Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[CH3:35][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (12.0 g, 24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid (7.57 g, 67%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.14 in 35% ethyl acetate/hexanes; mp 123-124° C.; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.66-7.63 (m, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.6 Hz, 1H), 6.91-6.79 (m, 4H), 4.21 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.53 (s, 6H); MS m/e calculated for C28H28NO5 (M++1) 458.2, found 458.2.
Reaction SMILES: C(O[CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.COC1C=[C:31]([NH:37]N)C=CC=1OC.[C:39](OC1CCC(=O)CC1)(=O)C1C=CC=CC=1>>[CH3:39][N:37]([CH3:31])[CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1
Reactant: COc1ccc(NN)cc1OC
Reactant: COc1cc2[nH]c3c(c2cc1OC)CC(OC(=O)c1ccccc1)CC3
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Product: COc1cc2[nH]c3c(c2cc1OC)CC(N(C)C)CC3

Procedure:
The 3-benzoyloxy-6,7-dimethoxy-1,2,3,4-tetrahydrocarbazole, m.p. 123°-125°C., was prepared from 102 g. of 3,4-dimethoxyphenylhydrazine and 109 g. of 4-benzoyloxycyclohexanone by following a procedure similar to that described in Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N-:19]=[C:20]=[O:21].[K+].FC(F)(F)C(O)=O>C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:20](=[O:21])[NH2:19])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: OCCc1ccc(OCc2cccc(F)c2)cc1
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: NC(=O)OCCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
Under an argon atmosphere and at room temperature, a suspension of 1.0 g of 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethanol and 0.66 g of potassium isocyanate in 2 ml of benzene was treated dropwise under stirring with 0.62 ml of trifluoroacetic acid. After stirring for 18 h at room temperature, the reaction mixture was diluted with water, then extracted three times with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. There were obtained 0.52 g (44% of theory) of carbamic acid 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl ester as a white solid; MS: m/e=290 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][C:4]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P:19]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:26])=[CH:5][C:4]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccc(C)c(-c2cc(CCl)ccc2CCl)c1
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)c(-c2cc(C)ccc2C)c1)OCC

Procedure:
50 g (180 mmol) of 2′,5′-bis-chloromethyl-2,5-dimethylbiphenyl are heated at 160° C. in 63 ml (366 mmol) of triethyl phosphite until the evolution of gas is complete. The residue which remains is employed in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15](OC)[O:16]C)=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[O:16])=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1CC=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of 2-tert-butyl-3-(2,2-dimethoxy-ethyl)-6-nitro-1H-indole (0.80 g, 2.6 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL, 50%) at 0° C. and the resulting solution was stirred at room temperature for 6 h. Saturated sodium bicarbonate was added until pH >7. The aqueous layer was extracted with methylene chloride several times. The combined organic layers were dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.62 g, 91%). LCMS (m/z): 261.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:12])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(CC(=O)O)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(=O)OCc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To 4-acetyl-2-chlorophenylacetic acid (2.65 g, 12.5 mmol) in DMF solution (26 mL) were added triethylamine (3.5 ml, 25 mmol) and 4-nitrobenzyl bromide (5.4 g, 25mol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to an ice cooled saturated potassium hydrogencarbonate solution, the organic layer was separated by a separatory funnel, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (silica gel 180 ml, hexane:EtOAc=2:1→1:1) to give 4-nitrobenzyl (4-acetyl-2-chlorophenyl)acetate (3.56 g, yield, 82%) as white crystals. The product was subjected to next reaction without further purification. To 4-nitrobenzyl(4-acetyl-2-chlorophenyl)acetate (3.56 g, 11.4 mmol) and triethylamine (2.0 ml, 15.9 mmol) in dichloromethane (36 ml) was dropped at 0° C. under stirring trifluoromethanesulfonic acid trimethylsilyl ether (2.4 ml, 14.8 mmol), and the mixture was stirred for 20 minutes. To the reaction mixture were added at 0° C. dichloromethane (50 mL), (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (4.6 g, 15.9 mmol), and zinc iodide (2.2 g, 6.8 mmol), and then the ice bath was removed. The mixture was stirred at room temperature for 4.5 hours and then added to an ice cooled saturated potassium hydrogencarbonate solution. The organic layer was separated by a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified with silica gel chromatography (silica gel 180 ml, hexane:EtOAc=4:1→0:1) to give 4-nitrobenzyl(4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)acetate (5.2 g, yield 79.7%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[ClH:24].[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:29]4[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][OH:25])[CH2:28]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: OCC1CCCNC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCC(CO)C1
Product: Cl
Yield: 84.8 %

Procedure:
By using the method of Example 89, 1.1 g (3.2 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.2 g (19.2 mmol) of 3-hydroxymethyl-piperidine were converted to 0.76 g the title compound, obtained as a yellow powder: mass spectrum (electrospray, m/e): M+H 524.0, (M+2H)+2262.3.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][C:8]1[CH:13]=[CH:12]N=[CH:10][CH:9]=1)SC)#[N:2].[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C>C(O)C>[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4]([NH:3][C:1]#[N:2])=[N:7][C:8]2[CH:13]=[CH:12][CH:27]=[C:26]3[C:9]=2[CH:10]=[CH:29][CH:28]=[N:25]3)=[CH:17][CH:16]=1
Reactant: CCN(CC)CC
Reactant: CSC(=Nc1ccncc1)NC#N
Reactant: NCc1ccc(N)cc1
Solvent: CCO
Product: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Temperature: 60 °C
Yield: 77 %

Procedure:
In a reaction flask under nitrogen with magnetic stirring 1-cyano-2-methyl-3-pyridin-4-yl-isothiourea (0.35 g, 1.82 mmol) and 4-aminobenzylamine (0.25 g 2.05 mmol) were suspended in ethanol (1.5 mL). Triethylamine (0.19 g, 1.36 mmol) was added followed by (4-dimethylamino)pyridine (6 mg, 0.05 mmol). This reaction mixture was heated at 60° C. for 4 hours then cooled to room temperature. The resulting solid was collected by filtration and washed with cold ethanol (10 mL) to give N-(4-amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine as a white solid in 77% yield. 1H NMR (DMSO-d6, ppm): 9.43 (s, 1H), 8.38 (d, 2H), 8.14 (s, 1H), 7.19 (d, 2H), 7.00 (d, 2H), 6.54 (d, 2H), 5.07 (s, 2H), 4.03 (d, 2H) ESMS 289.0 (M+23).
Reaction SMILES: Cl.[C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)(=[NH:4])[CH3:3].[C:34]([O:37][CH:38]([O:40][C:41](C1C=C([N+]([O-])=O)C=CC=1O)=[O:42])[CH3:39])(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:34]([O:37][CH:38]([O:40][C:41]([CH2:3][C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[NH:4])=[O:42])[CH3:39])(=[O:36])[CH3:35]
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: CC(=O)OC(C)OC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
A solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 0-(1-acetoxyethoxycarbonyl)-4-nitrophenol (63 mg) and diisopropylethylamine (72 mg) in DMF (4 ml) was stirred at 50t for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water, sodium hydrogen carbonate aqueous solution and brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give a colorless solid of the title compound (89 mg).
Reaction SMILES: [C:1](CC[NH-])#N.[CH3:6][NH:7][C:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15])=NC.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15])=[N:7][CH2:6][CH3:1])[CH3:30]
Reactant: CN=C(CCNC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C)NC
Reactant: N#CCC[NH-]
Reactant: CCN
Product: CCN=C(CCNC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C)NCC

Procedure:
Compound 272 was synthesized from cyanoethylamide 242 as described above for compound 270 using ethylamine (3 ml). ES MS: 351.53. (M+H+). H1-NMR (DMSO-d6): δ 0.86–0.88 (d, 6H, CH3 -isopentyl), 1.07–1.17 (t, 6H, CH3-ethyl), 1.42–1.60 (m, 3H, CH, CH2—CH), 2.67–2.72 (t, 2H, CH2CH2amidine), 3.12–3.21 (m, 2H, CH2-ethyl), 3.36–3.50 (m, 4H, CH2—NHCO and CH2-ethyl), 4.33–4.38 (t, 2H, CH2—N), 7.39 and 8.20 (d, 1H, pyrrole), 8.63–8.71 (NH-amidine), 9.30 (t, 1H, NHCO).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(OC(F)(F)F)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Yield: 33 %

Procedure:
Starting from 4.53 g (14.6 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoro-methoxy)phenyl]but-1-en-1-olate from example 3A and 3.56 g (19.8 mmol) of 3-chloro-phenylhydrazine hydrochloride, 1.98 g (4.8 mmol, 33% yield of theory) of product are obtained according to the method described in example 4A.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:14]([O-])(O)=[O:15].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[N:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])=[CH:10][CH:9]=1)=[C:14]=[O:15]
Reactant: O=C([O-])O
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1ccc(OCC(F)(F)F)cc1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
2,2,2-Trifluoro-ethanol (7.09 g, 70.09 mmol) and stirred for 30 min. A solution of 1-Fluoro-4-nitro-benzene (10 g, 70.09 mmol) in DMF (25 mL) was added at 5-15° C., allowed to rt, stirred for 2 h, quenched with ice-water, filtered, washed with water and dried under high vacuum to obtain 14 g (89%) 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow solid. Subsequently, a solution of 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene (50 g, 226.2 mmol) in methanol (400 mL) was purged with nitrogen and 10% Pd—C (4.6 g) was added under nitrogen. This was stirred at rt under hydrogen atmosphere (balloon pressure) for 24 h. The reaction mixture was filtered through a celite bed and washed with methanol and the filtrate was removed under reduced pressure and washed with hexane to get 37 g (87%) 4-(2,2,2-Trifluoro-ethoxy)-phenylamine as a brown liquid. LC-MS: 192.4 [M+1]+. To a solution of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (12 g, 62.82 mmol) in DCM (1000 mL) was added solid NaHCO3 (52.77 g, 628.2 mmol). After 10 min, triphosgene (27.96 g, 94.24 mmol) dissolved in toluene (30 mL) was added to the reaction mixture under cooling at 10° C. and stirred for 10 min. The reaction mixture was filtered and the filtrate was concentrated, azeotroped twice with dry toluene to give 10 g 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow oily liquid which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[N:17]2[C:18](=[O:30])[C:19]3[NH:20][CH:21]=[N:22][C:23]=3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]2=[N:15][N:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH2:12][C:13]1[N:17]2[C:18](=[O:30])[C:19]3[NH:20][CH:21]=[N:22][C:23]=3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]2=[N:15][N:14]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCNC(=O)OCc3ccccc3)nnc12
Agent: [Pd]
Solvent: CO
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCN)nnc12
Yield: 92.2 %

Procedure:
To a solution of benzyl[2-(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]carbamate (0.52 g, 1.2 mmol) in methanol (50 mL) was added 10% Pd/C (100 mg). The reaction mixture was shaken in a hydrogenation reactor under 50 Psi H2 for 3 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give the desired product (320 mg, 90% yield). LCMS calculated for C13H20N7O (M+H): 290.2. found: 290.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1N
Reaction time: 18 h
Yield: 31.2 %

Procedure:
HATU (1179 mg, 3.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (461 mg, 2.76 mmol), DIPEA (1.24 mL, 7.12 mmol) and 1-methylpiperazine (230 mg, 2.30 mmol) in DMF (12 mL) and the reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by elution through an SCX-2 column to afford the title compound as brown oil (179 mg, 31%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Br>C(O)C>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH2:12][CH2:11]1
Reactant: O=C(CBr)c1c(-c2ccccc2)noc1C1CC1
Reactant: Nc1ccccn1
Agent: Br
Solvent: CCO
Product: c1ccc(-c2noc(C3CC3)c2-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 2-bromo-1-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-ethanone (91.8mg, 0.3 mmol) and 2-aminopyridine (28.2 mg, 0.3 mmol) in ethanol (2 mL) containing hydrobromic acid (48%, 16.9 μL, 0.8 mmol) was heated under reflux under argon for 2 h. Another portion of 2-aminopyridine (28.2 mg, 0.3 mmol) was added and heating continued under reflux under argon for 1 h. After cooling to room temperature, the mixture was evaporated and poured onto saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 50:50) afforded the title compound (49 mg, 54%) which was obtained as an off-white solid. MS: m/e=302.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH2:10][C:11]#[N:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC=CC=1C.[CH:21](O)=[O:22]>O>[C:11]([CH2:10][N:9]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH:21]=[O:22])#[N:12]
Reactant: O=CO
Reactant: CC(NCC#N)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(c1ccccc1)N(C=O)CC#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a stirred mixture of 104.1 parts of (+)-2-[N-(1-phenylethyl)amino]acetonitrile and 1440 parts of dimethylbenzene are added dropwise 66 parts of formic acid (slightly exothermic reaction). Upon completion, stirring is continued for 3 hours at reflux temperature (water-separator). The reaction mixture is cooled to about 60° C. and washed successively with water, a sodium bicarbonate solution, a diluted sodium hydroxide solution and again twice with water. The organic phase is separated, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding (+)-N-(cyanomethyl)-N-(1-phenylethyl)-formamide (41%); m.p. 78.9° C.; [α] = +60.90° (1% CH3OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](C)=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1N.Cl.CO[C:16](=[NH:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.[CH3:30]O>>[CH3:30][O:11][C:9]([C:4]1[CH:5]=[CH:6][C:7]2[NH:29][C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:1][C:2]=2[CH:3]=1)=[O:10]
Reactant: CO
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: Cc1ccc(N)c(N)c1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
A mixture of 1,2-diamino-4-methylcarboxybenzene (3.6 g; 20 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (5.4 g; 20 mmol) in methanol (150 mL) was stirred at ambient temperature for 48 hours. Solution was concentrated to dryness. The residue was recrystallized from MeOH to obtain 3.8 g (56% yield) of the title compound as yellow solid, m.p. 185-188° C. Anal. Calcd. for C19H18N2O4: C, 67.45, H, 5.36; N, 8.28. Found: C, 67.25; H, 5.45; N, 8.28. Mass Spectrum: (EI; M+) m/z 338. 1H-NMR (DMSO-d6; 400 MHz) δ12.9 (broad s, 1H), 8.1 (s, 1H), 7.63-7.69 (d, 1H), 7.57-7.62 (d, 1H), 7.33 (d, 1H), 7.17-7.21 (dd 1H), 7.14-7.19 (d, 1H), 7.08-7.12 (d, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79 ppm (s, 3H)
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C([O:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][NH2:37])(C)(C)C.Cl>CO.O>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]([OH:40])=[O:33])=[O:7])[N:9]=1)#[N:28]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.21 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-Amino-2,2-dimethyl-propionic acid tert-butyl ester (71 mg, 0.41 mmol) in MeOH (1.5 mL) was microwaved at 120° C. For 1 h. Reaction mixture was diluted with water (80 mL), acidified by 1 N HCl and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Residue was then treated with 3 mL of (½) TFA/CH2Cl2. Resultant mixture was stirred at room temperature for 5 h and concentrated to provide the title compound 90 mg (0.21 mmol) in 100% yield. LC-MS ESI−: 422.07 (M−1)−.