Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>O1CCOCC1>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([O:14][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](Cc1cccc(C2CCCC2)c1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C2CCCC2)c1
Yield: 82 %

Procedure:
According to example 54, 0.50 g of 3-cyclopentyl-L-phenylalanine.HCl was treated with 25 mL of isobutylene in 20 mL of 1,4-dioxane in the presence of 0.3 mL of conc. H2SO4. Work-up followed by acidification of the free amine with ethereal HCl afforded 0.49 g (82%) of tert-butyl 3-cyclopentyl-L-phenylalaninate.HCl as a white powder, m.p. 154-156° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C=C(Cl)C=CC=1C1[C:28]([C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]1[C:28]([C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(C(F)(F)F)cc3F)n2)nc1

Procedure:
{4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-fluoro-4-(trifluoromethyl)benzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][C@@H:20]([OH:22])[CH2:19][CH2:18][NH:17]2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:24](Br)#[C:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>>[CH2:26]([N:17]1[CH2:18][CH2:19][C@H:20]([OH:22])[CH2:21][C@@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][C:12]=1[OH:23])[C:25]#[CH:24]
Reactant: CC#CBr
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN1CC[C@H](O)C[C@@H]1c1ccc(C(C)(C)CCCCCC)cc1O
Yield: 57 %

Procedure:
Employing the procedure of Example 10 with 321 mg (1.01 mmole) of cis-2-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-piperidinol, 82 microliter (1.06 mmole) or propynyl bromide and 292 mg (2.12 mmole) of potassium carbonate affords 205 mg (57%) of the title compound as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@H:48]([CH2:53]O)[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:55]([OH:58])(=[S:57])[CH3:56]>C1COCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@H:48]([CH2:53][S:57][C:55](=[O:58])[CH3:56])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[C:41]([CH3:42])([CH3:43])[CH3:44])=[O:38])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution triphenylphosphine (373 mg, 1.42 mmol) and diethyl azodicarboxylate (225 μL, 1.42 mmol) in THF (6 mL) at 0° was added a solution of N-tert-butyloxy carbonyl-L-tert-butylglycyl-L-leucinol 10 (313 mg, 0.950 mmol) and thioacetic acid (100 μL, 1.42 mmol) in THF (4 mL). The mixture was stirred at 0° for 2 h and the solvent was removed under vacuum. The residue was purified by flash chromatography (SiO2, 10-30% EtOAc-hexane) to give the corresponding title compound 11 in 63% yield (232 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH2:26][CH:27]2[CH2:31][C:32]([OH:34])=[O:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Br)ccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 70 °C

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.3 g, 24.1 mmol) was dissolved in acetonitrile (70 mL) and water (10 mL). To this mixture, potassium carbonate (10 g, 72.3 mmol) and 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (7.1 g, 28.9 mmol) were added. The resulting mixture was heated at 70° C. for 2 days. The mixture thus obtained was concentrated and ethyl acetate was added. 1 N HCl was then added slowly to the reaction solution until pH=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material thus obtained was purified by silica gel chromatography eluting with a gradient of 0% to 10% of methanol in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.28 (br s), 7.71-7.83 (m, 1H), 7.56-7.66 (m, 1H), 7.30-7.40 (m, 1H), 3.56-3.82 (m, 3H), 3.33-3.44 (m, 1H), 2.99-3.24 (m, 2H), 2.87 (m, 1H), 2.32-2.47 (m, 1H), 2.17-2.29 (m, 1H), 1.32-1.51 (s, 9H); MS (DCI+) m/z 444.1 (M+H)+.
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Cl:13])=[N:5][N:4]=1.[CH3:14][CH2:15][OH:16]>>[Cl:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:16][CH2:15][CH3:14])=[N:4][N:5]=1
Reactant: CCO
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Na]
Product: CCOc1nnc(Cl)c2ccccc12

Procedure:
Sodium (33.8 mg, 1.470 mmol) was allowed to react with EtOH (10 mL), then 1,4-dichlorophthalazine (279 mg, 1.4 mmol) was added and the reaction mixture was refluxing for 30 min. The hot solution was filtered and evaporated. The crude product was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 200 mg of the crude product 1-chloro-4-ethoxyphthalazine. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29-8.18 (m, 2H), 7.99-7.90 (m, 2H), 4.73 (q, J=7.1 Hz, 2H), 1.57 (t, J=7.2 Hz, 3H); MS: MS m/z 209.06 (M++1).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[N:52]=[CH:51][CH:50]=[N:49]2)[C:40]=1[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:41]([C:40]4[C:44]([N:48]5[N:52]=[CH:51][CH:50]=[N:49]5)=[CH:45][CH:46]=[CH:47][C:39]=4[F:38])=[O:42])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 6-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.98-7.73 (m, 2H), 7.52-7.28 (m, 2H), 7.19-6.73 (m, 1H), 5.88-5.43 (m, 1H), 4.50-4.24 (m, 1H), 4.21-3.85 (m, 5H), 3.82-3.40 (m, 2H), 3.24-2.77 (m, 6H), 2.31-1.91 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>COC(O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(Cl)c1
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Yield: 48.2 %

Procedure:
A mixture of 4.4 g (16.7 mmol) of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 2.67 g (18.3 mmol) of 3-chloro-4-fluoro aniline in 110 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was diluted with ethyl acetate and wash with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried over sodium sulfate and then the solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3 g yellow solid: mass spectrum (electrospray, m/e): 372.9.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][OH:18])[CH:8]3[N:9]=2)=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCCCCC>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:18][CH2:17][CH2:16][N:11]2[CH:8]3[N:9]=[C:10]4[C:6]([N:7]3[N:13]([CH3:14])[C:12]2=[O:15])=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3][N:2]4[NH2:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CN1C(=O)N(CCO)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one obtained in step 6 (3.5 g, 11 mmol), p-toluene sulphonylchloride (5.2 g, 27 mmol) were taken in pyridine (30 ml) and stirred at 25-27° C. for 16 hours. To the reaction mixture hexane (100 ml) was added and solid obtained was filtered off and washed with water (100 ml) followed by hexane (100 ml) to obtain 2-[5-amino-8-(2-furyl)-1-methyl-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1 g, 78%) as a brown solid.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([O:24][CH2:25][CH2:26][CH3:27])[N:16]=1.[N:28]([C@@H:31]1[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](N2C=C(C)C(=O)NC2=O)[CH2:32]1)=[N+:29]=[N-:30]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:33]2[O:34][C@H:35]([CH2:36][OH:37])[C@@H:31]([N:28]=[N+:29]=[N-:30])[CH2:32]2)=[C:17]([O:24][CH2:25][CH2:26][CH3:27])[N:16]=1
Reactant: CCCOc1nc(N)nc2nc[nH]c12
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CCCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C

Procedure:
To 500 ml of an aqueous pH 6.0 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-propoxypurine (0.0985 g, 0.5 mmol) and 3'-azido-3'-deoxythymidine (0.668 g, 2.5 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 25 mL solution of trans-N-deoxyribosylase (Example 2b) at an activity of 1500 units/mL was added. The reaction was heated at 50° C. Seven days later 0.0985 g, 0.5 mmol, of 2-amino-6-propoxypurine was added to the reaction. Eleven days after the reaction was started, another 0.0985 g, 0.5 mmol, of 2-amino-6-propoxypurine was added to the reaction. The reaction was terminated after twenty-three days. The reaction was heated to 80° C. to precipitate the enzyme and then filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on 180 g of silica gel (230-400 mesh) eluted first with chloroform/methanol (99:1, v/v) then with chloroform/methanol (98:2, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as an oil. The oil was dissolved in water and lyophilized to give a solid (56% yield). mp=145°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:30][CH2:29][CH2:28][Br:27])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: BrCCCBr
Product: COc1ccc(-c2nc(-c3ccc[nH]3)n(CCCBr)c2-c2ccc(OC)cc2)cc1

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(2-pyrrolyl)-1-(3-bromopropyl)imidazole is prepared analogously to Example 22 by reacting 4,5-bis(4-methoxyphenyl)-2-(2-pyrrolyl)imidazole with 1,3-dibromopropane. Melting point 97° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][O:19][CH3:20])[CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][O:19][CH3:20])[CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCn1cc(Br)sc1=Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
6.50 g (18.0 mmol) of methyl 6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridine-2-carboxylate was dissolved in 80 ml of tetrahydrofuran, 790 mg (36.0 mmol) of lithium borohydride was added thereto and the mixture was heated under reflux. After 1 hour, 790 mg (36.0 mmol) of lithium borohydride was added thereto followed by further heating under reflux for 1 hour, the reaction mixture was cooled to room temperature and water was added thereto. After water was added until no more bubbling took place, the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was washed with 100 ml of water for two times and then washed with 100 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography to give 2.67 g (8.09 mmol) of the title compound as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (162 mg, 0.42 mmol), glycine (2.11 g, 28 mmol) and NaOMe solution (42 mL, 21 mmol, 0.5M in MeOH) was refluxed for 32 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was further purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 131 mg of the title compound. MS: (+) m/z 430.08 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11](C3C4CNC(=O)C=4C=CN=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C2CNC(=O)C=2C=CN=1.Br[C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH2:46][NH:47][C:48]2=[O:53]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:44]3[CH:52]=[CH:51][CH:50]=[C:49]4[C:45]=3[CH2:46][NH:47][C:48]4=[O:53])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1NCc2c(Br)cccc21
Agent: O=C1NCc2c1ccnc2Cl
Product: O=C1NCc2c1cccc2-c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The synthesis of the title compound is performed starting from 100 mg (0.25 mmol) of the product from step 3 of example 1 in a manner analogous to the synthesis of the compound from example 1. In step 4, instead of the compound from example 22A, 4-bromo-2,3-dihydroisoindol-1-on (63 mg, 0.30 mmol) is used. The result is 74 mg (65% of theoretical yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17](I)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].[C:21]([C:23]1([OH:32])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1)#[CH:22]>N1CCCCC1.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.[Cu]I>[NH2:15][C:11]1[N:10]=[C:9]([N:8]2[C:7]3[CH:16]=[C:17]([C:22]#[C:21][C:23]4([OH:32])[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH2:25][CH2:24]4)[CH:18]=[CH:19][C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])[CH:14]=[CH:13][N:12]=1
Reactant: CCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1
Reactant: C#CC1(O)CCc2cccnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCOc1nc2ccc(C#CC3(O)CCc4cccnc43)cc2n1-c1ccnc(N)n1

Procedure:
A mixture of 4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (150 mg, 0.394 mmol) and 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol (118 mg, 0.59 mmol) was dissolved in piperidine (1 mL). The solution was de-gassed with nitrogen for 2 mins. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) and copper(I) iodide (6 mg, 0.031 mmol) were added and the resultant solution heated to 30° C. for 2 hr. The mixture was concentrated in vacuo, DCM (10 mL) added and re-concentrated in vacuo (twice). The residue was purified by column chromatography (Biotage, 0-10% MeOH gradient in DCM), followed by reverse phase preparative HPLC purification to give the title compound; 1H NMR (500 MHz, DMSO) delta 1.44 (3H, t, J=7.1 Hz), 2.36-2.42 (1H, m), 2.52-2.62 (1H, m), 2.83-2.95 (1H, m), 2.94-3.08 (1H, m), 4.63 (2H, q, J=7.0 Hz), 6.96 (1H, d, J=5.5 Hz), 7.08 (2H, s), 7.19-7.32 (2H, m), 7.44 (1H, d, J=8.2 Hz), 7.72 (1H, d, J=7.6 Hz), 8.13 (1H, s), 8.38 (1H, d, J=5.5 Hz), 8.44 (1H, d, J=4.8 Hz), 8.51 (1H, s); LC-MS: m/z=+413.05 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]1COCC1.[Si](C=[N+]=[N-])(C)(C)C.C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([N:23]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH3:41])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N[C@@H]2C(=O)NS(=O)(=O)c2ccc(F)cc2)ccn1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)[C@H]1NC(=O)[C@@H]1Cc1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 98 (18 mg, 1.0 eq.) in MeOH: THF (1 mL: 300 uL) was added 2.0M TMSCHN2 in hexanes (266 uL, 17 eq.). After 15 minutes, TLC showed complete conversion of starting material. The reaction was poured into ethyl acetate and then washed with 0.2N HCl, 1N NaHCO3 and brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo. The product was then purified via reverse phase HPLC (C18, acetonitrile/water with 0.1% TFA) to yield 99 (11.9 mg, 65%) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH3:32])[N:23]=3)[N:20]=2)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=1)=[O:12])[CH2:4][CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].[OH-].[K+].[CH2:43]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:43][O:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH3:32])[N:23]=3)[N:20]=2)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:14]=1)=[O:12])[CH2:4][CH2:5][S:6]([CH3:9])(=[O:7])=[O:8]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](CO)CCS(C)(=O)=O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](CCS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methanesulfonyl-propyl)-amide (102 mg, 0.173 mmol) was dissolved in THF (1.9 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (97 mg, 1.73 mmol), 18-crown-6 (46 mg, 0.173 mmol), and iodomethane (11 μl, 0.173 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-60% EtOAc) to afford 30 mg (29%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methanesulfonyl-propyl)-amide as an off-white solid. MS: [M+Na]+=627).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>O>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(O)cc1
Solvent: O
Product: CC(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.0 g of 4-hydroxycumene in 14 ml of water was added dropwise 4.0 ml of 70% nitric acid while cooling with ice and the temperature of mixture was raised to room temperature and the reaction was carried out for 40 minutes. After 500 ml of water was added thereto, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively, and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting silica-gel column-chromatography [eluent: ethyl acetate]to give 5.07 g of 4-isopropyl-2-nitrophenol.