Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2ccc(Br)cc2c(OCc2ccccc2)n1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 1-(benzyloxy)-7-bromo-3-chloroisoquinoline (1.00 g, 2.86 mmol, 1.0 eq), 3-methoxyphenylboronic acid (435 mg, 2.86 mmol, 1.0 eq), K2CO3 (2.13 g, 15.4 mmol, 5.4 eq) in dioxane (10 mL) and H2O (5 mL) was added Pd(PPh3)2Cl2 (100 mg, 0.15 mmol, 0.05 eq) under N2 atmosphere. The resulting mixture was stirred at 110° C. under N2 atmosphere overnight. The solvent was removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 250:1) to give 550 mg of lxvi-a as white solid (yield 37%). LCMS m/z=376.0 (M+1) (Method B) (retention time=2.43 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.NN>C(Cl)Cl.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)CSc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Chlorothiophenol (1.1 g, 7.61 mmol) was mixed with ethyl 4-chloro-acetoacetate (0.95 mL, 7.00 mmol) in CH2Cl2 (100 mL) at 0° C. Triethyl amine (1.5 mL, 10.8 mmol) was then added drop wise. After the resulting suspension was stirred at 0° C. for another 30 min, the reaction mixture was poured into water, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed by saturated NaHCO3, HCl (0.25 N), brine, concentrated in vacuo, and purified by flash column chromatography (ethyl acetate/hexanes=1/9) to afford TC-I-164 (1.82 g, 96%) as light yellow oil. Exposure to hydrazine in refluxing ethanol, generated TC-II-165.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:7][CH:8]=1>C(O)(=O)C.[Rh].[Pt](=O)=O>[F:18][C:2]([F:1])([F:17])[C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(F)(F)F)c1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 5-(trifluoromethyl)pyridin-3-ylcarbamate (3 g, 14 mmol) in glacial acetic acid (50 mL) was added 5% Rhodium on active carbon (0.5 g) and Platinum(IV) oxide (0.5 g) in the hydrogenation steel bomb. The mixture was sealed and hydrogenated at 200 psi and 70° C. for 48 h. the mixture was filtered through Celite and concentrated to give cis-(+/−)-tert-butyl 5-(trifluoromethyl)piperidin-3-ylcarbamate. LCMS (m/z): 269.1 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22](C(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.[O-]CC.[Na+]>C(O)C.C(=O)(O)[O-]>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Diethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]malonate (4.60 g, 9.95 mmol), was dissolved in ethanol (46 mL). Water (18 μL, 1.0 mmol) and 21% Sodium ethoxide in ethanol (0.37 mL, 1.0 mmol) were added. The reaction mixture was stirred at 75° C. for 1 hour. HPLC & LCMS analysis showed 60% decarboxylation. The heating was continued for another 2 hours (reaction complete). The reaction was diluted with aqueous bicarbonate, and extracted with EtOAc. The EtOAc extract was washed with brine, then dried (Na2SO4), and evaporated in vacuo to 3.4 g oil (88% yield). LCMS, HPLC, & NMR showed it to be clean enough to proceed. 1H NMR (400 MHz, DMSO-D6): δ7.20 (s, 1H); 5.20 (m, 1H, OCH); 4.10 (q, 2H, OCH2); 3.89 (s, 2H, CH2); 3.85 (s, 4H, OCH2); 1.5-2.0 (m, 8H); 1.15 (t, 3H, CH3). HPLC showed it to have UVmax 222 & 252 nm.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:15])[CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([B:16]([OH:21])[OH:17])=[CH:8][C:9]=1[CH3:15])#[N:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1C#N
Reaction time: 0.5 h

Procedure:
10.21 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 3.00 g of 4-bromo-2-methylbenzonitrile in 50 ml of dry tetrahydrofuran at −78° C. after stirring at this temperature for 30 minutes, 4.22 ml of triisopropyl borate are added, and then the mixture is stirred at −78° C. for a further 45 minutes. 30 ml of 1N are added to the reaction mixture. The phases are separated and the aqueeous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1,1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 100 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with penteane. Drying under high vacuum results in 1.82 g of the title compound as a white solid. Rt. 2.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].Br[CH2:15][C:16]1[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:15][C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)COc1ncc(O)cc1Cl
Reactant: COC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(COc2cnc(OCC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 5-chloro-6-isobutoxy-pyridin-3-ol (Preparation 1, 364 mg, 1.8 mmol) in DMSO (15 mL) was added methyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 3, 479 mg, 1.8 mmol) followed by potassium carbonate (500 mg, 3.6 mmol) and the resulting mixture stirred at room temperature for 18 hours under nitrogen. The mixture was poured onto water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined extracts were washed with water (20 mL), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the title compound (623 mg, 89%) as a light brown oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>ClCCl>[C:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2CC)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.06 g, 0.16 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.05 mL, 0.63 mmol) and propionyl chloride (0.03 mL, 0.3 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05, 77%), m.p. 111-112° C.;
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[CH2:6]([N:13]([CH2:17][CH2:18]O)[CH2:14][CH2:15]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[ClH:3].[CH2:6]([N:13]([CH2:17][CH2:18][Cl:3])[CH2:14][CH2:15][Cl:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.70 g (64.7 mmol) of thionyl chloride were added dropwise to a stirred solution of 5.00 g (21.6 mmol) of (2-[benzyl-(2-hydroxyethyl)amino]ethanol hydrochloride (XIX) in 100 ml of dry dichloromethane at 0° C., and the resulting reaction solution was then stirred at room temperature for 1 h. The solvent and excess thionyl chloride were removed in vacuo, and the reaction product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]([O-])=[O:25])[S:23][C:16]=12.[Li+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[Cl:14])[CH:21]=2)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid tert-butyl ester and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 382/384 (MH+); HPLC Rf: 5.72 min.; HPLC purity 94%.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:20])[C:7]1[C:12]([CH2:13]O)=[CH:11][C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][C:8]=1[F:19])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:15]([C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([C:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:20])=[C:8]([F:19])[CH:9]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC(=O)c1c(F)cc(C(C)(C)C)cc1CO
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(C)(C)C)cc(F)c1C(=O)NC(C)(C)C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of N,4-di-tert-butyl-2-fluoro-6-(hydroxymethyl)benzamide (4.3 g, 15.3 mmol, Eq: 1.00) in MeOH (100 ml) was added Pd—C 10% (50% wet) (1.19 g) and the reaction mixture was stirred under H2 atmosphere (balloon) for 3 h. Reaction mixture was filtered over a celite pad and the celite pad washed with EtOH(3×50 mL). The combined filtrate and washes were evaporated under vacuum to give 4.01 g of product as a white solid (99% yield); LC/MS, m/z 266[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (s, 9 H) 1.48 (s, 9 H) 2.41 (s, 3 H) 5.60 (br. s., 2 H) 6.90-6.95 (m, 1 H) 7.00 (d, J=0.51 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (5 g, 25 mmol) in anhydrous dichloromethane (150 mL) was added triethylamine (7.5 g, 75 mmol), DMAP (300 mg, 2.5 mmol) and tert-butyldimethylsilyl chloride (7.5 g, 50 mmol) sequentially. The resulting pale brown solution was stirred at room temperature for overnight. The reaction mixture was extracted with dichloromethane and water three times. The combined organic layers were dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo. The crude product was subjected to column chromatography with PE as eluant to afford the subtitle compound as a brown oil (7.1 g).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][N:5]([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH2:4]1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][N:5]([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)NCC(F)(F)F)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1CN(C(=O)NCC(F)(F)F)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 50 °C
Yield: 14.2 %

Procedure:
To a solution of (cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.306 g, 0.571 mmol) in 1,4-dioxane (10 mL) was added aqueous NaOH (1 N, 1.50 mL, 1.50 mmol). The reaction was heated at about 50° C. for about 1 h. The layers were partitioned between DCM (25 mL) and water (10 mL). The aqueous layer was acidified with 20% aqueous citric acid to about pH 4 and extracted with DCM (4×25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown residue. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give a racemic mixture of products as a brown residue. The compound was further purified using chiral preparative HPLC (Table 2, Method 55) to afford (3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Rt=14.5 min, or =negative) (0.031 g, 14%)[Example #36]: LC/MS (Table 1, Method a) Rt=1.62 min; MS m/z: 382 (M+H)1 and (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Rt=17.3 min, or =positive) (0.033 g, 15%)[Example #37]: LC/MS (Table 1, Method a) Rt=1.62 min; MS m/z: 382 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH3:9])[NH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=O)[CH:19]=[CH:20]N(C)C>C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[N:3]2[N:4]=[C:5]([CH3:9])[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:20][CH:19]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Solvent: CC(=O)O
Product: Cc1nn2c(-c3cc(Cl)ccc3Cl)ccnc2c1C#N
Yield: 70.3 %

Procedure:
A mixture of 12.2 g of 3-amino-4-cyano-5-methylpyrazole and 24.4 g of 2',5'-dichloro-3-dimethylaminoacrylophenone in 250 ml of glacial acetic acid was heated on a steam bath for 4 hours. The mixture was cooled and filtered and gave 21.28 g of 7-(2,5-dichlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile as off-white crystals.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([CH2:23][CH2:24][C:25]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:10])([CH3:1])[CH2:8][CH3:9])=[O:26])[CH2:14]1
Reactant: CCC(C)(O)CCCCO
Reactant: COC(=O)CCC1CC2CC1C1C3C=CC(C3)C21
Product: CCC(C)(O)CCCCOC(=O)CCC1CC2CC1C1C3C=CC(C3)C21
Yield: 87 %

Procedure:
By following the procedure of Synthesis Example 2 except that 5-methyl-1,5-heptanediol was used instead of 4-methyl-1,4-pentanediol and methyl 3-(8-tetracyclo-[4.4.0.12,5.17,10]dodecen-3-yl)propionate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 5-hydroxy-5-methylheptyl 3-(8-tetracyclo[4.4.0.12,5.17,10]-dodecen-3-yl)propionate. Yield 87%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=4[F:26])[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: N#Cc1cc(-c2ccc(F)c(F)c2F)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (13 mg, 15%), MS (ISP) m/z=342.4 [(M+H)+], mp 294° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]([NH:29]C(OCC1C=CC=CC=1)=O)([CH3:28])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)(=[O:8])[O:5]CC)C.CO>C(Cl)Cl>[NH2:29][C:11]([CH3:28])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)NC(=O)OCc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(C)(N)CCP(=O)(O)O)cc1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of (±)-diethyl 3-benzyloxycarbonylamino-3-methyl-5-(4-(octyl)phenyl)pentylphosphonic acid (0.097 g, 0.173 mmol) in methylene chloride (1 ml) was added aodotrimethylsilane (0.100 ml, 0.690 mmol). After stirring for 1 h, methanol was added (1 ml) and the reaction was concentrated. HPLC purification (YMC-Pack pro C18, 150×20 mm, acetonitrile/water+0.1% TFA 10/90 to 0/100 over 15 minutes, 20 ml/min, 254 nM) yielded a waxy solid (0.051 g): 1H NMR (500 MHz , CDCl3): δ7.09-7.14 (m, 4H), 2.64 (t, J=8.7 Hz, 2H), 2.56 (t, J=7.7 Hz, 3H), 1.98-2.02 (m, 2H), 1.88-1.92 (m, 2H), 1.75-1.82 (m, 2H), 1.56-1.59 (m, 2H), 1.39 (s, 3H), 1.24-1.34 (m, 12H), 0.89 (t, J=6.89 Hz, 3H); MS m/e 370.3 (M+).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45])[CH:39]=O>O1CCCC1>[C:2]([O:6][C:7](=[O:8])/[CH:9]=[CH:39]/[C:38]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:36]([F:35])[CH:37]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc([N+](=O)[O-])c(F)c1
Yield: 86 %

Procedure:
To a suspension of (tert-butoxycarbonylmethyl)triphenylphosphonium chloride (1.6 g, 3.9 mmol; [35000-37-4]) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (0.44 g, 3.9 mmol). After stirring for 15 min 3-fluoro-4-nitrobenzaldehyde (0.60 g, 3.5 mmol; [160538-51-2]) was added. After 1.5 h the suspension was poured on water, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash-chromatography using a gradient of n-heptane:tert-butyl methyl ether (100:0 to 80:20) to give the title compound (804 mg, 3.01 mmol; 86%) as light brown solid. MS: m/e=194.0 [M−C4H9O+].
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]>CO>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCOc1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCOc1cc(CO)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (39.7 g) is added in portions to a solution of 4-methoxy-3-(3-methoxypropoxy)-benzaldehyde (336 g) in methanol (3.36 liters), the reaction temperature being maintained at 0°-5° C. When the addition is complete, the batch is stirred for a further 60 minutes at room temperature and concentrated under reduced pressure, and the residue is partitioned between ice-cooled 2N hydrochloric acid and ethyl acetate (3×2 liters). The combined organic phases are washed with water and saturated sodium hydrogen carbonate solution, added over magnesium sulfate and concentrated. Purification of the residue by FC on silica gel (dichloromethane/methanol 96:4) yields the title compound in the form of an oil (326 g): Rf (ethyl acetate/hexane 2:1)=0.31. Anal. C12H18O4 (226.27): calc. C, 63.70; H, 8.02; found C, 63.70; H, 8.24.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].S(Cl)(Cl)(=O)=O.ClC(C(=O)COC)C(OC)=O.[NH2:27][C:28]([NH2:30])=[S:29]>CCO.C(Cl)Cl>[NH2:30][C:28]1[S:29][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:3][O:2][CH3:1])[N:27]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: NC(N)=S
Agent: COCC(=O)C(Cl)C(=O)OC
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Product: COCc1nc(N)sc1C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-methoxy-3-oxobutanoate (4.43 mL, 34.2 mmol) and DCM (30.00 mL). Sulfuryl chloride (2.91 mL, 35.9 mmol) was added dropwise with a syringe to the reaction mixture. The mixture was then stirred for 1 hour at 20° C. The solution was reduced to an oil under reduced pressure and dissolved in EtOH (50 mL). To this solution was added methyl 2-chloro-4-methoxy-3-oxobutanoate (6.18 g, 34 mmol) and thiourea (1.9 mL, 34 mmol). The reaction was then stirred at reflux for approximately 12 hours. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added, and the resulting solid was filtered and recrystallized from water and <5 mL EtOH to give methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate as rust colored crystals (4.85 g, 68%). LCMS (M+H) 203 calc. for C7H11N2O3S 203.2. 1H NMR (400 MHz, CD3OD): δ ppm 4.64 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H).