Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[C:14]([CH3:20])[CH:13]=2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32](/[CH:36]=[CH:37]/[C:38]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[O:39])=[CH:31][C:30]=2[CH3:46])=[N:26][CH:27]=1>CN(C=O)C>[OH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32](/[CH:36]=[CH:37]/[C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH2:18][C:15]4[CH:16]=[CH:17][C:12](/[CH:11]=[CH:10]/[CH2:9][O:8][C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:13][C:14]=4[CH3:20])[CH2:42][CH2:41]3)=[O:39])=[CH:31][C:30]=2[CH3:46])=[N:26][CH:27]=1
Reactant: Cc1ccc(OC/C=C/c2ccc(CCl)c(C)c2)cc1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(C)c1Oc1ccc(O)cn1
Solvent: CN(C)C=O
Product: Cc1ccc(OC/C=C/c2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(C)c4)CC3)c(C)c2)cc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
To a solution of (E)-3-[4-(chloromethyl)-3-methylphenyl]prop-2-en-1-yl 4-methylphenyl ether (0.180 g) and (E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}-1-(piperazin-1-yl)prop-2-en-1-one (0.222 g) in DMF (2 mL) was added KHCO3 (0.063 g) at room temperature under an Ar atmosphere. The mixture was heated at 100° C. for 3 hours, and then cooled to room temperature, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (AcOEt) to afford (2E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}-1-(4-{2-methyl-4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.286 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:6]2.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][CH:7]2[CH2:6][C:5]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8]2=[O:14])[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Temperature: 60 °C

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-yl)methyl]piperidine (4 g) was taken in acetone (60 ml). To which benzyl chloride (1.92 g), potassium carbonate (2.28 g) and a catalytic quantity of tetrabutylammonium iodide (TBAI) were added. The reaction mixture was heated at 60° C. and reaction was monitored on TLC. Solvent was removed by distillation after reaction completion and the residue was taken in water and extracted with ethyl acetate (100 ml). The organic extract was acidified with cone. HCl. The solvent was evaporated under vacuum to yield the salt as a residue. Yield: 5.14 g.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:24]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 421.08 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.[F:39][CH:40]([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:41][CH:40]([F:50])[F:39])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)n1
Temperature: 25 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.080 ml, 0.49 mmol) in dichloromethan (1 ml) was treated with trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (63 mg, 0.29 mmol) at 0° C. The cooling bath was removed after 30 min. and the reaction mixture was stirred at room temperature over night. The mixture was partitioned between aqueous saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with two 50-ml portions of a 1 M aqueous solution of sodium carbonate. The aqueous layers were each extracted with one 50-ml portion of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concenrated in vacuo. Purification by flash column chromatography gave the title compound (98 mg, 85%) as white solid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:15][C:1]1[CH:2]=[CH:3][C:4]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1ccc(CBr)cc1
Temperature: 10 °C

Procedure:
To the suspension of diethyl p-tolylphosphonate (0.73 g, 3.2 mmol) was added a small amount of azobisisobutyronitrile (0.016 g, 0.1 mmol, in portions) and N-bromosuccinimide (0.57 g, 3.2 mmol) in anhydrous CCl4 (30 mL). The mixture was refluxed for 4 h, then cooled to 10° C. and filtered to remove succinimide. The filtrate was washed with water (30 mL) and brine (30 mL) and then dried over anhydrous Na2SO4. After filtration, the crude product was obtained via evaporation of solvent and purified by chromatography on silica gel (hexene/ethyl acetate: 2/1 as eluent) to provide diethyl 4-(bromomethyl)phenylphosphonate as a colorless oil. 1H NMR (500 MHz, CD3Cl): δ 7.79-7.83 (m, 2H), 7.50-7.52 (m, 2H), 4.51 (s, 2H), 4.09-4.18 (m, 4H), 1.33-1.36 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[CH2:40]([Si:42](Cl)([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:41][CH2:40][Si:42]([O:37][C@@H:8]1[C@@:7]2([CH3:38])[C:5]([C@H:4]([OH:39])[C:3]3[C:15]([CH3:16])([CH3:17])[C@:14]([OH:21])([C@@H:13]([O:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])[C@@H:12]2[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9]1)[CH2:18][C@H:19]([OH:20])[C:2]=3[CH3:1])=[O:6])([CH2:45][CH3:46])[CH2:43][CH3:44]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H]1C[C@H]2OC[C@@]2(OC(C)=O)[C@H]2[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](O)C(=O)[C@]12C)C3(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
544 mg (1 mmol) of 10-deacetylbaccatine III, dissolved in 50 cm3 of anhydrous pyridine, are introduced under an argon atmosphere into a 100-cm3 round-bottomed flask equipped with a magnetic stirrer. 3.36 cm3 (3.014 g; 20 mmol) of triethylsilyl chloride are then added. The homogeneous, yellow reaction mixture is then stirred for 24 hours at 0° C. Ethyl acetate and water are then added. After settling has taken place, the separated aqueous phase is extracted with ethyl acetate. The combined organic phases are treated with saturated aqueous copper sulphate solution until the pyridine has been completely removed. The organic phases are washed with water and then with saturated sodium chloride solution, and then dried over anhydrous sodium sulphate. After filtration and evaporation of the solvents under reduced pressure, 2.73 g of a product are obtained, and this is purified on a silica column, eluting with a dichloromethane/methanol (99:1 by volume) mixture. 512 mg (0.778 mmol) of 10-deacetyl-7-triethylsilylbaccatine III are thereby obtained, in a 78% yield, in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH2:28].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[O:21][CH3:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Br)c2ccccc2n1
Reactant: COc1cnccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ccccc12
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
250 mg 4-Bromo-2-(5-chloro-2-fluoro-phenyl)-quinoline (cf. Example 5; M 336.59) and 94 mg of 3-methoxy-4-amino pyridine (Tyger Scientific) in 25 ml dioxane were treated under argon with 14 mg Pd2(dba)3 (Aldrich) and 22 mg Xanthphos (ABCR) under basic conditions adjusted with 485 mg Cs2CO3 at 85° C. internal temperature over night. Work-up was conducted by RP HPLC on a Gemini column Axia RP18-100×30 mm/10 μm-110 A. Elution was performed with a 30 min gradient of 1-99% buffer B (=0.3% TFA in CH3CN) in buffer A (=0.3% TFA in water) at 30 ml/min and monitoring at 215 nm. Pooled material after drying yielded 228 mg product of correct mass M+H+ 380 and Rt˜1.74 min in LC-MS system 2.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Place 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH to give the title compound (0.168 g, 59.4%): TOF MS ES+ 387.2031 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2031, time 0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 23 min], tR=8.7 min, 100% purity.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.S([O-])(=O)(=O)C.[SH:49][C:50]1[N:55]=[CH:54][CH:53]=[CH:52][N:51]=1>>[N:51]1[CH:52]=[CH:53][CH:54]=[N:55][C:50]=1[S:49][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1
Reactant: Sc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCSc3ncccn3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 34, from tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate via the corresponding mesylate by reaction with 2-mercaptopyrimidine there was obtained tert-butyl (3RS,4RS)-4-{4-[2-(pyrimidin-2-ylsulphanyl)-ethyl]-phenyl}-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil, which was used in the following step without further purification and characterization.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:2][CH2:3][CH:4]([OH:15])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[N:24]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2csc(NC(C)=O)n2)cc1OC
Yield: 82 %

Procedure:
α-(Aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride (2.88 g) and 2-acetamido-4-formyl-thiazole (2.1 g) were suspended in 14 ml methanol, and 1.8 ml triethylamine was added dropwise to this suspension with stirring. The resulting solution was heated under reflux for 30 minutes, and 0.70 g sodium borohydride was added in small portions with stirring under ice cooling. The crystals which separated out were collected by filtration, washed with water and methanol in that order and vacuum-dried, giving 3.55 g of α-[[[(2-acetamido-4-thiazoly)methyl]amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 204°-206° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:30])[F:31])[C:10](=[O:22])[NH:11]2)[C:6]([OH:33])=[C:5]1[C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccccc3C(F)(F)F)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.059 mmol), β-alanine (530 mg, 5.9 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [I-].[CH2:2]([Mg]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>CCOCC.[NH4+].[Cl-].[Cu]I>[CH3:5][C:4]([CH2:3][CH2:8][CH2:7][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH:13][CH2:12][CH2:11][CH2:15][OH:14]
Reactant: C1CCOC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [I-]
Solvent: CCOCC
Product: CC(=CCCCO)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1.5 g (4.26 mmol) of the Example 35, Part B iodide in 10 mL of THF at 0° C. was added 12.9 mL (25.8 mmol) of benzylmagnesium chloride in THF (purchased from Aldrich Chemical) followed by 10 mg (catalyst) of copper (I) iodide. The reaction was stirred at 0° C. for 1 h, and at room temperature for 3 h. The reaction was diluted with ether and aqueous NH4Cl solution. The organic fraction was washed with water and brine, dried (MgSO4) and concentrated to provide 2.70 g of a crude oil. The oil was purified by flash chromatography (250 g of silica gel) eluting with 8:2 ethyl acetate/hexane to provide 1.10 g (99%) of title compound as a colorless oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:14](=[O:25])[N:13]2[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH:16]=[CH:17][C:12]3=[N:11][C:10]([CH2:9][O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:26][N:13]3[C:14]2=[O:25])=[CH:19][CH:20]=1
Reactant: Oc1ccccc1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Temperature: 90 °C
Reaction time: 16 h
Yield: 149.1 %

Procedure:
Phenol (40 mg, 0.24 mmol) was added to a stirred suspension of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.107 g, 0.38 mmol) and K2CO3 (0.160 g, 1.15 mmol) in ACN (3 mL). The mixture was stirred at 90° C. for 16 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether to yield 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.12 g, 90% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.20 (s, 2H), 6.70 (d, J=7.8 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.38-7.45 (m, 2H), 7.83 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH2:3]1.[C:13]1([O:23][CH2:24][CH:25]2[O:27][CH2:26]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH:1][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10]2
Reactant: NC1CCc2cc(O)ccc2C1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: Oc1ccc2c(c1)CCC(NCC(O)COc1cccc3ccccc13)C2
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A solution of 2-amino-6-hydroxytetralin (2.6 g) and 1-naphthyloxy-2,3-epoxypropane (3.2 g) in ethanol (80 ml) is refluxed for 5 hours, and then allowed to cool to room temperature. The solvent is evaporated off under reduced pressure and the thus obtained oil is chromatographed on a silica gel column eluting first with ethyl acetate up to complete elution of the first spot, and then with a mixture ethyl acetate/reethanol 9/1 v/v up to complete elution of the product. The fractions are pooled and concentrated under reduced pressure. The residue is dissolved in isopropanol (20 ml) and a solution of fumaric acid (0.95 g) in isopropanol (10 ml) is then added thereto. The precipitate is recovered by filtration, washed with ethyl ether and dissolved in water. A concentrated sodium hydroxide solution is then added thereto up to a basic pH and the solution is extracted with ethyl acetate. The organic extract is dried over sodium sulfate and concentrated to dryness. The residue is triturated with a small amount of ethyl acetate and filtered yielding 1.9 g of N-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-naphthyloxy)propanamine; m.p. 118°-120° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH:7]2[CH2:15][CH2:16][N:17]([C:18](=[O:34])[CH:19]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:6]12)=[O:4].[OH-].[Na+]>CO>[C:30]([O:29][C:27]([NH:26][CH:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:18]([N:17]1[CH:6]2[CH:7]([N:8]([C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:15][CH2:16]1)=[O:34])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)C1CN(C(=O)C2CC2)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2C(=O)C1CC1)C1CCCCC1
Reaction time: 4 h
Yield: 109.3 %

Procedure:
A solution of 44 (580 mg, 1.21 mmol) in MeOH (20 mL) was treated with 1M NaOH (4 mL) at ambient temperature. After 4 h, the solution was concentrated and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 45 (613 mg) as a yellow-colored foam which was used without further purification. Mass spectrum, m/z [464.6] (M+H)+.
Reaction SMILES: N(C1SC=C(CSCCN)N=1)C(N)=N.COC1C(OC)=NS(=O)(=O)N=1.CO[C:28]1[C:32]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)=[N:31][S:30](=[O:48])(=[O:47])[N:29]=1.[NH2:49][CH2:50][CH:51]([OH:54])[CH2:52][OH:53]>>[OH:54][CH:51]([CH2:52][OH:53])[CH2:50][NH:49][C:28]1[C:32]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)=[N:31][S:30](=[O:47])(=[O:48])[N:29]=1
Reactant: NCC(O)CO
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Agent: COC1=NS(=O)(=O)N=C1OC
Agent: N=C(N)Nc1nc(CSCCN)cs1
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2NCC(O)CO)cs1

Procedure:
When a methanolic solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide by the procedure of Example 31 and the resultant 3-methoxy-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide is treated with 3-amino-1,2-propanediol, the title compound is thereby produced.