Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2].[Cl:19]C1C=CC2SC=CC=2C=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][CH:10]3[N:11]([Cl:19])[CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1ccc2sccc2c1
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Product: CCOC(=O)C1CSC23C=CC=CC2N(Cl)CCC13

Procedure:
6-Chloro-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester was synthesized by following the same procedure as the synthesis of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester in Example 1 except that 42.3 g of 5-chlorobenzothiophene was used in place of 33.6 g of benzothiophene in Example 1.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH:6]([C:5]1[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=1[O:3][CH3:2])[N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)=[C:23]([OH:28])[CH:22]=[CH:21]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2cc(Br)ccc12)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride and 6-bromo-2-naphthol.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:26]1[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2cccnc2)c1
Yield: 38.3 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.286 mmol), pyridine-3-boronic acid (53 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (42 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.62 (d, J=3.5 Hz, 1H), 7.86 (s, 1H), 7.46 (d, J=7.2 Hz, 2H), 7.38 (dd, J=4.9, 7.9 Hz, 1H), 7.15 (dd, J=8.7, 9.9 Hz, 1H), 5.32 (s, 1H), 4.69-4.57 (m, 1H), 2.68 (s, 6H), 1.70 (d, J=11.3 Hz, 6H), 2.08-0.94 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 149.9, 149.0, 136.6, 132.1, 127.3, 126.8, 126.7, 125.5, 125.3, 123.5, 116.4, 116.2, 71.5, 55.9, 55.0, 47.6, 46.7, 30.1, 29.66, 25.6, 24.8, 19.7 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.54 min; (M+1) 367.8.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:32])[C@@H:18]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.C(N1C[C@H]2[C@H](NC(=O)[C@@H](N3CCOCC3)CC(C)C)CC[C@H]2C1)C1C=CC=CC=1.[F:62][C:63]([F:75])([F:74])[C:64]1[CH:69]=[CH:68][C:67]([S:70](Cl)(=[O:72])=[O:71])=[CH:66][CH:65]=1.FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:31][N:23]([C@@H:18]([C@@H:19]([CH3:22])[CH2:20][CH3:21])[C:17](=[O:32])[NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([S:70]([C:67]3[CH:66]=[CH:65][C:64]([C:63]([F:62])([F:74])[F:75])=[CH:69][CH:68]=3)(=[O:72])=[O:71])[CH2:12]2)[CH2:15][CH2:14]1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N(C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting tert-butyl(2S,3S)-1-(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-3-methyl-1-oxopentan-2-yl(methyl)carbamate from Step A of Example 334 for (S)—N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and 4-(trifluoromethyl)benzene-1-sulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.66-8.72 (m, 1H), 8.05-8.13 (m, 2H), 7.88-7.91 (m, 2H), 4.69 (d, J=11.3 Hz, 1H), 4.15-4.22 (m, 1H), 3.73-3.87 (m, 1H), 3.16-3.23 (m, 1H), 3.11-3.18 (bs, 3H), 3.00 (t, J=8.3 Hz, 1H), 2.90 (t, J=8.4 Hz, 1H), 2.42-2.56 (m, 2H), 2.21-2.28 (m, 1H), 1.88-2.03 (m, 1H), 1.73-1.88 (m, 1H), 1.52-1.66 (m, 1H), 1.48 (s, 9H), 1.34-1.46 (m, 1H), 1.21-1.34 (m, 1H), 0.98-1.13 (m, 1H), 0.94 (d, J=6.3 Hz, 3H), 0.76-0.81 (m, 3H); MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15][O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cn2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (207 mg), 2,6-dichloro-3-nitrobenzyl bromide (400 mg) and potassium carbonate (580 mg) in N,N-dimethylformamide (8 ml) was stirred for 2 hours at 60° C. The mixture was cooled and diluted with water. The separated oil was extracted with dichloromethane. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (120 mg) as crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:18][CH2:17][CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(CN)OCC
Product: CCOC(CNCCC(c1ccccc1)c1ccccc1)OCC
Yield: 60.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 3,3-diphenylpropyl bromide (5.50 g, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (3.98 g, 61%).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)#[N:2].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:15])=[CH:7][CH:6]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CCOc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Product: N#CCOc1ccc(CCl)cc1

Procedure:
Schema 5 illustrates yet another route for preparing the compounds of the present invention wherein R1 is a disubstituted amino. In schema 5, the appropriately substituted (4-hydroxyphenyl)methan-1-ol (SM4) was reacted with a bromomethylisocyanate and a reducing agent, for example potassium carbonate, in a solvent, for example, DMF, in the manner disclosed above to form the corresponding (4-(cyanomethoxy)phenyl)methan-1-ol (BBB). The methan-1-ol (BBB) was then reacted with sulfinyl chloride in a solvent, for example, chloroform, at 0° C. to form the corresponding 4-(cyanomethoxy)-1-(chloromethyl)benzene (CCC), which was in turn reacted with the appropriately substituted naphthol or phenol (SM14) and a reducing agent, for example, potassium carbonate, in a solvent, for example DMF, in the manner described above to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(cyanomethoxy)benzene (DDD). The 4-(cyanomethoxy)benzene (DDD) was reacted with borane in a solvent, for example, THF, at 0° C. to form the appropriately substituted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(aminomethoxy)benzene (EEE). The 4-(aminomethoxy)benzene (EEE) was in turn reacted with the appropriate oxoalkyl chloride, for example, acetyl chloride, in a solvent, for example, pyridine or THF, at 0° C. to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(oxoalkylaminomethoxy)benzene (FFF). The 4-(oxoalkylaminomethoxy)benzene (FFF) was then reacted with borane in a solvent in the manner described above to yield the targeted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(alkylaminomethoxy)benzene (VIII). At this point, additional moieties can be optionally added to the amino group by reacting the 4-(alkylaminomethoxy)benzene (VIII) with the appropriate substituted alkyl, alkoxy, or alkoxyalkyl halide and a base, for example, triethylamine, to yield the target 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-((disubstituted amino)methoxy)benzene (IX).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]1([CH2:10][CH2:11][CH:12]([CH3:15])[CH:13]=[CH2:14])[OH:9].CC(C)([O-])C.[K+]>C1C2C(CCCC2)CCC1.C(OCC)C>[CH3:15][CH:12]1[CH2:11][CH2:10][C:3]2([OH:9])[C:2]([CH3:16])([CH3:1])[CH:7]3[CH:6]=[CH:5][C:4]2([CH3:8])[CH:13]1[CH2:14]3
Reactant: C=CC(C)CCC1(O)C(C)=CC=CC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCC2CCCCC2C1
Solvent: CCOCC
Product: CC1CCC2(O)C(C)(C)C3C=CC2(C)C1C3

Procedure:
0.500 g of a mixture containing equivalent amounts of the two diasteroisomers of 2,2,6-trimethyl-1-[3-methyl-pent-4-en-1-yl]-cyclohexa-3,5-dien-1-ol, obtained as indicated hereinbelow, and 0.025 g of potassium ter-butoxide in 8 ml of decaline were heated in an inert gas atmosphere in a sealed tube at 280° for 24 h. The reaction mixture was then diluted with diethyl ether, washed with water, dried over K2CO3 and finally concentrated. By bulb distillation 0.285 g of a fraction having B.p. 80°-100° /0.01 Torr were obtained. Pure 4,8,11,11-tetramethyltricyclo[5.3.1.03,8 ]undec-9-en-7-ol was isolated from the said fraction by vapour phase chromatography by means of a 5 % silicon column, of 5 mm x 2.5 m, at 190° . The yield of the final product, calculated on the amount used of the diastereomeric mixture of the starting alcohols, was of about 30 %.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:18][C:15]2[CH:14]=[N:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)=[CH:17][N:16]=2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CCCCCc1ccc(-c2cnc(O)cn2)cc1
Reactant: CCCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2cnc(OCc3ccc(CCC)cc3)cn2)cc1

Procedure:
A mixture of 10.4 g of 5-(4-pentylphenyl)-2-pyrazinol (obtainable analogously to Japanese Preliminary Published Application 144,770/84), 7.7 g of p-n-propylbenzyl bromide, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is heated at 90° for 10 hours. Customary working up gives 5-(4-n-pentylphenyl)-pyrazin-2-yl p-n-propylbenzyl ether.
Reaction SMILES: [CH3:1][C:2]([CH2:4][O:5][CH2:6][O:7][CH3:8])=[CH2:3].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl.O1CCCC1>[CH3:8][O:7][CH2:6][O:5][CH2:4][CH:2]([CH3:1])[CH2:3][Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10]
Reactant: C=C(C)COCOC
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCO[Si](CC(C)COCOC)(OCC)OCC
Yield: 39.9 %

Procedure:
Into a 200-ml flask, 5.81 g (50% by mol) of 2-methyl-4,6-dioxa-1-heptene, 0.026 g (0.05% by mol) of hexachloroplatinic(IV) acid hydrate, and 100 g of tetrahydrofuran were charged. Into the mixed solution, 10.68 g (65% by mol) of triethoxysilane was added dropwise under a nitrogen stream with stirring with a magnetic stirrer. After the addition, the mixture was reacted at ambient temperature for 24 hours. Then, the reaction mixture was distilled to afford 5.60 g of (3-(methoxymethoxy)-2-methylpropyl)triethoxysilane (corresponding to the compound of Formula (A-23)).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CO>[C].[Pd].O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(Cl)nn2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2cccnn2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
A mixture of 4-tert-butyl-N-[6-{2-(6-chloropyridazin-3-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (150 mg), 10% palladium-carbon (30 mg), triethylamine (52 mg), methanol (8 ml) and tetrahydrofuran (6 ml) is stirred at room temperature for five hours under hydrogen atmosphere (1 atm), and the mixture is filtered to remove the catalyst. The filtrate is concentrated to dryness under reduced pressure. The residue is treated with aqueous citric acid solution, and extracted with chloroform. The extract is washed, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyridazin-3-yloxy)ethoxy}pyrimidin-4-yl]benzenesulfonamide (111 mg) as crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([O:7]C2CCCCO2)[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:23])[CH:17]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C(O)(=O)C>O>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:23])[CH:17]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCCCC(C)C(O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(C)C(O)C=CC1CC(O)C(O)C1CCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 5.2 %

Procedure:
A mixture of 7-[2-hydroxy-5-(3-hydroxy-4-methyloct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (1.06 g.), glacial acetic acid (40 ml.) and water (20 ml.) was stirred at 40° C. for 4 hours. The mixture was then treated with water (50 ml.) and extracted with diethyl ether (2 × 50 ml.). The combined ethereal extracts were washed once with water, dried over magnesium sulphate, and concentrated in vacuo to low volume. Repeatedly, small portions of benzene were then added, concentrating in vacuo in order to remove last traces of acetic acid, and then the mixture was evaporated to dryness. The residue (0.5 g.) was subjected to preparative thin-layer chromatography on silica gel, using a mixture of ethyl acetate, cyclohexane and formic acid (40:40:1 by volume) as the eluent, to give 7-[2,3-dihydroxy-5-(3-hydroxy-4-methyloct-1-enyl)cyclopentyl]heptanoic acid (0.045 g.), νmax 1705 cm-1, 980 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][O:30][NH:31]C>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([NH:31][O:30][CH3:29])=[O:14])[O:7][CH2:6][CH2:5]2
Reactant: COc1c(Br)ccc2c1CCOC2C(=O)O
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CONC(=O)C1OCCc2c1ccc(Br)c2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylic acid (600 mg, 2.08 mmol) and CDI (475 mg, 2.93 mmol) in 20 mL of dry DCM was stirred at r.t. for 0.5 hours and then O,N-dimethyl-hydroxylamine (285 mg, 2.93 mmol) was added. The result mixture was stirred oversight. The solvents were removed under vacuum, and the residue was purified by preparative TLC to give 6-bromo-N,5-dimethoxy-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:6]([CH:8]1[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[ClH:33]>O1CCOCC1>[ClH:33].[CH2:1]([N:5]([CH2:21][C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:6]([CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN(Cc1ccc2c(c1)OCCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CN(Cc1ccc2c(c1)OCCCC2)C(=O)C1CNCCO1
Reaction time: 0.5 h

Procedure:
To a solution of 0.798 g (1.79 mmol) of (±)-tert-butyl 2-{[isobutyl(2,3,4,5-tetrahydro-1-benzoxepin-8-ylmethyl)amino]carbonyl}morpholine-4-carboxylate in 3.6 mL of dioxane cooled in an ice-bath was added 3.6 mL (14.4 mmol, 8 equiv) of 4M HCl in dioxane. The solution was stirred 30 minutes with cooling, then for 3.5 hours at ambient temperature. The solution was concentrated under reduced pressure, the residue triturated with ether, and dried under vacuum to give the product as a white solid. MS (m+1)=347.3; H NMR (400 MHz, CD3OD) 7.12 (m, 1H), 6.84 (m, 2H), 4.8-4.6 (m, 2H), 4.58-4.39 (m, 1H), 4.1-3.85 (m, 4H), 3.5-3.35 (m, 3H), 3.24 (m, 2H), 3.15-2.92 (m, 1H), 2.78 (m, 2H), 2.02 (m, 1H), 1.95 (m, 2H), 1.71 (m, 2H), 0.89 (m, 6H).
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:30])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:24][N:23]=[C:22]([C:25]([O:27]CC)=[O:26])[CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+]>>[NH2:7][C:8]1[N:9]=[C:10]([OH:30])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:24][N:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)c1cc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1cc(C(=O)O)n[nH]1)C2
Yield: 80.6 %

Procedure:
Upon saponification of ethyl 5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrazole-3-carboxylate (637 mg, 1.5 mmol) with 1N sodium hydroxide (3 mL) as described in Example 11, there is obtained 5-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrazole-3-carboxylic acid (368 mg, 80%, mp >260° C.): 1H NMR (DMSOd6) δ 12.90 (br s, 1H), 9.85 (br s, 1H), 6.67 (s, 1H), 6.42 (s, 1H), 6.27 (s, 1H), 5.96 (s, 2H), 3.16 (br d, 1H, J=107 Hz), 2.74 (m, 1H), 2.65 (m, 1H), 2.46 (brd, 1H, J=15.0 Hz), 1.90 (dd, 1H, J=15.0, 7.9 Hz), 1.68-1.47 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Pd].C(O)C>[CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A mixture of methyl 2-methyl-3-nitrobenzoate (30 g, 154 mmol), 10% palladium on charcoal (3.0 g) and ethanol (350 mL) was shaken under hydrogen at 50 psig. After 4 h, the mixture was filtered through Celite® and the solids were washed with additional ethanol. The filtrate was concentrated to provide the title product (24.4 g, 96%) as a tan oil: 1H NMR (CDCl3) δ 7.18 (m, 1H), 7.06 (m, 1H), 6.78 (m, 1H), 3.85 (s, 3H), 2.34 (s, 3H); high resolution mass spectrum (NH3 --CI) calculated (M+H+) 166.0868, found 166.0866.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH2:35])=[C:33]([O:41][CH3:42])[CH:32]=1>CC(O)CCC>[Br:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1N
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 73.5 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 0.829 g, 3.40 mmol), p-toluene sulphonic acid monohydrate (0.924 g, 4.86 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.8 g, 3.24 mmol) was heated at reflux in 2-pentanol (32 mL) under an atmosphere of N2 for 18 h. The mixture was then allowed to cool, and was then concentrated in vacuo. The resulting residue was triturated with CH3CN until a yellow precipitate formed. This solid was collected by filtration and was washed with diethyl ether. The solid was suspended in 10% CH3OH in CH2Cl2 and washed with saturated aqueous NaHCO3 (2×) followed by water. The organic solution was then concentrated in vacuo, and the resulting residue was triturated in CH3CN/water. The mixture was then filtered, and the collected solid was washed with CH3CN followed by diethyl ether and was then air dried to give the title compound (1.082 g, 74%) as a yellow solid; 1H NMR: 3.90 (3H, s), 4.05 (3H, s), 7.15-7.21 (1H, m), 7.26-7.31 (1H, m), 7.36 (1H, d), 7.52 (1H, s), 7.56 (1H, d), 8.34 (1H, s), 8.39 (1H, s), 8.40-8.45 (2H, m), 9.20 (1H, s); m/z: ES+ MH+ 454/456.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-]>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Cl)ccc2O1

Procedure:
43.0 g of 2-amino-4-chlorophenol was dissolved in 500 ml of anhydrous acetone containing 42.0 g of anhydrous potassium carbonate. That mixture was heated to reflux temperature and 23.0 g of ethyl 2,3-dibromopropionate was added slowly. In three additional portions each, additional ester and carbonate were added to the refluxing mixture until a total of 124 g of carbonate and 85.8 g of ester had been added. The mixture was refluxed for 21 hours. Solids were filtered from the mixture and the filtrate was stripped of solvent. The residue was taken up in water and the solution was extracted with ether. The ether extract was dried (MgSO4) and the solvent was stripped. The residue was recrystallized from ethanol, eluted through a silica gel column using a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane as eluent, and the product was recrystallized from ethanol, and then from ether, to give 2 as white crystals, m.p.: 85.5°-86.5°.