Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:55][C@H:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1>ClCCl>[C@H:56]1([NH:55][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:33][CH:32]=2)=[O:30])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CCOC(=O)c1c(CCCC(C)C)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCC(C)C)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 10.4 %

Procedure:
To a stirred solution of 4-[(9aS)-3-(ethoxycarbonyl)-2-(4-methylpentyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.100 g, 0.222 mmol) in 1 mL of dichloromethane, EDCI (0.051 g, 0.266 mmol), HOBT (0.036 g, 0.266 mmol) and (R)-(−)-1-aminoindane (0.065 g, 0.444 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography chromatography (ethyl acetate/hexanes (4:1)) to yield 0.013 g (20%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.83–7.76 (d, 2H, J=7.9), 7.44–7.38 (d, 2H, J=7.93), 7.35–7.29 (d, 1H, J=7.76), 7.27–7.17 (m, 3H), 6.52–6.44 (m, 1H), 5.71–5.63 (q, 1H, J=7.41), 4.70–4.63 (dd, 1H, J=10.3, J=6.38), 4.09–3.94 (m, 2H), 3.68–3.56 (m, 1H), 3.35–3.24 (m, 1H), 3.07–2.95 (m, 1H), 2.95–2.76 (m, 3H), 2.74–2.58 (m, 1H), 2.51–2.40 (m, 1H), 2.35–2.19(m, 2H), 1.97–1.84 (m, 1H), 1.83–1.64 (m, 2H), 1.61–1.48 (m, 1H), 1.43–1.31 (m, 1H), 1.30–1.20 (m, 2H), 1.01–0.93 (t, 3H, J=7.09), 0.89–0.81 (d, 6H, J=6.55); low resolution MS (ES+) m/e 566 (MH); RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=23.8 min, 99.9% purity.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:20]([N:6]1[C:5]2[CH:24]=[CH:25][C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[CH:18][NH:17][N:16]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 100 °C
Yield: 34.1 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (80 mg, 0.2 mmol) in DMF (3.5 mL), follow by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (49 mg, 0.22 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20 mg, 0.028 mmol) and 2M aq. Na2CO3 (0.4 mL, 0.8 mmol). The reaction mixture is heated under Argon at 100° C. for 10 hours. The residue is diluted with EtOAc, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-8% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (28 mg, 34%) as a pale-white solid. LCMS (ESMS): m/z 411.80 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:8]([C:17]([NH:19][C:20]3C=C(C=CC=3)C(O)=O)=[O:18])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:31][CH3:32])[CH:3]=1.FC1C=CC(OC2C(C(O)=O)=NC3C(N=2)=CC=CC=3)=C(OC)C=1.NC1[S:58][CH:59]=[C:60]([C:62]([O:64]CC)=[O:63])[N:61]=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:8]([C:17]([NH:19][C:20]3[S:58][CH:59]=[C:60]([C:62]([OH:64])=[O:63])[N:61]=3)=[O:18])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1cccc(C(=O)O)c1
Agent: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1nc(C(=O)O)cs1

Procedure:
2-(3-(4-Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)thiazole-4-carboxylic acid (37) was prepared using a similar experimental procedure as described above for cmpd (36) from 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid and ethyl 2-aminothiazole-4-carboxylate.
Reaction SMILES: [C:1]1([S:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:14](=[O:16])[CH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccsc1Sc1ccccc1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccsc1Sc1ccccc1

Procedure:
Following General Procedure BI above, and using (2-phenylthiothienyl)acetic acid and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tIc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C[O-].[Na+].[P:4]([O-:10])([O:8][CH3:9])([O:6][CH3:7])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=[O:17].FC(F)(F)C(O)=O>CO>[CH3:9][O:8][P:4]([CH:16]([OH:17])[C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:10])[O:6][CH3:7]
Reactant: COP(=O)([O-])OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(C(O)P(=O)(OC)OC)cc(OC)c1OC
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A round-bottom flask equipped with thermometer, condenser and gas inlet was charged with methanol (150 mL) and sodium methoxide (1.074 g, 20 mmol) and cooled to 0° C. under nitrogen protection. To a stirred solution were added subsequently dimethyl phosphate (19.52 g, 0.177 mol) and 3,4,5-trimethoxybenzaldehyde (30 g, 0.153 mol). A resulted solution was heated at 50° C. for 1 hour, cooled down to r.t. and treated with trifluoroacetic acid (4.6 ml). The mixture was concentrated under reduced pressure, the residue dissolved in EtOAc (300 mL), washed once with 18% brine, then once with saturated brine, dried over sodium sulfate. The filtered solution was concentrated until precipitation started. To the resulted suspension 1:1 mixture of t-butylmethyl ether and heptane was added (50 mL). Solid was filtered out, washed with two portions (20 mL) of the same solvent mixture and vacuum-dried to give 41.2 g (88%) of 1, LC purity 99.4% (AUC), m.p. 103-104° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([I:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:13].C(OCC)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([I:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:4]([F:11])=[CH:5][CH:6]=1
Reactant: O=C(c1c(F)ccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(I)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(I)cc23)c1F
Temperature: 60 °C
Yield: 87.3 %

Procedure:
In a reaction vial, (2,6-difluoro-3-nitro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (45, 0.123 g, 0.287 mmol) is mixed with 5.0 mL of ethyl acetate and 5.0 mL of tetrahydrofuran. Stannous chloride, dehydrate (0.223 g, 0.989 mmol) is added and the reaction is heated at 60° C. for 24 hours. The reaction is poured into a mixture of 25 mL of water and 25 mL of saturated aqueous sodium bicarbonate and treated with celite, then filtered through a bed of celite. The celite is washed with ethyl acetate. The organic layer is separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (46, 0.100 g). MS (ESI) [M+H+]+=399.9.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[S:15][C:16]=1[CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][C:16]1[S:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[C:12]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH3:23])(=[O:4])=[O:3]
Reactant: Cc1ccccc1-c1c(CO)sc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1c(COS(C)(=O)=O)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Methanesulfonyl chloride (158 μL, 2.04 mmol) was added dropwise to a solution of (3-o-tolylbenzo[b]thiophen-2-yl)methanol (432 mg, 1.70 mmol) and DIPEA (385 μL, 2.21 mmol) in anhydrous DCM (10 mL) at RT. Stirring at RT was continued for 18 h then the reaction mixture was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-o-tolylbenzo[b]thiophen-2-yl)methyl methanesulfonate as a brown oil (424 mg, 75%). 1H NMR (DMSO, 400 MHz): δ 8.05 (1H, d, J=8.04 Hz), 7.45-7.40 (3H, m), 7.38-7.32 (2H, m), 7.21 (1H, d, J=7.40 Hz), 7.12 (1H, d, J=7.98 Hz), 4.82 (1H, d, J=12.41 Hz), 4.76 (1H, d, J=12.41 Hz), 3.32 (3H, s), 1.99 (3H, s)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:14](=[O:17])[C:15]=2[CH3:16])=[CH:6][CH:5]=1.[CH2:30](I)[CH2:31][CH3:32]>CS(C)=O>[CH3:16][C:15]1[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:30][CH2:31][CH3:32])=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To 50 ml of a suspension of 0.36 g (0.018 mole) of sodium hydride in DMSO, 1.7 g (0.0048 mole) of 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone was added, followed by further dropwise addition of 1.0 g (0.0058 mole) of propyl iodide. The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was thereafter poured into ice water, followed by extraction with chlorofom. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, followed by recrystallization from a 2:1 mixed solvent of acetone and hexane to obtain 1.6 g of 3-methyl-1,6-diphenyl-2-(4-propoxyphenyl)-4(1H)-pyridinone having a melting point of 165°-168° C.
Reaction SMILES: Cl[CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1>[Zn].C(O)(=O)C>[C:13]([CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:14]
Reactant: N#CC(Cl)Cc1ccc(C(=O)O)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: N#CCCc1ccc(C(=O)O)cc1

Procedure:
100 parts of zinc powder are gradually added to a solution of 209.5 parts of 4-(2-chloro-2-cyanoethyl) benzoic acid in 500 parts of glacial acetic acid. The temperature rises quickly up to reflux and is maintained for approximately one hour. The solution is filtered when hot so as to eliminate the insoluble matter, then the filtrate is diluted with 1,000 parts of water and the precipitate formed is isolated. Thus 122 parts of 4-(2-cyanoethyl) benzoic acid are obtained. M.P.: 182° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][OH:27])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.N1C=CN=C1.[C:38]([Si:42](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:41])([CH3:40])[CH3:39]>O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][O:27][Si:42]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(CCO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-hydroxyvalerate (401 g) and DMF (2000 mL) were mixed. To the mixture were added imidazole (160 g) and tert-butylchlorodiphenylsilane (287 mL) at ice temperature. The mixture was stirred at RT for 1 hr. After pouring water (1.2 L) into the reaction, the mixture was extracted with toluene (2.3 L). The organic layer was washed with aqueous 20 w/v % citric acid (1.6 L), water (2 L) and 10 w/v % brine (1.6 L), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (744.2 g) as a crude product.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:13]2)[C:5]([O:26][CH2:27][CH3:28])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of benzyl 3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (0.35 g, 0.87 mmol) in methanol (5 mL) cooled at 0° C. was added sodium tetrahydroborate (0.040 g, 1.0 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with water, extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give the crude alcohol (0.31 g, 88%). LCMS calculated for C22H27ClNO4 (M+H)+: m/z=404.2; Found: 404.0,
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O-:22])=[O:21]>O1CCCC1.O>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (6.6 ml, 47.1 mmole) in tetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added 2.5N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for 30 minutes. To this reaction mixture were next added a solution of ethyl propionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and a solution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran (20 ml) in this sequence, and the resulting mixture was further stirred at -78° C. for 30 minutes. To the reaction mixture were added tetrahydrofuran (10 ml) followed by water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After the ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole) was added to the solution and stirred under heating at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature. Precipitates were collected by filtration, washed with toluene and desiccated to give ethyl 5-[hydroxy-(2-nitrophenyl)methyl]-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, the filtrate was concentrated and purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give a 3:1 mixture (6.09 g, 37.4%) of ethyl 4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and a compound a-2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+].[C:23]([O:27]C)(=[O:26])[CH:24]=[CH2:25].Cl>O1CCOCC1.ClCCl>[N:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][N:1]3[CH2:25][CH2:24][C:23]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: c1cc(Oc2ccc(OC[C@H]3CCCN3)cc2)ccn1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 144 (50 mg, 0.15 mmol) was treated with 20% NaOH (5 ml) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 ml) and methyl acrylate (0.4 ml, 2.8 mmol) were added and the mixture was stirred at rt overnight. The reaction mixture was dried down to give an oil. Excess 4.0M HCl in dioxane was added and the mixture was stirred overnight at rt. The solvent was removed in vacuo to give the title compound. (15 mg, 23%); LC/MS; m/z 343 (M+H) 99%; 1H NMR (DMSO-d6, 400 MHz) δ 1.79-2.29 (4H, m), 2.89 (2H, m), 3.16 (1H, m), 3.56-3.71 (3H, m), 3.97 (1H, m) 4.34-4.51 (2H, m), 7.18 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=9.6 Hz), 7.43 (2H, d, J=7.2 Hz), 8.80 (2H, d, J=7.2 Hz)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cc(C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1-c1ccncc1
Yield: 48.5 %

Procedure:
A mixture of methyl 2-bromo-5-methylbenzoate (5.2 g), pyridine-4-boronic acid (4.2 g), sodium carbonate (4.8 g), tetrakis(triphenylphosphine)palladium(0) (1.3 g), water (10 mL) and DME (50 mL) was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, and filtered through silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.