Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C(OC([N:43]1[CH2:46][CH:45]([N:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]2=[O:54])[CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:44][CH:45]([N:47]2[CH:52]=[CH:51][C:50]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:49][C:48]2=[O:54])[CH2:46]1
Reactant: CC(C)(C)OC(=O)N1CC(n2ccc(Br)cc2=O)C1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C3CNC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described in Example 26, followed by removal of the tert-butoxycarbonyl group using F3CCO2H in CH2Cl2. LC (method 4): tR=0.82 min; Mass spectrum (ESI+): m/z=502 [M+H]+; 1H NMR (CDCl3) δ 1.05 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.10-2.22 (m, 4H), 2.34 (m, 1H), 2.72 (m, 1H), 3.71 (m, 2H), 4.13 (m, 2H), 5.52 (m, 1H), 5.64 (m, 1H), 6.40 (m, 1H), 6.61 (m, 1H), 6.97 (d, 2H), 7.25 (m, 7H), 7.71 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10](=[S:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH2:16]([S:12][C:10]1[NH:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: S=c1[nH]nc(-c2ccncc2)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSc1nnc(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A mixture of 3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (2 g, 11.2 mmol), 3-bromoprop-1-yne (1.47 g, 12.3 mmol) and sodium acetate (5.34 g, 65.1 mmol) in DMF (20 mL) was stirred for 6 h at room temperature. The reaction mixture was then poured into water (50 mL) and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated to obtain the title compound (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[O:4]C(OC)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[OH:4]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Then, 125 g (0.43 mol) of methyl 2-bromo-4-fluoro-5-nitrophenoxyformate was suspended in 200 ml of water, to which 19 g (0.47 mol) of sodium hydroxide was added, and the mixture was stirred at 50° to 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with chloroform. The aqueous layer was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated, which afforded 104 g (0.43 mol) of 2-bromo-4-fluoro-5-nitrophenol.
Reaction SMILES: [OH-].[Li+].C(OC([N:10]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:21])=[CH:19][C:14]=2[S:13](=[O:27])(=[O:26])[CH:12]=[C:11]1[CH2:28][C:29]([O:31]C)=[O:30])=O)(C)(C)C>CO>[CH3:25][S:22]([N:20]([CH3:21])[C:18]1[CH:17]=[CH:16][C:15]2[NH:10][C:11]([CH2:28][C:29]([OH:31])=[O:30])=[CH:12][S:13](=[O:26])(=[O:27])[C:14]=2[CH:19]=1)(=[O:23])=[O:24]
Reactant: COC(=O)CC1=CS(=O)(=O)c2cc(N(C)S(C)(=O)=O)ccc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(c1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
A 2.0 M aqueous solution of lithium hydroxide (7.0 mL, 14.0 mmol) was added to a solution of 7-(methanesulfonyl-methyl-amino)-3-methoxycarbonylmethyl-1,1-dioxo-1H-1λ6-benzo[1,4]thiazine-4-carboxylic acid tert-butyl ester (Example 7d, 1.29 g, 2.80 mmol) in methanol at 25° C. The reaction mixture was stirred at 25° C. for 5 h, and then was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with a 5:1 mixture of diethyl ether and acetonitrile afforded the desired product, [7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid (0.286 g, 0.83 mmol, 30% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.96 (3H, s), 3.26 (3H, s), 3.48 (2H, s), 6.03 (1H, s), 7.29 (1H, d, J=8.6 Hz), 7.58 (1H, dd, J1=2.3 Hz, J2=9.5 Hz), 7.79 (1H, d, J=2.3 Hz), 10.80 (1H, s), 12.79 (1H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](I)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(I)cnn1Cc1ccccc1
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(-c2ccc(F)cc2)cnn1Cc1ccccc1
Temperature: 100 °C

Procedure:
2-Benzyl-5-iodopyridazine-3(2H)-one (5.0 g, 16 mmol), 4-fluorophenyl boronic acid (2.91 g, 20.8 mmol), Pd(Ph3P)4 (0.93 g, 0.80 mmol), and potassium carbonate (6.64 g, 48.1 mmol) were combined in dioxane (120 ml) and Water (40 ml). The reaction mixture was refluxed at 100° C. for 3 h, cooled to room temperature, and poured into ethyl acetate (200 mL) and water (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.38 (d, 1H); 7.25-7.92 (m, 10H); 5.27 (s, 2H). LRMS (APCI) calc'd for (C17H14FN2O) [M+H]+, 281.1. found 281.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@@:4]3([C@H:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:12]4[CH2:13][CH2:14][N:3]13)[CH2:5][CH2:6][CH2:7][CH2:8]2>O1CCCC1>[O:1]=[C:2]1[CH2:10][C@@H:9]2[C@@:4]3([C@H:11]4[CH2:17][CH2:16][C:15](=[O:18])[N:12]4[CH2:13][CH2:14][N:3]13)[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C1C=C[C@H]2N1CCN1C(=O)C[C@H]3CCCC[C@@]321
Solvent: C1CCOC1
Product: O=C1CC[C@H]2N1CCN1C(=O)C[C@H]3CCCC[C@@]321

Procedure:
700 mg (2.8 mmol) of (9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a, 10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole, dissolved in 30 ml of tetrahydrofuran, are hydrogenated with hydrogen in the presence of 70 mg of PtO2 at room temperature under normal pressure until the absorption of hydrogen ceases. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The resulting oil is crystallised from ethyl acetate. In this manner (9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole of formula ##STR6## is obtained, that is to say the compound of formula I in which R1, R2, R3, R4, R5, R6 and R7 are each a hydrogen atom, m is 2, n is 1 and the chiral C-atoms 9a, 9b and 13a have the above relative configuration (each R*) (melting range: 135° to 136°). The mother liquor is concentrated by evaporation in vacuo and chromatographed on silica gel (0.040-0.063 mm) with trichloromethane and trichloromethane/methanol (99:1) as eluants. There is thus obtained (9aR*,9bS*,13aS*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole, which is stereoisomeric as regards the relative configuration of the 9a C-atom, in the form of an oil which is crystallised from ethyl acetate and then melts at 177°-179°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([C:20]3([C:18]#[N:19])[CH2:22][CH2:21]3)=[O:24])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)C3(C#N)CC3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1-cyano-cyclopropanecarboxylic acid (CAS 6914-79-0) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=335.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (9.6 g, 16.1 mmol) in 4 M HCl in dioxane (60 mL), and water (15 mL) was heated at 100° C. for 20 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1 H), 8.22-8.14 (m, 2 H), 8.00-7.97 (m, 1 H), 7.72-7.65 (m, 3 H), 7.33 (d, J=7.2 Hz, 1 H), 3.04 (s, 3 H); Mass spectrum m/z: 553.40 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](N2C=CN=C2)=O)[N:2]=1.[OH:21][NH:22][C:23](=[NH:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:24]([C:23]1[N:26]=[C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:21][N:22]=1)[CH3:25]
Reactant: O=C(c1cc2c(cn1)[nH]c1ccccc12)n1ccnc1
Reactant: CCC(=N)NO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Reaction time: 72 h
Yield: 56.8 %

Procedure:
To a solution of Compound 1 (1.05 g, 4 mmol) in a mixture of toluene (50 mL) and DMF (50 mL), N-hydroxypropanimidamide (0.53 g, 6 mmol) was added. The resulting mixture was heated at 140°-150° C. for 7 h, and stirring continued for 3 days at room temperture. The solvents were removed in vacuo, and the oily residue precipitated from water. The white solid (1.0 g) was dried and submitted to column chromatography on silica gel with CH2Cl2 /methanol(9:1) as eluent. This afforded the title compound (0.6 g, 56%). M.p. 146°-149° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]2[C:6]([CH:11]=1)=[N+:7]([O-])[O:8][N:9]=2.P(OCC)(OCC)OCC>C(O)C>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]2=[N:9][O:8][N:7]=[C:6]2[CH:11]=1
Reactant: [O-][n+]1onc2cc(Cl)c(Br)cc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: Clc1cc2nonc2cc1Br
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
6-Bromo-5-chlorobenzo[c][1,2,5]oxadiazole 1-oxide (4.8 g, 19 mmol) was taken up 150 ml ethanol, heated to reflux, treated with triethyl phosphite (8.8 g, 53 mmol) and heated for 3.5 h. After cooling, the volatiles were removed by rotary evaporation, the residue was taken up in 100 mL dichloromethane and stirred with 50 mL bleach solution for 30 min. The organic phase was washed with 20 mL saturated NaCl, dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography with a 0-30% ethyl acetate-hexane gradient to give the title compound as an orange solid (3.5 g, 79%): mp 68-69° C.; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.05 (s, 1H); EIMS m/z 232.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([CH2:59][OH:60])[CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][CH:41]([CH2:59][OH:60])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(CO)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 63.5 %

Procedure:
To a solution of 39 (17 mg, 21 umol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (30 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 40 (6.2 mg, 64%).1H NMR (300 MHz, CD3OD) δ 7.37 (s, 1H), 7.06 (s, 4H), 6.88 (s, 1H), 4.16-4.34 (m, 1H), 3.98 (AB pattern, J=12.0 Hz, 2H), 3.88 (d, (d, J=9.6 Hz, 1H), 3.74-3.80 (m, 3H), 3.51-3.61 (m, 3H), 3.30-3.35 (m, 1H, under the solvent), 2.57 (q, J=7.5 Hz, 2H), 2.28 (d, J=13.5 Hz, 1H), 2.11 (dd, J=12.3, 15.0 Hz, 1H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 465 (M+H), 487 (M+Na).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.COC1C=CC(C[O:22][CH2:23][C:24]2[CH:25]=[C:26]3[CH2:49][C:31]4([C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:32]4=[O:48])[O:30][C:27]3=[N:28][CH:29]=2)=CC=1>ClCCl.O>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[CH2:49][C:31]3([C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[C:32]3=[O:48])[O:30][C:27]2=[N:28][CH:29]=1
Reactant: COc1ccc(COCc2cnc3c(c2)CC2(O3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(CO)cnc3O2)c2cccnc21
Temperature: 23 °C
Reaction time: 1 h

Procedure:
DDQ (0.533 g, 2.35 mmol) was added to a solution of 5-(((4-methoxybenzyl)oxy)methyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.61 g, 1.2 mmol) in dichloromethane (16 mL) and water (4 mL) at 0° C. The resulting mixture was gradually warmed to 23° C. and stirred for 1 h, then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=400.2 (M+1).
Reaction SMILES: [B].[C:2]1([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[C:15]([CH:10]1[CH2:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][C:11]1=[O:14])(=[O:17])[CH3:16]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [B]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CC(=O)C1CC(c2ccccc2)CCC1=O
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
5.5 g of boron trifuloride/acetic acid complex was cooled with ice and a benzene solution of 2 g of 4-phenylcyclohexanone and 2.35 g of acetic anhydride was added thereto dropwise. After stirring under ice cooling for 30 min and then at room temperature for four hours, 10 ml of a saturated aqueous solution of ammonium acetate was added thereto and the obtained reaction mixture was stirred at 80° C. for 1.5 hour and purified by extracting with ether to give 1.77 g of 2-acetyl-4phenylcyclohexanone. m.p.: 53-54° C. NMRδTMSDMSO-d6 : 1.90 (3H, m), 2.10 (3H, s), 2.50 (6H, m), 7.26 (5H, s) and 10.58 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1>[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Pd]
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 1-(2-Methoxy-ethyl)-1H-pyrazol-3-yl amine instead of 2-chloro-4-aminopyridine to yield {2-[1-(2-Methoxy-ethyl)-1H-pyrazol-3-ylcarbamoyl]-6-methyl-pyridin-3-yl}-carbamic acid tert-butyl ester as a yellow oil, MS (ISP): m/e=376.5 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide as a yellow oil, MS (ISP): m/e=276.3 (M+H+). Palladium catalysed arylation in accordance with the general method described in example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-bromopyridine yielded the final compound as a light brown solid, MS (ISP): m/e=388.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])/[CH:10]=[C:11](/[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=1I)\[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CCC)CCC)CC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=2)[NH:13][C:11]=1[CH3:12])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CNC(=O)OC(C)(C)C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCN(CCC)CCC
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(CNC(=O)OC(C)(C)C)cc2c1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a mixture of (E)-3-[4-(tert-butoxycarbonylamino-methyl)-2-iodo-phenylamino]-but-2-enoic acid benzyl ester (5.25 g, 10 mmol) and tripropylamine (1.9 mL, 10 mmol) in DMF (10 mL) was added palladium acetate (112 mg, 0.5 mmol). The mixture was stirred at 120° C. for 1 hour and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate and hexanes to give 1.9 g (48%) of the desired product as a yellowish solid: MS(APCI−): m/z 393.1.4 (M−H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[C:24]4[CH2:25][CH2:26][CH2:27][C:23]=4[N:22]=[C:21]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]>O.CO>[CH:28]1([C:21]2[N:20]=[C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([C:7]4([C:5]([OH:6])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:17][CH:16]=3)[C:24]3[CH2:25][CH2:26][CH2:27][C:23]=3[N:22]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)C1(c2ccc(Nc3nc(C4CCCC4)nc4c3CCC4)cc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc(Nc3nc(C4CCCC4)nc4c3CCC4)cc2)CCCC1
Temperature: 90 °C
Yield: 93.6 %

Procedure:
A solution of sodium hydroxide (4.14 g, 100 mmol) in water (100 mL) was added to a solution of 1-[4-(2-cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid methyl ester (7.0 g, 17.2 mmol) in MeOH (100 mL) and the mixture was heated at 90° C. for 8 hours. After evaporation of MeOH under reduced pressure, the mixture was cooled to a temperature in the range of 15° C. to 40° C., and acidified with hydrochloric acid to adjust pH to 3-4. The precipitate formed after standing at a temperature in the range of 15° C. to 40° C. was filtered and washed several times with water, and dried under vacuum. The solid was recrystallized from MeOH to afford the title compound as a white powder (6.3 g, 94% yield).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C:10]3=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([C:7]2[N:8]=[C:9]3[CH2:16][CH2:15][NH:14][CH2:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)N1CCc2nc(N3CCOCC3)cnc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1nc2c(nc1N1CCOCC1)CCNC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 2-morpholin-4-yl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate (105 mg, 0.359 mmol) is dissolved in MeOH (5 mL) and H2O (5 mL). KOH (1.00 g, 17.9 mmol) is added, and the reaction mixture is stirred overnight at 50° C. The mixture is cooled and partitioned between brine (50 mL) and DCM (50 mL). The mixture is extracted with DCM (2×50 mL). The combined organic extracts are dried and evaporated to yield the title compound. MS (+VE) m/z 221.21 (M++1).
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:16]=[C:15]([Br:17])[S:14][C:11]2=[CH:12][N:13]=1)=[O:7])CCC.[NH2:19][CH2:20][C:21]([OH:23])=[O:22]>C[O-].[Na+].CO>[Br:17][C:15]1[S:14][C:11]2=[CH:12][N:13]=[C:8]([C:6]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:7])[C:9]([OH:18])=[C:10]2[CH:16]=1
Reactant: CCCCOC(=O)c1ncc2sc(Br)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2sc(Br)cc2c1O
Yield: 105.7 %

Procedure:
2-Bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (7 mg, 0.020 mmol, example 1.g) and glycine (38 mg, 0.5 mmol) were suspended in 1 mL of 0.5 N sodium methoxide in methanol. The resultant mixture was heated to 120° C. for 10 min. using a CEM microwave reactor. The reaction mixture was cooled, concentrated to ca. 0.2 mL under high vacuum, and diluted with 1 mL of 1.0 N HCl. The resultant precipitate was collected on a fine glass filter funnel, washed twice with water, and dried under hi-vacuum to yield 7 mg of the title compound. MS: (−) m/z 328.98, 331.03 (M−1, 79Br/81Br)
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[Cl:12].[Li+].[OH-].Cl>C1COCC1.CO.O.O>[Cl:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To 2-chloro-4-methoxy-benzoic acid methyl ester (1.1 g) in THF/MeOH/water (12 mL/3 mL/3 mL) at room temperature was added LiOH (461 mg) dissolved in water. After 2 h, the reaction mixture was adjusted to pH 4 with 1N HCl and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO4. Trituration of the resulting solid in ether afforded 1.0 g (98%) of the title compound. MS: 187 (MH+), HPLC tR: 2.04 min.