Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCC1C=NC(C)=NC=1.C(OC(OCC)CCCNC)C.[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH2:43][CH2:44][C:45]1[CH:46]=[N:47][C:48]([CH3:51])=[N:49][CH:50]=1)[CH:38]=[C:37]2[CH2:52][CH2:53][NH:54][CH3:55].C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH2:43][CH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[N:47][CH:46]=1)[C:38]1[CH2:55][N:54]([CH3:3])[CH2:53][CH2:52][C:37]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCc2cnc(C)nc2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cc1ncc(CCBr)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CCN(C)C3)cn1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 5-(2-bromoethyl)-2-methylpyrimidine, and triethylamine (General Method 1), 3,1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine (Example 1) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-(2-methylpyrimidin-5-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine (Example 10), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].[H][H]>[Pd].N1C=CC=CC=1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Agent: [Pd]
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2ccccc2F)cc1

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 29.6 g., was reduced in a Parr Instrument Company Series 3910 Low-Pressure Shaker-Type Apparatus, using 450 ml. of pyridine, and 0.3 g. of five percent palladium on barium sulfate; reduction was carried out at room temperature for 30 minutes and at an initial hydrogen pressure of 30 psig. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was vacuum distilled to give 20.5 g. of solid which was recrystallized from methanol to give 4-(2 -fluorophenyl)-1-vinylbenzene, mp 38°. The material contained traces of pyridine and 1-ethyl-4-(2-fluorophenyl)benzene, as shown by nuclear magnetic resonance analysis. The following elemental analysis was obtained:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH3:31]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:29][CH2:30][CH3:31])[S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: CCS(=O)(=O)NC1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to Example 11b, 7.5 g (20 mmol) of 6-benzyloxy-4-(ethylsulfonyl)amino-2,2-dimethylchroman (Example 11a) were introduced in portions at 10° C. into a suspension of 0.82 g (27 mmol) of sodium hydride (80% dispersion) in 100 ml of DMA. After stirring at RT for 2 h, 2.4 ml (26.2 mmol) of 1-propyl bromide were added dropwise. After work-up, the residue was chromatographed on silica gel using n-heptane/EA (1:1) and 6.0 g of product were crystallized from appropriate fractions using petroleum ether, m.p. 102-103° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])=[O:32].O>CN(C)C=O>[N+:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31](=[O:32])[CH2:30][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1=[O:1])([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)c2ccccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (100 mg) was added to a suspension of 60% sodium hydride (22 mg) in N,N-dimethylformamide (5 ml), the mixture was stirred at room temperature for 15 minutes. Subsequently, 2-bromo-2′-nitroacetophenone (102 mg) was added thereto, and stirred at room temperature for one hour. Water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration and collected by filtration, to thereby to obtain 76 mg of the title compound as a light yellow solid (Yield: 52%).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=O)C>C1COCC1>[CH3:20][CH:18]([Si:14]([CH:21]([CH3:23])[CH3:22])([O:13][C:9]1[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=1)[CH:15]([CH3:16])[CH3:17])[CH3:19]
Reactant: CC(=O)Oc1cccc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc(O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
An aqueous (50 ml) solution of NaOH (3.25 g, 81 mmol) was added to a solution of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate (5 g, 16.2 mmol) in THF (50 ml). After stirring overnight at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered, and evaporated under vacuum. The crude product was chromatographed over silica gel to yield 3.89 g (90%) of 3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenol. NMR 1H Cl3CD δ: 7.06 (t, 1H, J=8.0 Hz), 6.42 (m, 3H), 1.28 (m, 3H), 1.10 (d, 18H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=3[C:14]3[C:13]4[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=4[CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:9]5[CH:10]=[CH:11][C:12]6[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=6[C:14]=5[C:15]5[C:16]6[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=6[CH:18]=[CH:19][C:20]4=5)=[CH:4][CH:3]=3)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: Brc1ccc(-n2c3ccc4ccccc4c3c3c4ccccc4ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccc6ccccc6c5c5c6ccccc6ccc54)cc3)c3ccccc23)cc1
Yield: 54.6 %

Procedure:
In a 200 mL three-neck flask were placed 1.7 g (4.0 mmol) of 7-(4-bromophenyl)-7H-dibenzo[c,g]carbazole and 1.2 g (4.0 mmol) of 10-phenylanthracene-9-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene, 5.0 mL of ethanol, and 4.0 mL of an aqueous solution of sodium carbonate. This mixture was degassed by being stirred while the pressure was reduced. To this mixture was added 0.23 g (0.20 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 90° C. for 10 hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was removed by suction filtration. The collected solid was dissolved in about 50 mL of hot toluene, and this solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). A solid obtained by concentration of the filtrate was washed with toluene/hexane to give 1.3 g of a pale yellow powder, which was the object of the synthesis, in a yield of 55%. A synthesis scheme (d-2) of Step 4 is illustrated below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[Br-].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+].Cl.CCOCC>C1COCC1>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-n2nnc(-c3ccccn3)n2)cc1
Reactant: [Zn+]c1ccccn1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2ccc(-n3nnc(-c4ccccn4)n3)cc2)nc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of 2-[2-(4-bromophenyl)-2H-tetrazol-5-yl]pyridine (300 mg, 1 mmol), 2-pyridylzinc bromide (0.5M in THF, 2 mL) and tetrakis-(triphenylphosphine)palladium(0) (100 mg, 0.085 mmol) in anhydrous THF (10 mL) was degassed for 15 min and heated to 60° C. After 4 hours, a further equivalent of 2- pyridylzinc bromide (0.5M in THF, 2 mL) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was then quenched with brine (25 mL), extracted with EtOAc (3×25 mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was chromotographed on silica gel, eluting with EtOAc to afford a yellow solid. This was dissolved in anhydrous THF (10 mL) and HCl in ether (1.5 equiv) was added and the resulting precipitate was filtered to afford a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C(N(C(C)C)CC)(C)C.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Br)c(F)c1
Reaction time: 12 h

Procedure:
A stirred solution of 4-bromo-3-fluoro-aniline (120 g, 0.63 mol) and diisopropylethylamine (162 g, 1.26 mol) in acetonitrile (1.0 L) was heated to 60° C. and ethyl bromoacetate (105 g, 0.63 mol) was added dropwise within 2 h. The reaction mixture was stirred at this temperature for 12 h and was then evaporated to dryness. Water was added to the residue and the solid was filtered. Crystallization from petroleum ether and ethyl acetate (5:1) provided the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[NH:10][CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:12])[C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(C)c2cccs2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(NC(C)c2cccs2)c2cccc(N)c2)cc1
Yield: 85.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(2-thienyl)ethyl]amine (2.11 g) [prepared as described in step (a) above] in ethanol (40 ml), nickel chloride hexahydrate (2.71 g) and sodium borohydride (863 mg) were reacted, to afford the title compound (1.66 g) as a dark brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[N:41]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[N:41]1([CH2:47][CH2:48][NH:49][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: NCCN1CCOCC1
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCCN3CCOCC3)cc2OC)cc1O

Procedure:
Example 237 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and 2-morpholin-4-yl-ethylamine. Mass Spectrum: 648 (M+1).
Reaction SMILES: Cl.[CH3:2][C@:3]1([N:8]2[C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].O>C(Cl)Cl>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([C:16]2[C:11]3[CH2:10][CH2:9][N:8]([C@@:3]4([CH3:2])[CH2:7][CH2:6][N:5]([CH:31]5[CH2:35][CH2:34][NH:33][C:32]5=[O:36])[CH2:4]4)[C:12]=3[N:13]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:22][N:21]=1
Reactant: O=C1NCCC1Br
Reactant: C[C@]1(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[C@]1(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)CCN(C2CCNC2=O)C1
Yield: 47.8 %

Procedure:
To a stirred solution of the product of Example 4, Step 2, 5-{7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (320 mg, 0.764 mmol) and TEA (232 mg, 2.29 mmol) in DCM (16 mL) was added 3-bromo-pyrrolidin-2-one (188 mg, 1.15 mmol) at 25° C. The mixture was stirred at 40° C. for 3 days, whereupon water (10 mL) was added. The mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated to give a crude product (400 mg) as a yellow solid. The residue was purified by preparative TLC (silica gel, 10:1 DCM/MeOH) to give the racemic title compound (170 mg, 48%) as a yellow solid. This material was separated by preparative SFC column (AS, 250 mm×30 mm, 10 μm), mobile phase: 45% MeOH and NH3 in H2O, with a flowrate of 80 mL/min) to give the title compounds: Enantiomer 1 (Example 6), retention time 6.23 min (50 mg, 29%) as a yellow solid and enantiomer 2, retention time 6.21 min (19 mg) as a yellow solid. Enantiomer 1: SFC Retention time: 6.23 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.76-3.68 (m, 10 H), 3.43-3.33 (m, 5 H), 3.14-3.12 (m, 2 H), 3.05-3.00 (m, 1 H), 2.89-2.85 (m, 1 H), 2.56-2.53 (m, 1 H), 2.35-2.30 (m, 1 H), 2.14-2.10 (m, 1H), 2.00-1.95 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+. Enantiomer 2 (Example 7): SFC Retention time 6.21 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.82-3.68 (m, 12 H), 3.46-3.40 (m, 1 H), 3.36-3.33 (m, 1 H), 3.14-3.10 (m, 3 H), 3.03-3.00 (m, 1 H), 2.95-2.90 (m, 1 H), 2.54-2.51 (m, 1 H), 2.40-2.35 (m, 1 H), 2.14-2.11 (m, 1 H), 2.04-2.02 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2S(C)(=O)=O)C3)cc1
Temperature: 150 °C
Yield: 48.7 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.066 g, 0.23 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979), (0.088 g, 0.47 mmol) and N,N-diisopropylethlamine (0.041 mL, 0.23 mmol) was heated in a sealed tube via microwave (Emrys Optimizer model, Personal Chemistry) for 30 min at 150° C. The reaction mixture was cooled to r.t. and poured into water (20 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to leave an oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give the title compound as a white solid (0.049 g).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[N:8]=[CH:9][O:10][CH:11]=1)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[O:10]1[CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[N:8]=[CH:9]1
Reactant: CCOC(=O)C=Cc1cocn1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCCCc1cocn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a sol. of 3-oxazol-4-yl-acrylic acid ethyl ester (13.1 g, 90.5 mmol) in dry CH2Cl2 (50 mL) at −78° C. was added dropwise DIBAL (1M in hexane, 181 mL, 181 mmol). The reaction mixture was stirred at −78° C. for 1 h, then was allowed to warm slowly to rt while being stirred overnight. Aq. sat. potassium sodium tartrate was added, and the aq. phase was extracted three times with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. This crude product was purified by FC(CH2Cl2/MeOH; 49:1→48:2→47:3→46:4→45:5). To a sol. of this material in dry EtOH (120 mL) was added Pd on charcoal (10%, 700 mg), and the mixture was stirred at rt under H2 for 3 h. The mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. Drying the residue under high vacuum yielded the title compound (8.45 g, 73%). LC-MS: tR=0.45, ES+: 128.15.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5]>O1CCOCC1>[CH3:2][O:3][C:4]([CH:6]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:8][NH:7]1)=[O:5]
Reactant: COC(=O)C1CN(c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CN(c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4M HCl in dioxane solution (8 ml) was added in one portion to a stirred solution of 4-[6-(3,4-Dichloro-phenyl)-pyrimidin-4-yl]-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.36 g, 0.75 mmol) in dioxane (2 ml) and the mixture was stirred at room temperature overnight. After this time the reaction mixture was concentrated and the resulting residue was partitioned between DCM (100 ml) and saturated sodium bicarbonate (75 ml) and stirred at room temperature for 10 minutes. The mixture was then extracted with DCM (3×100 ml), the organic layers were combined, separated and washed with brine (50 ml). The organic layer was removed, dried (MgSO4) filtered and concentrated to give the title compound (0.27 g, 87% yield) as a yellow solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])=[O:5])[CH3:3].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[NH2:1][C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])=[O:5])[CH3:3].[F:42][C:41]([C:39]([OH:45])=[O:40])([F:44])[F:43]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
BOC-Ala-Gly-Thr(Bzl)-Pro-NH2 (10.5 g.) was added to TFA (35 ml.) at -5° C., and, after stirring for 30 minutes, concentrated in vacuo. The residue was treated with ethyl ether, and the precipitated material was filtered and dried in vacuo over sodium hydroxide to obtain H-Ala-Gly-Thr(Bzl)-Pro-NH2.TFA. THF (100 ml.) was added thereto, and triethylamine was added at -5° C. to adjust the pH to 5.0. BOC-Val-Gly-OH (5.49 g.) and HOBT (2.66 g.) were added thereto. To this mixture WSC (3.61 ml.) was added dropwise at -5° C., and the mixture stirred at -5° C. for 1 hour and at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in chloroform (300 ml.). The solution was washed twice with NaCl-saturated 1 N HCl (200 ml.), twice with NaCl saturated 5% sodium bicarbonate solution (200 ml.) and saturated NaCl solution (75 ml.) in this order. After the solution was dried with anhydrous sodium sulfate, the organic layer was concentrated in vacuo. Recrystallization from methanol - ethyl ether gave BOC-Val-Gly-Ala-Gly-Thr(Bzl)-Pro-NH2 (12.0 g., Yield: 88.3%). m.p.: 121° - 135° C. (decomp.). TLC: one spot. (solvent system 6).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([NH:32][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCC1CO1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCCCCCCCC(O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of 1,2-epoxydodecane (1.84 g, 10.0 mmol) in anhydrous acetonitrile (5 mL) is added anhydrous magnesium perchlorate (2.23 g, 10.0 mmol). After 15 minutes, benzylamine (1.1 mL, 10.0 mmol) is added dropwise and the solution is stirred for 50 hours at room temperature. The mixture is concentrated, diluted with water, and extracted twice with ethyl acetate. The combined organic extracts are washed with water, brine, dried over magnesium sulfate, and concentrated to afford 2.9 g of the title compound as a white solid; 1H NMR (200 MHz, CDCl3)δ7.38-7.25 (m, 5 H), 3.87 (d, J=2 Hz, 2 H), 3.80-3.65 (m, 1 H), 3.00-2.75 (m, 3 H), 2.60-2.45 (m, 1 H), 1.40-1.20 (m, 18 H), 0.88 (t, J=7 Hz, 3 H).