Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:61](O)(=[O:64])[CH2:62][OH:63]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:62](=[O:63])[CH2:61][OH:64]
Reactant: O=C(O)CO
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCNC(=O)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.7 %

Procedure:
A solution of 3-[4-(3-amino-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (18 mg, 0.043 mmol, Example 81) in DCM (2 mL) is treated with DIPEA (22 mg, 0.171 mmol), TBTU (19 mg, 0.06 mmol) and glycolic acid (5 mg, 0.064 mmol). The mixture is stirred at rt for 1.5 h before it is separated by chromatography on prep. TLC plates with DCM:methanol 9:1 to give N-(3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl)-2-hydroxy-acetamide (7 mg) as a white solid; LC-MS: tR=1.01 min, [M+1]+=470.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH2:32][CH3:33])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imdazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-bromopropane using potassium carbonate as a base in DMF at 80° C. Mass: 452.08 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[N:6][CH:5]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cncc(Cl)n1
Product: Nc1cncc(-c2ccc(F)cc2)n1

Procedure:
Prepared in analogy to example 1d, starting from 2-amino-6-chloropyrazine and 4-fluorobenzeneboronic acid. The title compound was obtained as a slightly brown solid (yield: 91%).
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4])=[CH2:2].[CH2:12]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH:1]([C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)=[CH:30][CH:29]=2)=[O:32])=[CH:9][CH:10]=1)=[O:4])=[CH2:2]
Reactant: C=CC(=O)c1ccc(O)cc1
Reactant: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(CCCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
A mixture of 4-hydroxyphenyl vinyl ketone (c) (1 g), 4′-heptyl-1,1′-biphenyl-4-carboxylic acid (1.8 g), DCC (1.9 g) DMAP (0.1 g) and methylene chloride (30 mL) was stirred at room temperature for 12 hours. The white solid precipitated was filtrated out, and the solvent was evaporated away from the filtrate. The residue was dissolved in ethyl acetate, and washed with aqueous 2 M NaOH solution and then with water. The solvent was evaporated away, and the residue was purified through column chromatography (eluent: toluene) and then through recrystallization (ethanol) to obtain 0.5 g of colorless crystals, compound (1-13-8). The NMR and MS spectra of the compound well support the structure thereof.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]([O:15][C:14](=[O:16])[CH2:13][CH2:12][C:5]1[CH:4]=[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]([OH:1])=[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)OCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid benzyl ester was prepared from 278 g (1 mol) of 3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid and 108 g (1 mol) benzyl alcohol by azeotropic esterification in toluene with 0.5 g of 4-toluenesulfonic acid. The product was analyzed and the results of this analysis were as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:24])[CH2:9][CH3:10])=[CH:4][CH:3]=1.I[C:26]1[CH:31]=[CH:30][N:29]([CH3:32])[C:28](=[O:33])[CH:27]=1>>[CH3:23][C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:24])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:31]=[CH:30][N:29]([CH3:32])[C:28](=[O:33])[CH:27]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1
Reactant: Cn1ccc(I)cc1=O
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](C)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.55 min, m/z=417 (M+1); 1H NMR (CDCl3) 7.41 (1H, d, J=7.03 Hz), 7.33 (2H, d, J=8.20 Hz), 7.29-7.19 (5H, m), 7.10 (1H, d, J=8.20), 6.95 (1H, d=1.76), 6.55 (1H, dd, J=2, 7.03 Hz), 5.51 (1H, q, J=6.49, 9.66 Hz), 3.65 (3H, s), 3.00-2.95 (1H, m), 2.44-2.36 (1H, m), 2.33-2.15 (2H, m), 2.06-1.86 (2H, m), 1.64 (3H, s), 1.02 (3H, t, J=7.32 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:23][CH:20]3[CH2:22][CH2:21]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NC1CC1
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(NC1CC1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 92.5 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and cyclopropylamine (100 μL, 1.0 mmol) to give 310 mg of the title compound (93%): mp 222°~225° C.; 1H NMR (270 MHz, DMSO-d6) δ12.13 (s, 1H), 8.22 (d, 1H, J=4.0 Hz), 7.18 (bs, 1H), 7.16 (bs, 1H), 5.02~5.06 (m, 1H), 2.79 (dm, 1H, J=16.8 Hz), 2.45~2.62 (m, 2H), 2.36 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 0.62 (dm, 2H, J=7.2 Hz), 1.33~1.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH2:21]([O:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:20][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:35])=[CH:32][N:31]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(COCc2ccccc2)nc1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(COCc2ccccc2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-benzyloxymethyl-nicotinic acid. MS: 499.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[C:17]=1[CH2:26][CH2:27][CH3:28].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:29]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[OH:1])=[C:17]([CH2:26][CH2:27][CH3:28])[C:18]=1[OH:25])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCI
Reactant: CCCc1c(OCCCCCCc2cccc(O)c2O)ccc(C(=O)O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)c1ccc(OCCCCCCc2cccc(O)c2O)c(CCC)c1O
Yield: 83.2 %

Procedure:
A mixture of 1.00 g (2.57 mmol) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 0.76 mL (5.15 mmol) of n-hexyl iodide and 0.26 g (3.36 mmol) of sodium bicarbonate in 15 mL of anhydrous dimethylformamide was stirred and heated at 70° for 16 hours. The solvent was removed on the oil pump, water was added and the product was extracted with ethyl acetate. The dried extract was concentrated under reduced pressure to an oil which was purified by chromatography on silica gel using 5% ethyl acetate-toluene to give 1.01 g (83% yield) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid hexyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:5]2.C1COCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Li]CCCC.[F:45][C:46]1[CH:55]=[CH:54][C:49]([CH2:50][N:51]=[C:52]=[O:53])=[CH:48][CH:47]=1.Cl>C(Cl)Cl>[F:45][C:46]1[CH:47]=[CH:48][C:49]([CH2:50][NH:51][C:52]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:5]3)=[O:53])=[CH:54][CH:55]=1
Reactant: O=C(O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Reactant: O=C=NCc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCCCc1cc2cc(C(=O)NCc3ccc(F)cc3)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A solution of 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 100 mg, 0.260 mmol) in THF (4.00 mL, 49.3 mmol) in a flame dried vial under an atmosphere of nitrogen gas was treated with lithium hexamethyldisilazide (1M/THF, 780 uL). The reaction mixture stirred at RT for 10 min before it was cooled to −78° C. in an acetone/dry ice bath. A solution of nBuLi (2.5M/hexane, 229.0 uL) was slowly added and the reaction progressed for 5 minutes at −78° C. before addition of 4-fluorobenzyl isocyanate (398 uL, 3.12 mmol). The reaction was stirred at −78° C. for 20 minutes, acidified with 10% HCl to pH 1, and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate, concentrated and chromatographed (5-100% EtOAc/hexanes) to provide 2 (28 mg; Yield=24%, LCMS (M+H)=439).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1.C1COCC1.O.[OH-].[Li+].Cl>O>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:27])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 60 °C
Yield: 98.1 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (18.96 g, 50.92 mmol) in inhibitor free THF (100 mL) was treated with a near solution of lithium hydroxide monohydrate (8.4 g, 200.2 mmol) in water (100 mL) at room temperature and heated at 60° C. for 4 h. The reaction mixture was cooled, diluted with water, acidified with aq. 2N HCl and extracted with ethyl acetate. The organic layers were combined, washed with 1/1 water/brine, brine, dried (MgSO4), filtered and concentrated to give 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid (17.89 g, 98.0%) as an off white solid. LC-MS (ES) calculated for C20H13F3O3, 358.32; found m/z 357 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)n1
Yield: 10.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 100 mg, 0.329 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 126 mg, 0.46 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH2Cl2 (5 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.34-8.30 (m, 2H), 8.17 (d, J=7.5 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.83-7.78 (t, J=7.8 Hz, 1H), 7.73-7.67 (m, 5H), 7.40 (d, J=8.7 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 1.17 (s, 9H); MS [M+H]+: 557.18.
Reaction SMILES: [OH:1][CH2:2][C@@:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][C@H:4]1[CH2:6][OH:7].CO[CH:15](OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:16]1([CH:15]2[O:7][CH2:6][C@H:4]3[C@:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH2:5]3)[CH2:2][O:1]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@]1(CO)C[C@H]1CO
Reactant: COC(OC)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCCCC1
Product: CCOC(=O)[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Temperature: 2.5 °C
Yield: 64.8 %

Procedure:
A solution of ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate (10.5 kg, 60.3 mol) in cyclohexane (105.0 L) was added in a reactor. Then, benzaldehyde dimethylacetal (11.6 kg, 76.4 mol) followed by camphor sulfonic acid (73.0 g) was added into the reactor. The reaction mass was heated to reflux and a portion of solvent was distilled azeotropically. The progress of the reaction was monitored by HPLC. On completion of the reaction, the reaction mass was distilled to remove most of the solvent under reduced pressure below 45° C. To the concentrate, petroleum ether (32.0 L) was added and stirred to precipitate the product. The slurry was cooled to 0-5° C. and stirred for 15 min. The slurry was filtered and washed with cold petroleum ether (11.0 L). The product was dissolved in dichloromethane (210.0 L) and washed with water (52.0 L) followed by brine (53.0 L). The organic layer was dried over sodium sulfate (5.5 kg) and was distilled to remove most of the solvent. Petroleum ether (21.0 L) was added and stirred at 25-30° C. for 30 min to get the complete precipitation of the product. The slurry was further cooled to 0-5° C. and stirred for 60 min. The slurry was filtered and washed with cold petroleum ether (11.0 L). The product was dried in a vacuum tray dryer for 12 hours below 45-50° C. to afford 10.25 Kg (64.5%) of the title compound (4c).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]([CH2:29][CH3:30])[C:19]=4[N:20]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]([CH2:29][CH3:30])[C:19]=4[N:20]=3)[CH2:11][CH2:10]2)=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)nc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(N)cc4)CC3)nc21

Procedure:
A solution of 3.40 g of 2-[4-(p-nitrobenzyl)-1-piperazinyl]-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 200 ml of acetic acid was hydrogenated over 0.55 g of 5% palladium-on-charcoal catalyst at room temperature until 3 mole equivalents of hydrogen were absorbed. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. To the residue was added 30 ml of water and the resulting solution was neutralized with a saturated sodium bicarbonate solution. The crystalline precipitate was collected by filtration and dissolved with warming in 100 ml of ethanol. After removal of the insoluble material by filtration, the filtrate was kept under cooling to give the crude precipitated product (1.80 g), which was dissolved in a minimum amount of chloroform and chromatographed on 14 g of silica gel, using chloroform-methanol (a 50:1 ratio by volume) as eluent. Fractions containing the desired product were pooled and concentrated to dryness. The resulting solid was recrystallized from ethanol to give the pure product, m.p. 198°-201° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].O[Li].O>C1COCC1.CO.O>[CH2:1]([S:3][C:4]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1c(SCC)nc2cnccc2c1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1nc2cnccc2c(C)c1C(=O)O
Temperature: 75 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of ethyl 2-(ethylthio)-4-methyl-1,7-naphthyridine-3-carboxylate [synthesized according to the methods described for example 1, sections a-d] (2.30 g, 8.33 mmol, 1 eq) in a mixture of THF (30 ml) and methanol (15 ml) was added a solution of LiOH.H2O (3.50 g, 83.33 mmol, 10 eq) in water (7.5 ml) at RT. The resulting mixture was stirred at 75° C. for 5 h. Afterwards the solvents were evaporated and the residue was washed with EtOAc (80 ml). The aq. layer was acidified with a 4M aq. HCl (50 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to provide 2-(ethylthio)-4-methyl-1,7-naphthyridine-3-carboxylic acid (0.85 g, 3.43 mmol, 41%) which was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Cl.Cl[CH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=2>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2cc(CCl)cnc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc(O)c(Cc2cnc3cc(OC)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (121 mg, 519 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.57 mL, 1.14 mmol) at RT followed by 3-(chloromethyl)-7-methoxyquinoline hydrochloride MDE 32012 (136 mg, 557 μmol) and the mixture was stirred at 150° C. for 2 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (50 mL) and H2O (10 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 34 mg of 1-ethyl-6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (3.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 31 as a brown solid (40 mg, 16% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][C:23]([F:47])([F:46])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]>>[F:22][C:23]([F:46])([F:47])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44][N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(OCc4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-benzyloxy-phenyl)-piperazine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.[NH4+].[Cl-]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cc2c(ncc3cnc(C4CCCCC4)n32)[nH]1
Temperature: 90 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
To a solution of 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.020 g, 0.051 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.380 mL, 0.760 mmol). The reaction mixture was heated to about 90° C. After about 5 h, the reaction mixture was cooled to ambient temperature and diluted with EtOAc (10 mL) and saturated aqueous NH4Cl (10 mL). The organic layer was separated and washed with water (10 mL) followed by brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine as a tan solid (0.011 g, 90%): LC/MS (Table 2, Method a) Rt=1.92 min; MS m/z: 241 (M+H)+.