Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Cl>>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[C:20](=[O:27])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4ccccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorobenzyl chloride gave the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]2[C:22]([I:23])=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=2[N:17]=[CH:18][N:19]=1.[CH:32](OCC)=[O:33]>O1CCCC1>[Cl:13][C:14]1[C:15]2[C:22]([I:23])=[C:21]([CH:32]=[O:33])[N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C=O)c(I)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (2.9 g, 29 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C. and treated drop-wise with n-butyllithium (2.5 M, 11.6 mL, 29 mmol). The reaction mixture was stirred at 0° C. for 1 hour, and then cooled to −78° C. A solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (8.0 g, 20 mmol) in tetrahydrofuran (10 mL) was added drop-wise, and stirred was continued at −78° C. for 1 hour. After drop-wise addition of a solution of ethyl formate (2.6 g, 35 mmol) in tetrahydrofuran (10 mL) to the −78° C. reaction mixture, it was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0° C., and the reaction was quenched by addition of saturated aqueous ammonium chloride solution (20 mL), then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 5.0 g, 11 mmol, 55%. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.80 (s, 1H), 6.05 (s, 2H), 3.55-3.62 (m, 2H), 0.89-0.96 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].N1([C:18]([C:20]2[C:21]([NH:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=2)=[O:19])C2C=CC=CC=2N=N1.Cl.[CH3:35][CH2:36][O:37][C:38]([CH3:40])=[O:39]>C1COCC1>[CH2:36]([O:37][C:38](=[O:39])[CH2:40][C:18]([C:20]1[C:21]([NH:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=[O:19])[CH3:35]
Reactant: CCOC(C)=O
Reactant: CSc1ncc(C(=O)n2nnc3ccccc32)c(NC2CCCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cnc(SC)nc1NC1CCCC1
Temperature: -78 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
A solution of lithium diisopropylamide (1.8 M in toluene, 26.6 mL) was added, dropwise, at −78° C., to a solution of EtOAc (2.33 mL, 23.92 mmol) in THF (100 mL), and the resulting mixture was stirred at −78° C. for 1 h. A solution of benzotriazol-1-yl-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanone (7.698 g, 21.74 mmol) in THF (60 mL) was added via cannula to the reaction mixture, and the resulting mixture was stirred at −78° C. for 4 h and at RT for 15 h. The reaction mixture was then treated with HCl (1 M aq) and then with HCl (6 M aq) until pH 2. The resulting mixture was stirred at RT for 1 h, was then diluted with EtOAc. The organic layer was separated and washed 3 times with water; the aqueous layers were combined and extracted 3 times with EtOAc and 3 times with a mixture of isopropanol and chloroform (1:1). The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (heptane/EtOAc, 100/0 to 80/20) to give 3.03 g (42% yield) of 3-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH3:15])[CH2:11][C@H:12]([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[C:18]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:23][C:19]=2[N:20]=[CH:21][N:22]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:3]([N:10]([CH3:15])[CH2:11][C@H:12]([O:14][C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=3)=[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:23][C:19]=2[N:20]=[CH:21][N:22]=1)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: C[C@@H](O)CN(C)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)CN(C)Cc4ccccc4)c23)cc1

Procedure:
Add 167 mg (4.18 mmol) sodium hydride (as 60% dispersion in mineral oil) to a solution of 600 mg (3.35 mmol) (2R)-1-[benzyl(methyl)amino]propan-2-ol in 7 ml THF at room temperature. After stirring for ten minutes, add a solution of 1177 mg (3.51 mmol) 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine in 8 ml THF and 62 mg (0.17 mmol) tetra-n-butylammonium iodide. Stir the reaction mixture for 16 h under reflux. After adding water and ethyl acetate, wash the separated organic phase with 1 N hydrochloric acid and satd. sodium chloride solution. Re-extract the aqueous phase with ethyl acetate. Combine the organic phases and dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Take up the residue in cyclohexane/ethyl acetate/dichloromethane and chromatograph on silica gel (solvent: cyclohexane/ethyl acetate 5:1, 2:1, 1:1, then ethyl acetate). 1366 mg (83% of theor.) of the desired product is obtained.
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH:10]([NH2:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:8])=[O:7])(C)(C)C.FC1C=CC=C(F)C=1O[C:23]1[O:24][C:25]([CH3:34])([CH3:33])[C:26]([CH3:32])([CH3:31])[S:27](=[O:30])(=[O:29])[N:28]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([NH:18][C:23]2[O:24][C:25]([CH3:34])([CH3:33])[C:26]([CH3:32])([CH3:31])[S:27](=[O:30])(=[O:29])[N:28]=2)[CH2:9][S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)NS(=O)(=O)CC(N)c1ccc(F)cc1
Reactant: CC1(C)OC(Oc2c(F)cccc2F)=NS(=O)(=O)C1(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(NC(CS(N)(=O)=O)c2ccc(F)cc2)=NS(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
50 mg of N-(tert-Butyl)-2-amino-2-(4-fluorophenyl)ethanesulfonamide enantiomer 1 and 58 mg of 2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide were dissolved in 1 ml of dichloromethane, and the mixture was stirred at room temperature for 5 hours. The completeness of the conversion was checked by LCMS. Since no conversion had taken place yet, 60 μl of N,N-diisopropylethylamine were added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 20 ml of ethyl acetate and washed with 10 ml of 0.1 N hydrochloric acid and 10 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 1 ml of trifluoroacetic acid and dissolved at room temperature for 20 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (25.8 mg) was obtained with a molecular weight of 407.5 g/mol (C15H22FN3O5S); MS (ESI): m/e=408 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NC(CO)CO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NC(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 34 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-1,3-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 4-(2-fluoro-4-iodoanilino)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34%) as a white solid; m.p. (EtOAc/Hexane) 93-98° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.22 (s, 1H), 7.61 (dd, J=9.9, 1.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.21 (t, J=8.4, 1H), 5.78 (d, J=1.1 Hz, 1H), 4.12 (p, J=5.6 Hz, 1H), 3.72 (ddd, J=15.1, 11.2, 5.6 Hz, 4H), 3.51 (s, 3H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0323. HPLC 89.9% (254 nm).
Reaction SMILES: [C:1]([OH:32])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(OC([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:46])[CH:42]([CH3:44])[CH3:43])=O)(C)(C)C>>[C:1]([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:46])[CH:42]([CH3:43])[CH3:44])(=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 50 %

Procedure:
Starting from triacontanoic acid (452 mg) and dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (526 mg), dibenzyl N-(N-triacontanoyl-L-valyl)-L-glutamate (430 mg) was obtained as powder according to a similar manner to that of Example 28.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C.[Ta]>[OH:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sncc12
Agent: [Ta]
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2sncc12
Yield: 69.9 %

Procedure:
50 g of 4-methoxy-1,2-benzisothiazole are suspended in 700 ml of acetic acid containing 10% by weight of hydrogen bromide and 5 g of red phosphorus, and the suspension is heated for 30 hours at 100° C. in a tantalum autoclave. After cooling, the material discharged from the autoclave is concentrated under reduced pressure and the residue is partitioned between methylene chloride and 2 N sodium hydroxide solution. The water phase is filtered to remove insoluble matter, washed with methylene chloride, acidified with hydrochloric acid and then repeatedly extracted with methylene chloride. The combined extracts are dried over magnesium sulfate and then concentrated under reduced pressure. 32 g (65% of theory) of 4-hydroxy-1,2-benzisothiazole of melting point 133°-134° C. are obtained. C7H5ONS (151)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1Br)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[CH3:15][N:16]1C(=O)CCC1.N>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:15]#[N:16])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)CCC2
Reactant: CN1CCCC1=O
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1C#N)CCC2
Temperature: 125 °C

Procedure:
A mixture of 5-acetamido-6-bromoindan (143 g), cuprous cyanide (65.5 g) and NMP (600 ml) was stirred and heated to 125° C. for 30 minutes. The mixture was cooled to ambient temperature and poured into a mixture of concentrated aqueous ammonia solution (specific gravity 0.88, 1 L) and ice (3 L). The mixture was stirred for 15 minutes. The precipitate was isolated and washed with water (3 L). A mixture of the solid so obtained and methylene chloride (2 L) was stirred at ambient temperature for 30 minutes. The mixture was filtered and the filtrate was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether (1.5 L). There was thus obtained 5-acetamido-6-cyanoindan (104 g), m.p. 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:14][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCCl.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:14][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCCc2sc(-c3ccncc3)cc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: Clc1ccc(C2CCCCc3sc(-c4ccncc4)cc32)cc1
Temperature: 100 °C
Yield: 82.3 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-4-ol (745.8 mg, 2.10 mmol) in 1,2-dichloroethane (11.0 mL, 140 mmol) were added triethylsilane (3.35 mL, 20.9 mmol) and trifluoromethanesulfonic acid (0.927 mL, 10.5 mmol) and the resulting reddish solution was heated at 100° C. for 16 hr. The reaction mixture was allowed to cool to rt then was neutralized to pH 7 by the addition of a saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% EA/DCM) to give the title compound as a white foam (587.4 mg, 95% yield). LCMS: (FA) ES+ , 354. 1H NMR (400 MHz, DMSO-d6) δ: 8.45-8.49 (dd, J=1.5 Hz, J=4.7 Hz, 2H), 7.36-7.44 (m, 4H), 7.16-7.20 (dd, J=8.2 Hz, 2H), 7.10-7.12 (br s, 1H), 4.28-4.33 (m, 1H), 2.75-3.0 (m, 2H), 2.10-2.20 (m, 1H), 1.88-1.95 (m, 1H), 1.60-1.80 (m, 4H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH:21]2[N:15]([N:16]([CH3:49])[C@@H:17]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41]CC4C=CC=CC=4)=[CH:37][CH:36]=3)[C:18](=[O:33])[N:19]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:20]2)[C:14](=[O:50])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.CCCCCC>C(O)(=O)C.Br>[CH2:1]([NH:8][C:9]([N:11]1[CH:21]2[N:15]([N:16]([CH3:49])[C@@H:17]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)[C:18](=[O:33])[N:19]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:20]2)[C:14](=[O:50])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)N(Cc2cccc3ccccc23)CC2N(C(=O)NCc3ccccc3)CCC(=O)N21
Agent: Br
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1[C@@H](Cc2ccc(O)cc2)C(=O)N(Cc2cccc3ccccc23)CC2N(C(=O)NCc3ccccc3)CCC(=O)N21
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
(2S)—N-benzyl-2-(4-(benzyloxy)benzyl)-1-methyl-4-(naphthalen-1-ylmethyl)-3,9-dioxooctahydropyrimido[1,2-b][1,2,5]triazepine-6(7H)-carboxamide (Compound 1-267) 33 mg (0.05 mmol) was dissolved in 25% HBr acetic acid solution 0.2 ml and the mixture was stirred at room temperature for 5 hr. Ether 1.2 ml and n-hexane 0.8 ml were added to the reaction mixture and the mixture was concentrated in vacuo. The precipitation was purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 7.3 mg (yield 25%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[F:19][C:20]1[C:21]([O:40][CH3:41])=[CH:22][C:23]([CH2:35][C:36]([F:39])([F:38])[F:37])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:20]1[C:21]([O:40][CH3:41])=[CH:22][C:23]([CH2:35][C:36]([F:39])([F:38])[F:37])=[C:24]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[CH:4][CH:3]=2)[CH:25]=1
Reactant: COc1cc(CC(F)(F)F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: N#Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CC(F)(F)F)c(-c2ccc3c(C#N)nn(C4CCCCO4)c3c2)cc1F
Temperature: 110 °C
Yield: 30.8 %

Procedure:
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 2, 3.99 g, 13.03 mmol) and 2-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 36, 7.46 g, 15.63 mmol) in dioxane (60 mL) was added a solution of potassium phosphate (18.8 g, 39.09 mmol) in water (12 mL). The mixture was degassed with nitrogen, treated with tetrakis (triphenylphosphine) palladium(0) (3.01 g, 2.6 mmol) and heated at 110° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in EtOAc (500 mL) and filtered through Arbocel®, washing with EtOAc (2×500 mL). The combined organic phases were washed with water (300 mL), dried over MgSO4 and concentrated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel, eluting with 25% EtOAc in heptanes, to give the title compound (1.737 g) in a 31% yield.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CCN(CC)CC.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.CCOC(C)=O>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][S:40]([C:37]5[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=5)(=[O:42])=[O:41])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(C34CCC(OS(=O)(=O)c5ccc(C)cc5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 100 mg of 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purin-2,6-dione (Example 13a) (0.28 mmol) in CH2Cl2 (10 ml) was added 40 μL of Et3N and the reaction mixture cooled in an ice bath. To this was added 100 mg of p-toluenesulfonyl chloride (0.52 mmol) and the reaction kept at 10° C. overnight. The reaction mixture was conc'd in vacuo and the residue taken up in EtOAc and washed 2× with dilute HCl (10 ml). The organic layer was dried over NaSO4 and conc'd. The residue was triturated in acetonitrile to afford 78 mg (54%) of pure white solid (MH+=515.10).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH2:1]([N:8]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)CNCc1ccccc1
Reactant: CC1CO1
Solvent: CCO
Product: CCC(O)CN(Cc1ccccc1)CC(C)O
Temperature: 150 °C

Procedure:
To a solution of 1-benzylamino-butan-2-ol (Intermediate 482, 8.5 g, 47.48 mmol) in ethanol (150 mL) was added propylene oxide (8.8 g, 151 mmole) and the mixture was heated at 150° C. for 2 h in autoclave. After concentration of the mixture under reduced pressure, the residue was purified by column chromatography using methanol in dichloromethane to give product as an oil. Yield: 10.2 g (93%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[CH3:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[CH3:17]
Reactant: CCn1ncc(C)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To a solution of 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (130 mg, 0.48 mmol) [from Example 245(b)] in DCM (5 mL) at 25° C. was added PyBrOP (250 mg, 0.54 mmol) in one portion, followed by addition of DIPEA (0.7 mL, 4.01 mmol). After 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.50 mmol) was added to above solution. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (210 mg, 79%) as a white solid: LC-MS m/z (ES) 551 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C([OH:25])C>[Ni]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:11]=[N:10]2)=[CH:5][CH:4]=1)=[O:25]
Reactant: CCO
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C#N)cc1
Agent: [Ni]
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
To a solution of 1-(4-cyanophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.43 g) obtained in Example 64b) in ethanol (15 ml) was added Raney-nickel (0.09 g), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a pale-yellow powder (0.11 g, 24%).