CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of 64.25 g of 4-chlorophenol, 98 g of anhydrous potassium carbonate, 40 g of chloroacetonitrile and 100 ml of dimethyl sulfoxide was heated with stirring in a 500 ml round-bottomed three-necked flask at 70°-80° C. for 3.0 hours. The reaction mixture was then poured into ice and water. After the ice melted, the mixture was filtered and the product washed well with water which gave 77.5 g of 4-chlorophenoxyacetonitrile.