Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[CH3:13].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH2:22].N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH:22][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([CH3:12])[C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1
Reactant: Nc1cnc(Cl)cc1Cl
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
With ice cooling, 1.20 g of 4-methoxy-3,5-dimethylbenzoyl chloride, dissolved in 1 ml of dry dichloromethane were initially added dropwise to a solution of 0.82 g of 4,6-dichloropyridin-3-ylamine in 8 ml of dry dichloromethane. A solution of 0.4 ml of absolute pyridine in 1 ml of dry dichloromethane was then added, and the reaction was stirred at 0° C. for 2 h, the product partially precipitating slowly. Approx. 10 ml of 10% strength aqueous sodium bisulfate solution were then added, and the mixture was stirred for five minutes. The aqueous phase was then decanted off and the solid-containing organic phase was concentrated under reduced pressure and freeze-dried. This gave 1.63 g (100%) of the product, which was used for the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:28][C:26]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)=[O:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: NC(=O)Nc1ccc(F)cc1
Product: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccc(F)cc3)ccc2c1O

Procedure:
7-[3-(4-Fluoro-phenyl)-ureido]-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-Fluorophenylurea. MS ESI(+) m/e: 370.0130 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.CCN(CC)CC.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) To a mixture of (2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-yl)methanamine (50 mg, 141 μmol) and Et3N (300 μl, 2152 μmol) in DCM (5 mL) was added pivaloyl chloride (100 μL, 813 μmol). The solution was stirred at rt for 1 h. The mixture was partitioned between DCM (10 mL) and aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica with 1-5% (2N NH3-MeOH) in DCM to give the product as a yellow solid after concentration (20 mg, 32%). LCMS (ESI, pos. ion): calc'd for C24H27ClN4O2:438.2; found: 439.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.21-1.28 (m, 12 H) 3.19-3.35 (m, 4 H) 3.95-4.08 (m, 4 H) 4.58 (d, J=6.06 Hz, 2 H) 6.37 (br. s., 1 H) 6.93 (d, J=4.89 Hz, 1 H) 7.83 (dd, J=8.90, 1.66 Hz, 1 H) 8.00 (d, J=2.15 Hz, 1 H) 8.10-8.25 (m, 5 H) 8.61 (d, J=2.15 Hz, 2 H) 8.79 (d, J=4.89 Hz, 2 H)
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH2:19][CH:20]([OH:24])[C:21]([OH:23])=O)=[O:17])=[CH:10]2>>[OH:24][CH:20]([C:21](=[O:23])[N:3]([O:4][CH3:5])[CH3:2])[CH2:19][NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17]
Reactant: O=C(NCC(O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 69 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.0 mmol) and 3-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2RS)-hydroxy-propionic acid (0.95 mmol) were coupled according to Procedure A (0-25° C., washed with acid, then base) and the crude product triturated with ether giving a colorless solid: Yield 69%; HPLC (60/40) 3.18 minutes (96%); mp 192-192.5° C.; PBMS 326/328 (MH+,100%);
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH2:36][CH:37]([CH:47]([CH3:49])[CH3:48])[CH2:38][O:39][Si](C(C)(C)C)(C)C>>[OH:39][CH2:38][CH:37]([NH:36][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH:47]([CH3:48])[CH3:49]
Reactant: CC(C)C(N)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)C(CO)NC(=O)SCCN
Yield: 417.1 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (0.58 g) and 2-amino-1-tert-butyldimethylsilyloxy-3-methylbutane (acetate: 0.52 g) were subjected to the reactions described in References 2 and 4 to give 2-(1-hydroxymethyl-2-methylpropyl)aminocarbonylthioethylamine (formate: 1.03 g). The product (0.83 g) was dissolved in anhydrous methanol (10 ml), to which were then added triethylamine (0.91 ml) and mitomycin A (372 mg: 0.82 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 48 (290 mg) in the form of grayish blue powders with a yield of 52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: CCCN[C@@H]1CCc2cccc(OC)c2C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(C(=O)Cc1cccs1)[C@@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 39 mg (0.18 mmol) enantiomerical pure (R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe) and 0.05 mL (0.41 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34].O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(NC(=O)CCCCCNC(=O)OCc2ccccc2)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)CCCCCNC(=O)OCc1ccccc1)c1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound (961 mg) obtained in Example 48-1 was dissolved in DMF (20 ml). After having been cooled to 0° C., the solution was added with 60% sodium hydride (72.9 mg) and warmed back to room temperature and the whole was stirred for 30 minutes. 1-Iodopropane (0.30 ml) was dropped to the solution and the whole was stirred for additional 3 hours. After having been cooled to 0° C., the solution was added with water to stop the reaction and concentrated. The residue was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (317 mg) as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 33.7 %

Procedure:
A solution of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a (2.8 g, 9.9 mmol) in anhydrous DMF (10 mL) was treated with 60% dispersion of NaH in mineral oil (0.5 g, 13 mmol) while stirring under nitrogen. After effervescence the reaction was stirred for an additional 30 minutes. At this time the reaction was treated with MeI (0.98 g, 7 mmol) and continued to stir under nitrogen for 2 hours. Water (50 mL) was added slowly and the mixture was filtered and then concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate to afford 142a (0.7 g, 24%), which was used directly without further purification. LCMS: (M+H)+ 297.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>C(#N)C.C(N(CC)CC)C>[CH2:49]([CH:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:48][CH2:47]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCC(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a suspension of 2.19 g (6.86 mM) of 1-(4-aminobutan-1-yl)-4-benzylpiperidine dihydrochloride and 3.87 ml (27.8 mM) of triethylamine m in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.[CH2:26]([Li])CCC.IC>>[ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([CH3:26])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: [Li]CCCC
Agent: Cl
Agent: [Li]C
Solvent: CI
Product: Cc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Yield: 11.4 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.350 g, 0.930 mmol), MeLi (0.639 mL, 1.02 mmol), butyllithium (0.409 mL, 1.02 mmol), and iodomethane (0.165 g, 1.16 mmol) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-methyl-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.037 g, 12.8% yield). 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 7.60 (m, 2H), 7.54 (s, 1H), 7.42 (m, 2H), 7.37 (m, 1H), 6.84 (s, 1H), 5.32 (s, 2H), 2.32 (s, 3H), 2.29 (s, 3H). Mass spectrum (apci) m/z=312.1 (M+H-HCl).
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].[CH3:20][C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>C(N(CC)CC)C>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][C:29](=[O:30])[NH:28][C:22]3[CH:23]=[CH:24][C:25]([Br:27])=[CH:26][C:21]=3[CH3:20])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: Cc1cc(Br)ccc1N=C=O
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Solvent: CCN(CC)CC
Product: C#CCN1CCC(OC(=O)Nc2ccc(Br)cc2C)N(c2nnc(S(C)=O)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 2-methyl-4-bromophenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-[N-(2-methyl-4-bromophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:25]=[C:26]([C:27]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:28])[CH:30]=[CH:31][CH:32]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1
Reactant: C1CCNC1
Product: O=C(c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1)N1CCCC1

Procedure:
Example 96 (E96) was prepared from pyrrolidine and 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid (E95) using the procedure outlined for Example 90 (E90); MS (ES+), m/e 419 [M+H]+.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[S:32]([O:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)([C:29]1[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C/C(=N\O)c1ccccc1O2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O/N=C2\CC3(CCN(C(=O)OC(C)(C)C)CC3)Oc3ccccc32)cc1
Yield: 81.6 %

Procedure:
A mixture of tert-butyl (4E)-4-hydroxyiminospiro[chromane-2,4′-piperidine]-1′-carboxylate (448 mg, 1.34 mmol) and 4-methylbenzenesulfonyl chloride (514 mg, 2.70 mmol) were stirred in pyridine (2.1 mL) at 0° C. for 6 hours. The reaction mixture was poured over ice and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to give (E)-tert-butyl 4-(tosyloxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (532 mg, 81%). ESI-MS m/z calc. 486.2, found 487.5 (M+1)+; Retention time: 2.20 minutes (3 min run).
Reaction SMILES: Br[C@H:2]([C@H:7]([CH2:9]Br)[OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CN(C)C=O.C(OCC)(=O)C.[I-].[K+]>[C:11]([O:14][CH2:9][C@@H:7]1[O:8][C@@H:2]1[C:3]([O:5][CH3:6])=[O:4])(=[O:13])[CH3:12]
Reactant: COC(=O)[C@H](Br)[C@@H](O)CBr
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1O[C@H]1COC(C)=O
Temperature: 52.5 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
The general procedure of Manchand, et. al. (Manchand, et al., 1988) is employed. Methyl 2,4-dibromo-2,4-dideoxy-L-threonate (131 g, 474 mmol) is added to a stirred solution of potassium acetate (102 g, 1.04 mol) and potassium iodide (3.94 g, 23.8 mmol) in dimethyl formamide (500 mL). This mixture is stirred under nitrogen gas at 50-55° C. for 4 hours and overnight at room temperature. The reaction mixture is diluted with ethyl acetate (1 L) and filtered. The filter cake is washed with ethyl acetate (250 mL). The combined ethyl acetate portion is washed with saturated sodium bicarbonate solution (500 mL) and saturated brine (2×500 mL) and dried over magnesium sulfate. The solvent is removed to yield the title compound as a dark oil (82.0 g, 99% theoretical yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([NH:7][C:8](=[NH:11])[O:9][CH3:10])[CH2:3][CH2:2]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([NH:7][C:8](=[N:11][C:14](=[O:15])[CH2:13][Cl:12])[O:9][CH3:10])[CH2:3][CH2:2]1
Reactant: COC(=N)NN1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=NC(=O)CCl)NN1CCOCC1
Yield: 98.4 %

Procedure:
Following the procedure of Example IB, 7.2 g (0.05 mole) of the above isourea, 5.65 g (0.05 mole) of chloroacetyl chloride, 5.05 g (0.05 mole) of triethyl amine and 150 ml of tetrahydrofuran were combined to yield 11.6 g of N-morpholino-N'-(chloroacetyl)-O-methylisourea, nD30 1.4853.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[C:32]([CH3:33])=[N:31][CH:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[C:32]([CH3:33])=[N:31][CH:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.90 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]([NH2:8])[CH2:6][CH3:7].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[CH3:2][O:3][CH2:4][CH:5]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([CH2:17][CH2:16][O:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH:19]=1)[CH2:6][CH3:7]
Reactant: CC[C@H](N)COC
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Agent: Cl
Product: CCC(COC)NCc1cccc(CCOC2CCCCO2)c1

Procedure:
The sub-titled compound was prepared from (S)-1-methoxymethyl-propylamine hydrochloride (0.36 g) and 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (Example 50, step a, 0.5 g) using the method of Example 75, step b. Yield 0.6 g.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:14]1([S:20]([CH2:23][CH2:24][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CCn1c2ccccc2c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.8 g 9H-carbazole and 9.8 g phenylvinylsulphone are suspended in 3 ml of tetrahydrofuran, cooled to 0° C., combined with 60 μl benzyltrimethylammonium hydroxide (40% solution in water) and stirred for 20 minutes. Then the mixture is heated to 115° C. for 7 hours. Then it is divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][C:3]=1[F:29].[Cu][C:31]#[N:32].CN1C(=O)CCC1.Cl>O>[C:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:13]=2)=[CH:4][C:3]=1[F:29])#[N:32]
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)c(F)c4)nc3)cc2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.5 g (0.008 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 1.1 g (0.012 mol) of copper (I) cyanide were added to 31 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.2 g of FeC13.6H2 o, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was maintained on a warm water bath at 60° C. for one hour. The crystals deposited were filtered, washed with water and treated through a silica gel column with chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from acetone to yield 1.9 g (0.005 mol) of 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine. The phase transition temperature of this compound measured by DSC, was: ##STR32##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C:45](=[NH:62])[NH:46][CH2:47][CH2:48][CH2:49][C@@H:50]([C:59]([OH:61])=O)[NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:77])[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>CN(C=O)C>[CH2:70]([O:69][C:68](=[O:77])[NH:67][CH2:66][CH2:65][NH:64][C:59](=[O:61])[C@H:50]([CH2:49][CH2:48][CH2:47][NH:46][C:45]([NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])=[NH:62])[NH:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
419.3 mg (1.1 mmol) of HATU and 258.5 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 408.4 mg (1 mmol) of N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 253.76 mg (1.1 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.