Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)=CCSc1ccc(Br)cc1

Procedure:
A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol (Compound 40) and 2.7 g (67.7 mmol) of sodium hydroxide in 50 ml acetone was heated at reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 10.0 g (67.1 mmol) of 4-bromo-2-methyl-2-butene (Compound 45) in 10 ml acetone and the mixture heated at reflux for a further 24 hours. The mixture was then cooled and solvent removed in-vacuo. The residue was treated with 50 ml water and extracted with 3×75 ml ether. The ether extracts were combined and washed successively with 3×30 ml of 5% NaOH, 50 ml of water and 50 ml of saturated NaCl and then dried (MgSO4). Solvent was then removed in-vacuo and the residual oil purified by kugelrohr distillation (70 degrees C., 0.1 mm) to give the title compound as a colourless oil. PMR (CDCl3 ): & 1.58 (3H, s), 1.70 (3H, s) 3.5 (2H, d, J~7.0 Hz), 5.27 (1H, t, J~7.0 Hz), 7.17 (2H, d, J~8.3 Hz), 7.36 (2H, d, J~8.3 Hz).
Reaction SMILES: C1[C:10]2[C:5](=C[C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].C(OC)(=O)CCCCCCCCC(OC)=O.O=[Sb]O[Sb]=O.P(OC)(OC)(OC)=O>C(O)CO.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.CO>[C:15]([OH:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:10][CH2:9][CH2:8][CH2:7][C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: COC(=O)CCCCCCCCC(=O)OC
Solvent: OCCO
Solvent: COP(=O)(OC)OC
Solvent: CO
Product: O=C(O)CCCCCCCCC(=O)O

Procedure:
Dimethyl 2,6-naphthalenedicarboxylate and dimethyl sebacate were dispersed in ethylene glycol. Then, 0.029 part of manganese acetate tetrahydrate, 0.028 parts of antimony trioxide and 0.1% of spherical silica particles having a mean particle size of 0.3 μm were added to 100 parts of the total of dimethyl 2,6-naphthalenedicarboxylate and dimethyl sebacate, and heated with stirring to conduct the reaction. The temperature was elevated to 235° C. while removing methanol produced as a by-product. After the by-production of methanol was completed, 0.03 part of trimethyl phosphate was added thereto. Then, the pressure was reduced to 0.3 Torr while elevating the temperature to 285° C., thereby conducting the polymerization. Dyes described in JP-A-7-168309, compounds 1-6 and I-24, were each further added to the solid matter in an amount of 54 ppm. The copolymerization ratio of sebacic acid (SA) and the intrinsic viscosity of a polyester thus obtained are shown in Table II-1.
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][C:23](=O)[CH:24]=[CH2:25])[CH:17]=[CH:18][CH:19]=1>[OH-].[K+]>[CH2:1]([C@:5]12[CH2:6][CH2:7][C:8]3[C:17]4[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=4[CH2:20][CH2:21][C:22]=3[C:23]1=[CH:24][CH2:25][C:9]2=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1C(=O)CCC1=O
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC2=O
Yield: 32.5 %

Procedure:
Condense n-butylcyclopentane-1,3-dione (2.8 g) in 0.12% methanolic potassium hydroxide solution (8 cc) with 6-m-methoxyphenylhex-1-en-3-one (5 g) by heating the mixture at 80° for 10 hours. Evaporate the solvent under reduced pressure and heat the residue with toluene-p-sulfonic acid (2 g) in benzene (50 cc) for 45 minutes using a Dean-Stark trap to effect double cyclodehydration. Add ether to the cooled reaction mixture, and evaporate the washed and solution; recrystallize ether solution;recrystallize the residue from ethanol to obtain 13β-butyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (1.9 g), m.p. 53°-55°; ultraviolet absorption peak at 312 mμ (ε29,200).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:34])C.[OH-].[K+].Cl>C1COCC1.O>[Br:34][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[CH:25][C:19]=4[CH:18]=3)=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccc(C(=O)CCC(C)(C)C)cc4s3)ccc2c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CCC(=O)c1ccc2cc(-c3ccc4c(Br)c(OCC(=O)O)ccc4c3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of {1-bromo-6-[6-(4,4-dimethyl-pentanoyl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester (0.167 g, 0.310 mmol) and potassium hydroxide (0.056 g, 1.0 mmoles) in THF (20 mL) and water (20 mL) was stirred for one hour at ambient temperature. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 65° C. for 13.5 hours to yield {1-bromo-6-[6-(4,4-dimethyl-pentanoyl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid as a light yellow solid (0.119 g, 74.8%): MP: 246–7° C.; mass spectrum (−EI, [M−H]−) m/z 509/511. −H NMR (500 MHz, DMSO-d6): δ8.74 (s, 1H), 8.40(d, 1H, J=1.68 Hz), 8.21 (d, 1H, J=9.00 Hz), 8.11–8.15 (m, 3H), 7.97–7.98 (m, 2H), 7.48 (d, 1H, J=9.16 Hz), 5.01 (s, 2H), 3.01 (s, 2H), 1.05 ppm (s, 9H). Elemental Analysis for C26H23BrNO4S: Calcd: C, 61.06; H, 4.53; N, 0.00; Found: C, 60.94; H, 4.59; N, 0.00.
Reaction SMILES: [C:1]([C:6]1(C)[C:10](=[O:11])[C:9]([OH:12])=[C:8]([CH3:13])[O:7]1)(OCC)=O.[OH-].[Na+].Cl>O>[OH:11][C:10]1[C:9](=[O:12])[CH:8]([CH3:13])[O:7][C:6]=1[CH3:1]
Reactant: CCOC(=O)C1(C)OC(C)=C(O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=C(O)C(=O)C(C)O1
Temperature: 30 °C
Yield: 71.2 %

Procedure:
A solution of 9 g of 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan and 5.4 g of sodium hydroxide in 50 ml of water is kept at room temperature under nitrogen for 20 hours. The reaction mixture is acidified with hydrochloric acid, then stirred at 30° C. for an hour and continuously extracted for 6 hours with ether. The ether extract is dried and the solvent is removed under vacuum, the residue is dissolved in a mixture of 5 ml of dry ether and 5 ml of dry pentane. The solution is cooled to -10° C. and filtered. The solid product is dried, yielding 4.1 g (70%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan. The isolated product is identical (NMR and IR) with a sample of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan prepared from rhamnose (loc cit). M.p. 82°-84° C.
Reaction SMILES: CN(C)C(=O)C.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:27]([CH3:30])([CH3:29])[CH3:28]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O:14][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:13])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 10 h

Procedure:
To N,N-dimethylacetamide 50 mL solution of 4-bromo-2-nitrobenzoic acid 5.0 g were added potassium carbonate 41 g, benzyltriethylammonium chloride 4.6 g and 2-bromo-2-methylpropane 69 mL at room temperature and it was stirred at 55° C. for 10 hours. After the reaction mixture was cooled to room temperature,2-bromo-2-methylpropane 12 mL was added to it, and it was stirred at 55° C. for 4 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Methanol was added to the obtained residue, solid matter was filtrated to give tert-butyl 4-bromo-2-nitrobenzoate 3.0 g of white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].OP(O)(O)=O.B(F)(F)F.CCOCC.[CH3:27][C:28](=[CH2:30])[CH3:29].[OH-].[NH4+]>ClCCl>[C:28]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:12])[CH2:10][CH3:11])([CH3:30])([CH3:29])[CH3:27]
Reactant: CCC(=O)c1c(O)cccc1O
Reactant: C=C(C)C
Agent: FB(F)F
Agent: O=P(O)(O)O
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)c1c(O)cccc1OC(C)(C)C
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
To a 100 mL round bottom flask is added 2′,6′dihydroxypropiophenone (25 g, 0.15 mol) and to it is then added dichloromethane (50 mL). This is then cooled to −75° C. and then 2.6 mL of H3PO4 is added to it followed by 6.22 mL of boron trifluoride etherate and then isobutylene (125 mL). The reaction is then stirred at −75° C. for 1.5 hrs and then at room temperature overnight. The reaction mixture is then poured into a 2N ammonium hydroxide solution (200 mL) and extracted with dichloromethane. The organic layer is then washed with water and then with brine and dried over sodium sulfate and filtered. The crude residue obtained after concentration of the filtrate is purified by flash chromatography using silica gel (ethyl acetate:hexanes) to afford the above product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=CC=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.[C:40](O)([C:42]([F:45])(F)F)=O>C(Cl)Cl>[F:45][C:42]1[CH:40]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3cc(F)ccc3F)cc2N1

Procedure:
Prepared from {2′,5′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K93) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (67 mg).
Reaction SMILES: [OH-].[NH4+:2].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=O)[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH2:2])=[O:11])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (20 mL, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydro-2H-pyran-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17]Cl)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[C:19]1([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:29]3[CH2:30][CH2:31][C:26](=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:27][CH2:28]3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(=O)c2ccc(OCCCCl)cc2o1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cc(=O)c2ccc(OCCCN3CCC(=C(c4ccccc4)c4ccccc4)CC3)cc2o1
Yield: 79 %

Procedure:
A mixture of 0.4 g (1.5 mmol) 2-cyano-7-(3-chloropropyloxy)-4-oxo-4H-1-benzopyran, 0.38 g (1.5 mmol) 4-diphenylmethylenepiperidine, 0.225 g (1.5 mmol) sodium iodide and 0.21 g (1.5 mmol) potassium carbonate in 200 ml dry acetone was refluxed for 48 hours. After removing the solvent, the solid residue was extracted with chloroform. The chloroform solution was evaporated to dryness and the residue was put on a silica gel column and eluated with a mixture of diethylether/ethyl acetate(5:1). Removing the solvents of the collected fractions (Rf=0.39) afforded the compound (6), 2-cyano-7-[3-(4-diphenylmethylenepiperidin-1-yl)propyloxy]-4-oxo-4H-benzopyran as a thick colorless oil (yield: 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[O:38][CH:39]=[CH:40][N:41]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: ClCc1ncco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ncco6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 2-(chloromethyl)oxazole (25.3 mg) were suspended in dimethylformamide (2.0 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 2-(chloromethyl)oxazole (25.3 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 30.9 mg; LC (method 23): tR=2.09 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[Cl:11]C1C(CCl)=CC(Cl)=C(Cl)N=1>>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([Cl:11])=[C:4]([Cl:10])[N:3]=1
Reactant: ClCc1cc(Cl)c(Cl)nc1Cl
Reactant: O=Cc1ccc(Cl)nc1Cl
Product: O=Cc1cc(Cl)c(Cl)nc1Cl

Procedure:
Obtained analogously to the process described for 2,6-dichloropyridine-3-aldehyde, using 2,5,6-trichloro-3-chloromethylpyridine instead of 2,6-dichloro-3-chloromethylpyridine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:11]=[C:6]2[NH:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][N:7]2[CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=[C:3]([S:2][CH3:1])[N:11]=[C:6]23)=[CH:17][CH:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CSc1nc2ccc[nH]c-2n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSc1nc2cccn(Cc3ccc(Cl)nc3)c-2n1
Yield: 48.1 %

Procedure:
A solution of 2-methylsulfanyl-4H-imidazo[4,5-b]pyridine (900 mg, 5.45 mmol), 2-chloro-5-(chloromethyl)pyridine (1.32 g, 8.17 mmol) and triethylamine (1.1 mL, 8.17 mmol) in benzene (18 mL) was stirred at 100° C. for 12 h (microwave). After cooling to room temperature the benzene was decanted off and the resulting solid was triturated with boiling benzene (3×15 mL). The benzene phases were combined and the solvent was removed under reduced pressure. The resulting solid was triturated with CH2Cl2, filtered and dried under reduced pressure to yield 760 mg (2.62 mmol, 48%) of compound E1.4.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(C(=O)O)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(=O)O)c1O
Temperature: 0 °C

Procedure:
3-methylanthranilic acid (12.5 g) was added slowly with stirring to sulfuric acid (61 ml: 7.5M) cooled to 0° C. A solution of sodium nitrite (5.7 g) in water (19 ml) was added dropwise maintaining the temperature below 5° C. The mixture was stirred for half an hour at room temperature and heated at 79-80° C. for one hour then cooled. Water was added and the mixture allowed to stand over the weekend. The mixture was filtered and the precipitate collected and washed with water. It was dissolved in ethyl acetate and the solution washed with water, stirred with barium chloride for 2 hours to remove any residual sulfuric acid, filtered, washed with water, dried and evaporated under reduced pressure to give 3-methylsalicylic acid, m.p. 160-2° C.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13].CN1C(=O)CCC1.N>O>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(F)c(Br)c(Cl)c1
Agent: N
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1c(F)cc(N)cc1Cl
Temperature: 160 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g), copper(I)cyanide (980 mmol, 88 g) and NMP (1000 ml) were added into the reaction flask, heated up to 160° C. and stirred for 3 h to complete the reaction. The reaction mixture was cooled to RT. Water and 25% ammonia solution was added keeping the mixture at RT. The mixture was stirred overnight and the formed precipitate was separated by filtration and flushed with water. The filtered precipitate was dried under vacuum to give 117.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.41-6.47 (m, 1H), 6.58-6.62 (m, 1H), 6.86 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CC(O)=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccnc(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccnc(NC(C)=O)c1
Yield: 76.9 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (0.5 g, 3.29 mmol) in AcOH (6.6 mL) at room temperature was added acetic anhydride (0.37 mL, 3.94 mmol), and the mixture was refluxed for 1 hour. The mixture was cooled and transferred to a 100 mL round-bottom, where the product was precipitated out of solution by slowly adding water (˜6 mL). The suspension was then filtered and washed with water. The solid was dried in vacuo overnight, furnishing Intermediate 62A (0.491 g, 76% yield) as a light yellow solid. HPLC: Rt=1.927 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=195.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, s), 8.57 (1H, s), 8.48 (1H, d, J=5.04 Hz), 7.51 (1H, dd, J=5.04, 1.51 Hz), 3.88 (3H, s), 2.11 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C@:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[Se](=O)=[O:25]>O1CCOCC1.O>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C@:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([CH:1]=[O:25])[CH:11]=[CH:10]3
Reactant: O=[Se]=O
Reactant: Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (1.30 g, 4.31 mmol) and selenium dioxide (718 mg, 6.47 mmol) in dioxane (50 mL) and H2O (5 mL) was heated at reflux for 4 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10. Product-containing fractions were combined, toluene was added, and the mixture was concentrated in vacuo to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]([OH:54])CO)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC(O)CO)CCCCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC=O)CCCCC1
Reaction time: 4 h

Procedure:
A solution of EXAMPLE 167E (600 mg) in acetone (30 mL) was treated with a solution of sodium periodate (852 mg) in water (5 mL). After about 4 hours, the solvent was removed by distillation and the residue was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product which was purified by flash column chromatography (20% ethyl acetate in hexane) to give the pure product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][CH:22](Br)[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH:22]([CH3:21])[C:23]([O:25][CH3:26])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
To the phenol (Example 35, Step 2) (1 g) in methyl ethyl ketone (20 ml) was added methyl DL-2-bromo-propionate (2 g) and K2CO3 (1 g). The mixture was heated overnight at reflux filtered and evaporated. Flash chromatography of the residue using 10% ethyl acetate in hexane afforded the title compound. Recrystallization from ethyl acetate hexane afforded the title compound: m.p. 101°-102°.