Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:20]([OH:37])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:49][C:50](Cl)=[O:51].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[N:30]([CH:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[C:50](=[O:51])[CH2:49][O:37][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(NC4CCOCC4)cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCOCC3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl(1-(4-(6-hydroxy-3-phenyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)phenyl)cyclobutyl)carbamate (240 mg, 0.46 mmol) in dry THF (11 mL) was added N,N-diisopropylethylamine (0.41 mL, 2.32 mmol). 2-chloroacetyl chloride (0.19 mL, 2.32 mmol) was added dropwise at 0 C. The resulting mixture was stirred overnight at room temperature. A saturated solution of NaHCO3 (8 mL) was added and the mixture was stirred under reflux for 2 hours. After allowing to cool to room temperature, the organic phase was separated and the aqueous phase extracted with AcOEt (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (154 mg, 59%). 1H NMR (500 MHz, CDCl3): 7.45 (1H, s), 7.24-7.22 (5H, m), 7.19-7.17 (2H, m), 7.14-7.12 (2H, m), 4.94 (1H, s), 4.71 (2H, s), 4.60-4.55 (1H, m), 4.07-4.03 (2H, m), 3.45 (2H, t), 2.63-2.54 (2H, m), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (3H, m), 1.40-1.10 (9H, br).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1-c1ccccn1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-tert-butyl-benzenesulfonyl chloride and 4-chloro-2-pyridin-2-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=401.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 40.4 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (127 mg, 0.537 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (113 mg, 40%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J=2.4 Hz, 1H), 7.73 (dd, J=8.4, 2.4 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (d, J=1.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.09 (dd, J=7.5, 2.7 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.64 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 3.63 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].Br[CH2:15][C:16]([OH:18])=[O:17].C(OCC)C>CN(C=O)C.C(O)C.[Cl-].[Na+].O>[F:11][C:8]([F:9])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C(O)CBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)COc1ccccc1C(F)(F)F
Temperature: 85 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
A solution of 2-hydroxybenzotrifluoride (3.00 g, TCI) in a mixture of DMF (16.5 ml) and ethanol (1.8 ml) was added with sodium hydroxide (1.5 g, WAKO) and bromoacetic acid (2.6 g, TCI), and the mixture was stirred at 85° C. for 24 hours. The reaction mixture was added with diethyl ether and saturated brine, and successively washed with 1 N aqueous hydrochloric acid and saturated aqueous sodium carbonate. The layer produced between the aqueous layer and oil layer was dried to obtain a crude product of the title compound (Compound No. CA54, 2.36 g).
Reaction SMILES: [CH3:1][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][C:18]([NH:20][C@H:21]([C@H:111]([OH:129])/[CH:112]=[CH:113]/[CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH2:123][CH2:124][CH2:125][CH2:126]CC)[CH2:22][O:23][CH:24]1[O:29][CH:28]([CH2:30][OH:31])[CH:27]([O:32][CH:33]2[O:38][CH:37]([CH2:39][OH:40])[CH:36]([O:41][CH:42]3[O:47][CH:46]([CH2:48][OH:49])[CH:45]([OH:50])[CH:44]([O:51][CH:52]4[O:57][CH:56]([CH2:58][OH:59])[CH:55]([O:60]C5(C([O-])=O)OC([C@@H](O)[C@@H](O)CO)[C@H](NC(C)=O)C(O)C5)[CH:54]([OH:81])[CH:53]4[OH:82])[CH:43]3[NH:83][C:84]([CH3:86])=[O:85])[CH:35]([O:87]C3(C([O-])=O)OC([C@@H](O)[C@@H](O)CO)[C@H](NC(C)=O)C(O)C3)[CH:34]2[OH:108])[CH:26]([OH:109])[CH:25]1[OH:110])=[O:19].[Na+].[Na+].C([O-])(=O)C.O>C(Cl)(Cl)Cl>[CH3:1][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][C:18]([NH:20][CH:21]([CH:111]([OH:129])/[CH:112]=[CH:113]/[CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH2:123][CH2:124][CH2:125][CH3:126])[CH2:22][O:23][CH:24]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([O:32][C@@H:33]2[O:38][C@H:37]([CH2:39][OH:40])[C@H:36]([O:41][C@@H:42]3[O:47][C@H:46]([CH2:48][OH:49])[C@H:45]([OH:50])[C@H:44]([O:51][C@@H:52]4[O:57][C@H:56]([CH2:58][OH:59])[C@H:55]([OH:60])[C@H:54]([OH:81])[C@H:53]4[OH:82])[C@H:43]3[NH:83][C:84]([CH3:86])=[O:85])[C@H:35]([OH:87])[C@H:34]2[OH:108])[C@H:26]([OH:109])[C@H:25]1[OH:110])=[O:19]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](COC1OC(CO)C(OC2OC(CO)C(OC3OC(CO)C(O)C(OC4OC(CO)C(OC5(C(=O)[O-])CC(O)[C@@H](NC(C)=O)C([C@@H](O)[C@@H](O)CO)O5)C(O)C4O)C3NC(C)=O)C(OC3(C(=O)[O-])CC(O)[C@@H](NC(C)=O)C([C@@H](O)[C@@H](O)CO)O3)C2O)C(O)C1O)NC(=O)CCCCCCCCCCCCCCCCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCC/C=C/C(O)C(COC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
A 1 ml quantity of 0.5% ganglioside GDla solution, 1 ml of 40 mM acetate buffer (pH 5.0) and 1 ml of sterilized water were mixed together, and to the mixture was added 1 ml of aqueous solution of Isozyme L (8 U/ml). The mixture was allowed to react at 37° C. for 1 hour, and 1/10 part by volume of chloroform was added thereto to stop the enzyme reaction. Asialo GM1 was extracted from the reaction solution with use of a mixture of chloroform and methanol (2:1) and then lyophilized, giving 2.0 mg of asialo GM1 as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([OH:10])[CH3:9])[CH2:3][CH:4](O)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOCCOCCOCCOC>O.[Ru](Cl)(Cl)Cl>[CH3:5][CH:4]1[CH2:3][N:2]([CH3:1])[CH:7]=[C:8]([CH3:9])[O:10]1
Reactant: CC(O)CN(C)CC(C)O
Agent: Cl[Ru](Cl)Cl
Agent: COCCOCCOCCOCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC1=CN(C)CC(C)O1
Temperature: 180 °C
Yield: 65 %

Procedure:
A mixture of N-methyl-bis-(2-hydroxypropyl)amine (75g, 0.51 mol), trans-4-phenyl-3-buten-2-one (75g, 10.51 mol), ruthenium trichloride hydrate (0.626g 12.3 mmole), triphenylphosphine (2.0g 17.6 mmole), and tetraglyme (30g) was added to a 250-ml 3-neck round bottom flask connected with a fractional distillation set and a thermometer. The reaction was heated to 180° C. under nitrogen and the products were distilled out through the distillation set. The products (organic layer) were then fractionally distilled again to obtain a 65% yield of 3,4-dihydro-2,4,6-trimethyl-2H-1,4-oxazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.C1COCC1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1cc(Nc2nc3n(n2)CCCCC3=O)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CCCCC3(O)c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a suspension of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7,8-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-9(6H)-one (28 mg, 0.075 mmol) in THF (0.5 mL) was added (4-fluorophenyl)magnesium bromide/THF (0.188 mL, 0.188 mmol) at −20° C. under nitrogen. After warming from −20° C. to rt, the mixture was stirred for 16 h. An additional portion of (4-fluorophenyl)magnesium bromide/THF (0.225 mL, 0.225 mmol) was added. The rxn was stirred an additional 3 h at rt, then 4 h at 60° C. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dichloromethane (2 mL). The solution was washed with water (1 mL) and then loaded onto silica gel. The crude product was purified using silica gel column chromatography (0-80% EtOAc/hexanes). The fractions containing product were combined and concentrated. The residue was repurified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound (3.4 mg, 7.25 μmol, 9.7% yield). LC-MS (M+H)+=469.1. 1H NMR (500 MHz, chloroform-d) δ ppm 1.43-1.52 (m, 1 H) 1.82-1.95 (m, 2 H) 1.99-2.10 (m, 1 H) 2.11-2.21 (m, 1 H) 2.59 (ddd, J=14.34, 6.41, 2.14 Hz, 1 H) 3.85 (s, 3 H) 3.86-3.93 (m, 1 H) 4.43 (ddd, J=11.60, 2.90, 2.59 Hz, 1 H) 6.77 (s, 1 H) 6.95 (dd, J=8.39, 2.29 Hz, 1 H) 7.02-7.09 (m, 3 H) 7.09-7.17 (m, 3 H) 7.39 (d, J=2.14 Hz, 1 H) 7.53 (d, J=1.22 Hz, 1 H).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][N:19]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:18]=4)[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[CH:21]=[CH:20][N:19]([C:22]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[N:18]=5)[CH:15]=4)[N:10]=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccc(-c3ccc4ncnc(N5CCNCC5)c4c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCN(c3ncnc4ccc(-c5ccn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 125.1 %

Procedure:
100 mg 4-piperazin-1-yl-6-(1-trityl-1H-pyrazolyl) quinazoline (compound in Example 827) and 54 mg 1-chloromethyl-4-methyl benzene were dissolved in N,N-dimethylformamide, then 79 mg potassium carbonate was added thereto, and the mixture was stirred for about 5 hours at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to give 150 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]([NH:31][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=2)[CH2:24][NH:23][C:22](=[O:32])[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: Nc1cccc(CNC(=O)OCc2ccccc2)c1
Reactant: O=C(O)COCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccc(Br)cc1)Nc1cccc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 67A (245 mg, 1 mmol) and 66A (268 mg, 1.05 mmol) in DMF (4 mL), was added EDCI (288 mg, 1.5 mmol), HOAt (14 mg, 0.1 mmol) and DIEA (0.54 mL, 3 mmol). The mixture was stirred rt for 16 h, then was quenched with water and extracted with EtOAc (3×20 mL). The organic layer washed by brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-40% EtOAc in hexanes) gave 67B (300 mg, 62%). MS (ESI) m/z 483.3 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:5]([C:8](=[O:88])[NH:9][C@@H:10]([CH2:84][CH:85]([CH3:87])[CH3:86])[C:11](=[O:83])[N:12]([CH3:82])[C@@H:13]([CH2:78][CH:79]([CH3:81])[CH3:80])[C:14](=[O:77])[NH:15][C@@H:16]([CH3:76])[C:17](=[O:75])[NH:18][C@H:19]([CH3:74])[C:20](=[O:73])[N:21]([CH3:72])[C@@H:22]([CH2:68][CH:69]([CH3:71])[CH3:70])[C:23](=[O:67])[NH:24][C@@H:25]([CH2:63][CH:64]([CH3:66])[CH3:65])[C:26](=[O:62])[N:27]([CH3:61])[C@@H:28]([CH:58]([CH3:60])[CH3:59])[C:29](=[O:57])[N:30]([CH3:56])[C@@H:31]([C@H:48]([OH:55])[C@H:49]([CH3:54])[CH2:50]/[CH:51]=[CH:52]/[CH3:53])[C:32](=[O:47])[NH:33][C@@H:34]([C@H:44]([OH:46])[CH3:45])[C:35](=[O:43])[N:36]([CH3:42])[CH2:37][C:38]([O:40]C)=[O:39])[NH:6][CH3:7])([CH2:3][CH3:4])[CH3:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH:1]([C@@H:5]([C:8](=[O:88])[NH:9][C@@H:10]([CH2:84][CH:85]([CH3:87])[CH3:86])[C:11](=[O:83])[N:12]([CH3:82])[C@@H:13]([CH2:78][CH:79]([CH3:81])[CH3:80])[C:14](=[O:77])[NH:15][C@@H:16]([CH3:76])[C:17](=[O:75])[NH:18][C@H:19]([CH3:74])[C:20](=[O:73])[N:21]([CH3:72])[C@@H:22]([CH2:68][CH:69]([CH3:70])[CH3:71])[C:23](=[O:67])[NH:24][C@@H:25]([CH2:63][CH:64]([CH3:65])[CH3:66])[C:26](=[O:62])[N:27]([CH3:61])[C@@H:28]([CH:58]([CH3:59])[CH3:60])[C:29](=[O:57])[N:30]([CH3:56])[C@@H:31]([C@H:48]([OH:55])[C@H:49]([CH3:54])[CH2:50]/[CH:51]=[CH:52]/[CH3:53])[C:32](=[O:47])[NH:33][C@@H:34]([C@H:44]([OH:46])[CH3:45])[C:35](=[O:43])[N:36]([CH3:42])[CH2:37][C:38]([OH:40])=[O:39])[NH:6][CH3:7])([CH2:3][CH3:4])[CH3:2]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@@H](C(=O)N[C@H](C(=O)N(C)CC(=O)OC)[C@@H](C)O)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC)C(C)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C/C=C/C[C@@H](C)[C@@H](O)[C@@H](C(=O)N[C@H](C(=O)N(C)CC(=O)O)[C@@H](C)O)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC)C(C)CC
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of methyl (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-3-sec-butyl-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-24-isopropyl-8,12,15,17,23,26,32-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oate (230 mg) in MeOH (4 ml) was added 1N LiOH (1.84 ml) under ice-bath cooling. After being stirred for 1 hr at the same temperature, the solution was acidified with 5% citric acid to be pH 5, concentrated in vacuo to remove MeOH, and extracted with AcOEt (20 ml). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with Et2O to give (3S,6S,9S,12S,15R,18S,21S,24S,27S,30S)-3-sec-butyl-30-[(1R)-1-hydroxyethyl]-27-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,21-tetraisobutyl-24-isopropyl-8,12,15,17,23,26,32-heptamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-2,5,8,11,14,17,20,23,26,29,32-undecaazatetratriacontan-34-oic acid (188 mg) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(O)(=O)=O>C1CCCCC1>[OH:17][C:11]1[CH:16]=[CH:15][C:14]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: C1CCCCC1
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 70 %

Procedure:
4-Hydroxy benzoic acid (13.8 g; 0.10 mole), phenol (10.3 g; 0.11 mole), 98% methane sulphonic acid (50 ml; 75.5 g; 0.8 mole) and cyclohexane (10 ml) were mixed and heated to reflux temperature. The solution was refluxed for 12 hours using a Dean and Stark apparatus (no sampling). The reaction mixture was worked up to give 4,4'-dihydroxy-benzophenone in 70% yield.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)ncc1I
Product: FC(F)(F)c1cc(Cl)c(I)cn1

Procedure:
A solution of 5-iodo-2-(trifluoromethyl)pyridin-4-ol (4.8 g, 16.6 mmol) in POCl3 (30 mL) was heated to 100° C. for 30 minutes. The resulting solution was concentrated under vacuum and the residue was neutralized by the addition of ice and aqueous potassium carbonate. The solution was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give 4-chloro-5-iodo-2-(trifluoromethyl)pyridine. Retention time (min)=2.594, method [1], MS (ESI) 307.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(-c3ccc(OC)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution of 2-(4-methoxy-phenyl)-benzo[b]thiophene-6-carboxylic acid methyl ester (500 mg, 1.7 mmol) in dichloromethane (15 mL) at 0° C. is added BBr3 (4.2 mL, 1 M in dichloromethane). The reaction mixture is stirred at ambient temperature overnight. The reaction is quenched by the addition of methanol and concentrated under reduced pressure. The residue is partitioned between EtOAc and 1 N HCl. The organic layer is concentrated and the residue is purified via chromatography eluting with 0 to 25% EtOAc in hexanes to give the title compound (57 mg, 12%) as a tan solid. LC-ES/MS m/e 283 (M−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10](C)C)[N:3]=1.[CH3:13][N:14](C=O)C>CCOCC.[NH4+].[OH-].[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:4]1[N:3]=[C:2]([C:13]#[N:14])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)nc(N(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(C#N)nc(N)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 4-chloro-6-methoxy-N,N-dimethylpyrimidin-2-amine (0.350 g, 2.19 mmol, 1 eq) in 10 ml anhydrous DMF was degassed with Ar for 5 min. Zn(CN)2 (0.155 g, 1.32 mmol, 0.6 eq) and Pd(PPh3)4 (0.253 g, 0.219 mmol, 10 mol %) were added and the mixture was heated to 95° C. After 23 h the reaction was cooled to room temperature and the mixture was diluted with Et2O and NH4OH (28%). After stirring for 1 h the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.214 g (1.43 mmol, 65% yield) of 2-amino-6-methoxypyrimidine-4-carbonitrile.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[C:9](OC(C)=O)[C@@H:8]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]1[O:20][C:21]([CH3:23])=[O:22])=[O:3].N1C=CC=CC=1.Cl.C(Cl)(Cl)Cl.[OH:35][NH2:36]>>[C:17]([O:16][C@H:8]1[C@H:7]([O:20][C:21](=[O:22])[CH3:23])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][CH2:10][C:9]1=[N:36][OH:35])(=[O:18])[CH3:19]
Reactant: NO
Reactant: CC(=O)OC[C@H]1OC=C(OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OCC(=NO)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
[litt=F. W. Lichtenthaler and P. Jarglis. Tetrahedron Letters 21 (1980) 1425-1428] To a solution of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal (7.90 g, 23.9 mmol) in dry pyridine (40 mL, 496 mmol), HONH2, HCl (5.85 g, 84.2 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated and dissolved in CHCl3 (300 mL). The organic phase was washed with 1 M HCl (aq., 75 mL), sat. aq. NaHCO3 (75 mL) and H2O (75 mL), dried (MgSO4) and evaporated to a syrup of 2, (7.19 g, 99%). By addition of a small volume of EtOH the product crystallysed (4.43 g, 61%, mp 86-89° C.). Two recrystallisations from toluene afforded an analytical sample: mp 90-92° C.; [α]D−39.4° (c 1.3, CHCl3) [Lit. mp 89-90° C., [α]D−39.0 (c 0.4, CHCl3)].
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:25]([NH:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:23])=[O:22])[C:26]([OH:28])=[O:27]
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)C(=O)O

Procedure:
In a manner similar to Example 3(b), 4-phenyl-piperidine hydrochloride was condensed with (R)-2-(4-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid to give the title compound, mp=163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:21]C(=O)OC(C)(C)C)[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)=[O:13])=[N:6][CH:7]=1.[ClH:29].CC1CCNCC1>>[ClH:29].[NH2:21][C@@H:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13]
Reactant: CC1CCN(C(=O)[C@H](CCCc2ccc(N)cn2)NC(=O)OC(C)(C)C)CC1
Agent: CC1CCNCC1
Agent: Cl
Product: CC1CCN(C(=O)[C@@H](N)CCCc2ccc(N)cn2)CC1

Procedure:
The same procedure as in Example 1.5 is used. Thus, starting with 1,1-dimethylethyl [(S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]carbamate (10.2 g; 26.0 mmol), 9.5 g of 1-[(2S)-2-amino-5-(5-aminopyrid-2-yl)-1-oxopentyl[-4-methylpiperidine hydrochloride are obtained in the form of a hygroscopic amorphous powder, which is used without further purification in the following step.