Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])=[CH:26][CH:25]=2)[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([O:8][C:9]([C:11]1([N:16]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:53][N:52]=[N:51][N:37]=3)=[CH:26][CH:25]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCC1
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCC1

Procedure:
A mixture of 3.2 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine, 3.3 g (9.8 mmol) of tributyltin azide and 35 ml of o-xylene is heated to reflux for 24 hours. Working-up of the mixture in a manner analogous to that described in Example 23 yields the N-(1-benzyloxycarbonylcyclopentyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of a yellow oil [Rf : 0.37 (system S2)], which can be used for further reactions in crude form.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[F:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1.CCCCCC>[F:14][C:15]1[C:20]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: Fc1cnccn1
Reactant: O=C1CCOCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of nbuli (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) was first cooled to −78° C. To the cooled solution was added dropwise, 2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bath was then switched to a 0° C. bath. The reaction mixture was stirred for 10 min at 0° C. and then the dry ice bath was switched back to recool the reaction mixture to −78° C. To the cooled solution was added 2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at −78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol) in 0.6 mL of THF was added dropwise. The resulting mixture was allowed to gradually warm to room temperature overnight. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Purification by Biotage (0-100% EtOAc/hexane) produced product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(Cl)Cl.O1CCOCC1>[ClH:23].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1Cc2ccccc2C12CCNCC2
Yield: 75 %

Procedure:
295 mg (0.92 mmole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine]-2-oxide [prepared as described in step (a) above] were dissolved in 3 ml of methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added, whilst ice-cooling. The mixture was stirred, whilst ice-cooling, for 1 hour, and then the crystals which deposited were collected by filtration, to give 173 mg (yield 75%) of the title compound as white crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=2)[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25]1.O>CN(C=O)C.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.[Cu]I>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=2)[C:26]([C:2]2[N:7]=[C:6]3[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]3=[N:4][CH:3]=2)=[N:25]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(F)(F)F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C(F)(F)F)ccc34)nc12
Temperature: 90 °C
Yield: 50.4 %

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (0.3 g, 0.81 mmol), 1-methyl-3-(tributylstannyl)-6-(trifluoromethyl)-1H-indazole (0.98 g, 1.51 mmol), Pd(PPh3)4 (174 mg, 0.151 mmol) and CuI (58 mg, 0.302 mmol) in dry DMF (10 mL) was heated to 90° C. for 3 hours. Water (10 mL) was added. The formed precipitate was separated by filtration, washed with petroleum ether (3 mL) to afford methyl 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (200 mg, 50%) as a white solid. LCMS: (M+H)+=490.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([O:14][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:13])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 2(S)-(p-toluenesulfonyloxy)propionic acid (4.4 g) to a cold solution of 10 ml of isobutylene and 0.4 ml of concentrated sulfuric acid in 30 ml of methylene chloride in a pressure vessel, seal, and agitate at room temperature for 48 hours. Pour into 50 ml of 15% sodium carbonate solution, dry over magnesium sulfate and concentrate to obtain t-butyl 2(S)-(p-toluenesulfonyloxy)propionate as an oil (NMR δ1.37). Distilled material (Kugelrohr, 120°) has [α]D26 =-45.9° (EtOH, c=1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[F:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:32])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(F)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-fluoro-1H-indol-3-yl)acetic acid in step 12 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 12 (B), the title compound was prepared. MS (ESI) (M+H)+=449.95 1H-NMR (500 MHz, CD3OD) δ 7.45 (s, 2 H), 7.32-7.41 (m, 2 H), 7.24 (dd, J=9.77, 2.44 Hz, 1 H), 6.84-7.02 (m, 1 H), 4.54 (s, 2 H), 3.95 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29](O)=[O:30])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:41][CH2:42][CH2:43][NH2:44])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([NH:6][C@H:7]([C:29]([NH:44][CH2:43][CH2:42][S:41][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: NCCSC(=O)c1ccccc1
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-benzoylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 70%). 17 is collected in the form of a foam which, after trituration in hexane, provides a colorless foam (Yd=77%). Rf (CH2Cl2/ether, 6/4):0.76. [α]D20=+7.8° (c 1.03, CHCl3).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(O)cc1

Procedure:
The catalytic reduction was carried out in the same manner as in Example 1 except that the water-containing acetic acid was employed in an amount of 3 times (Example 15) or 8.8 times (Example 16) the weight of 4-hydroxymandelic acid. The yields of 4-hydroxyphenylacetic acid were 78% by mole (Example 15) and 95% by mole (Example 16).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (8.5 g), water (30 mL) and sodium bicarbonate (10.5 g). The mixture was heated to about 90-100° C. and maintained at the same temperature for about 8-9 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 25-30° C. followed by addition of water (100 mL) and toluene (50 mL). The mixture was stirred for about 20 minutes and layers were separated. The organic layer was washed with water (50 mL). The organic layer was separated and subjected to complete distillation under vacuum at 60-65° C. followed by cooling to room temperature and subsequent addition of n-heptane (75 mL). The mixture was stirred for about 2 hours followed by isolation of solid by filtration and washing with n-heptane (10 mL). The solid isolated was subjected to drying under vacuum at 60-65° C. for 1 hour to afford the title compound in about 80% yield having HPLC purity of about 99.03%.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13]([CH:15]1[CH2:20][C:19]([C:36]#[N:37])([C:21]2[C:29]3[C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[O:26][C:25]=3[C:24]([O:34][CH3:35])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16]1=O)=O>CO>[CH3:35][O:34][C:24]1[C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[C:21]([C:19]2([C:36]#[N:37])[CH2:18][CH2:17][C:16]3[N:10]=[CH:8][NH:9][C:13](=[O:12])[C:15]=3[CH2:20]2)=[CH:22][CH:23]=1
Reactant: N=CN
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a stirred solution of sodium methoxide (185.3 mg, 3.5 mmol) in 10 ml of methanol was added formamidine acetate (290 mg, 2.78 mmol) and the compound obtained in example 1. The reaction mass was allowed to stir at 60-70° C. for 18 hrs under nitrogen atmosphere. Most of the methanol was evaporated under vacuum and residue was purified by column chromatography to get 200 mg (67.3% yields) of the product.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:18][CH:17]=2)[CH2:12][C:11]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCN([S+](F)F)CC.[FH:65].[FH:66].F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:18][CH:17]=2)[CH2:12][C:11]1([F:66])[F:65])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@H]3CC[C@H](OC(=O)c4ccccc4)C(=O)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(OC(=O)c4ccccc4)C(F)(F)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Yield: 87.2 %

Procedure:
To a solution of tert-butyl 4-(6-((1S,45)-4-(benzoyloxy)-3-oxocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (730 mg, 1.034 mmol) in DCM (7 mL) at RT was added XtalFlour-E (939 mg, 4.14 mmol) followed by triethylamine trihydrofluoride (0.674 mL, 4.14 mmol). The resultant mixture was stirred at RT for 5 hours. The mixture was filtered and the filtered solution was directly applied for ISCO separation: 24 g silica gel, 0 to 70% EtOAc in Heptane, 30 min. A light yellow solid (670 mg, 0.902 mmol, 87% yield) was obtained. LC-MS (m/z): (MH+) 728.0 at 0.95 min (non-polar MS method). 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 2H) 1.19-1.39 (m, 21H) 1.48-1.68 (m, 11H) 1.86-2.08 (m, 2H) 2.08-2.21 (m, 1H) 2.26-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.21-3.44 (m, 1H) 5.22-5.51 (m, 1H) 7.41-7.55 (m, 4H) 7.60 (s, 1H) 7.96 (d, J=7.82 Hz, 1H) 8.06-8.19 (m, 2H) 8.42 (s, 1H).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].CN1CCCC1=O.[Cl:16][C:17](Cl)=[CH:18][C:19]([CH3:24])([CH3:23])[CH:20]([CH3:22])[CH3:21]>C(Cl)Cl>[Cl:16][CH:17]=[C:18]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]([CH3:24])([CH3:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(C)(C)C=C(Cl)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)C(C)(C)C(=CCl)Oc1ccccc1
Temperature: 200 °C
Yield: 70.6 %

Procedure:
487 g of sodium phenolate are introduced into 1.6 liters of N-methylpyrrolidone at about 100° C., and dissolved by heating the mixture to 200° C. 360 g (2 mols) of 1,1-dichloro-3,3,4-trimethyl-pent-1-ene are added dropwise in the course of 3 hours at a rate such that the temperature of the reaction mixture does not fall below 195° C. Thereafter, the mixture is heated at 200°-210° C. for 8 hours. Working-up is carried out by diluting the solution with methylene chloride and extracting it by shaking withh dilute sodium hydroxide solution. After drying and stripping off the solvent, 406 g of crude product remain, this product being distilled at 105°-120° C./0.1 mbar. 337 g (71% of theory) of 1-chloro-2-phenoxy-3,3,4-trimethyl-pent-1-ene are obtained. ##STR18##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[CH2:15]2)[N:7]=1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(N(C)C)nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)n1
Temperature: 160 °C
Yield: 87.1 %

Procedure:
A mixture of 2-chloro-4-dimethylamino-6-methylpyrimidine (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.38 g), triethylamine (0.30 g), and isopropanol (2.9 mL) was heated at 160° C. in a microwave reaction apparatus for 3.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=95:5) to obtain 1-((S)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.43 g). (2) 1-((S)-3-(4-Dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone obtained in (1) was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.58 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diisopropyl ether to obtain the title compound (0.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.O1CCOCC1>C(OCC)(=O)C>[NH2:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Cn1cc(Br)cc(N=C(c2ccccc2)c2ccccc2)c1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(Br)cc(N)c1=O
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 5-bromo-3-(diphenylmethyleneamino)-1-methylpyridin-2(1H)-one (3.82 g, 10.4 mmol) in ethyl acetate (10 mL) was added 4 MHCl/dioxane (7.8 mL, 31.3 mmol). The reaction mixture was stirred for 0.5 h and concentrated under reduced pressure. The residue was washed with tert-butyl methyl ether and filtered. The solid was dissolved in ethyl acetate (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to between 7 and 8 by adding K2CO3 gradually. The water phase was separated and extracted with dichloromethane for three times. The combined organic layer was concentrated under reduced pressure to afford 325a as a yellow solid (1.1 g, 52%). MS-ESI: [M+H]+ 202.9.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:20]=[CH:19][C:11]([N:12]([CH2:16][CH2:17]I)[CH2:13][CH2:14]I)=[CH:10][CH:9]=1.[Br:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:38])[N:28]2C(OC(C)(C)C)=O)=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:21][C:22]1[CH:30]=[C:29]2[NH:28][C:27](=[O:38])[C:26]3([CH2:17][CH2:16][N:12]([C:11]4[CH:19]=[CH:20][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Reactant: Clc1ccc(N(CCI)CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Br)ccc2C12CCN(c1ccc(Cl)cc1)CC2
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.6 %

Procedure:
Cesium carbonate (2.09 g, 6.4 mmol) was added in portions over 5 mins to a solution of 4-chloro-N,N-bis(2-iodoethyl)aniline (preparation 14c, 0.73 g, 1.68 mmol) and tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (preparation 8a, 0.50 g, 1.60 mmol) in N,N′-dimethylformamide (20 mL) was added and the mixture was stirred for 48 hours. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was taken up in 1,4-dioxane (15 mL) and 5M aqueous hydrochloric acid (5 mL) and the mixture was stirred and heated to 70° C. After 30 minutes, the mixture was evaporated and partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was combined with an insoluble solid which separated and the mixture was evaporated. The residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (0.11 g, 17%) as a pink solid.
Reaction SMILES: [F:1][C:2]1([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C=O)C>[O:32]=[C:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27](=[O:37])[N:31]1[CH2:15][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C

Procedure:
To a solution of 3-2 (6.78 g, 17.5 mmol) in 70 mL DMF was added potassium phthalimide (4.21 g, 22.7 mmol) and the mixture was heated at 150° C. for 2.5 h. The mixture was allowed to cool to ambient temperature, poured into H2O (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo, giving 11.0 g of crude 3-3 as a tan solid. 1H NMR (CDCl3, 300 MHz): 7.85 (dd, J=5.4, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.0 Hz, 2H), 3.96 (br, 2H), 3.04 (m, 2H), 1.70 (m, 6H), 1.43 (s, 9H); MS (Electrospray): m/z 385.2 (M+Na), 347.3 (M−Me+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([CH2:36][OH:37])[C:27]=1[CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].O>CN(C=O)C>[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([CH2:36][O:37][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([O:10][CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=2)[C:27]=1[CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cc(Cl)c(OCC2CCOCC2)nc1Cl
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COc2nc(OCC3CCOCC3)c(Cl)cc2Cl)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
2,3,5-trichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (214 mg) and [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (222 mg) were dissolved in DMF (5 mL), and 60% sodium hydride (40 mg) was added thereto, followed by stirring at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (80 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-2-({[3,5-dichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-2-yl]oxy}methyl)-3-methylquinoline (250 mg).