Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]2[C@@H:11]([CH2:12][CH3:13])[CH2:14][O:15][C:29]2=[O:31])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:19]([CH3:26])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=1[CH3:24]
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H]1COC(=O)N1c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester (106 mg, 0.27 mmol), triphosgene )27 mg, 0.090 mmol), triethylamine (27 mg, 0.27 mmol) in dry THF was stirred at room temperature for 2 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, arid concentrated to dryness to give 13.6 g of crude product as a white glass foam. The foam was triturated with hexane/diethyl ether to give a white solid, mp. 144-145.5° C., Anal. For C21H23ClN2O5 calc.: C, 60.22; H, 5.53; N, 6.69; found: C, 60.10, H, 5.79; N, 6.66.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].Cl.[NH2:25][OH:26].C(=O)(O)[O-].[Na+]>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:25][OH:26])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(C=NO)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) in methanol (5 ml) were added hydroxylamine hydrochloride (90 mg) and sodium bicarbonate (106 mg). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (6:4:1, v/v) to afford 6,9-dihydroxy-4-hydroxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (105 mg).
Reaction SMILES: CN(C)C=O.[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>O>[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([S:26][C:24](=[O:27])[CH3:25])[CH2:14]1)([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
2.7 l of dimethylformamide are placed in a reactor under inert atmosphere. 251.4 g of N-BOC-3(R,S)-methylsulfonyloxy-piperidine are added with warming. At an internal temperature of 50° C. 256.8 g of potassium thioacetate are added at once. After stirring for 90 min at 95° C. the reaction mixture is transferred into a reactor filled with 4 l of water. 4.2 l of petroleum ether are added. After vigorous stirring for 5 minutes the aqueous phase is removed. After readdition of water the pH is adjusted to >8 with sodium hydroxide. The organic phase is separated, washed with water and treated with active charcoal. The solution is evaporated to dryness. After flash chromatography on silica with petroleum ether, toluene, and ethyl acetate and concentration of the product containing solution crystallization occurs on cooling and 110 g of N-BOC-3(R,S)-acetylthio-piperidine are obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[CH3:22][N:23]([CH3:38])[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[S:34](Cl)(=[O:36])=[O:35].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:34]([C:29]1[C:30]2[C:25](=[C:24]([N:23]([CH3:38])[CH3:22])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=1)(=[O:36])=[O:35])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCN=[N+]=[N-])cccc12
Yield: 86 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.321 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.241 g, 2.38 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (0.328 g, 86%). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, 1H), δ 8.28 (d, 1H), δ 8.22 (d, 1H), δ 7.53 (t, 1H), δ 7.50 (t, 1H), δ 7.17 (d, 1H), δ 5.58 (t, 1H), δ 3.28 (t, 2H), δ 3.03 (q, 2H), δ 2.85 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 152.3, 134.8, 130.9, 130.1, 129.7, 128.9, 123.4, 118.9, 115.6, 51.0, 45.6, 42.6 ppm; HRMS (ESI) calcd for C14H17N5O2S (M+) 319.1103. Found 319.1104.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:15]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: OO
Reactant: N#Cc1cccc(-c2ccccn2)c1
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2cccc[n+]2[O-])c1

Procedure:
Starting from 2-(3-cyanophenyl)-pyridine, the title compound is prepared by oxidation with H2O2 in glacial acetic acid [J. Heterocycl. Chem. 11, 299 (1974)].
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][CH2:47][F:48]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:46][CH2:47][F:48])[CH:21]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: FCCCBr
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OCCCF)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 77.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (520 mg, 0.99 mmol) in DMF (9 mL) and add cesium carbonate (1.9 g, 5.9 mmol) and 1-bromo-3-fluoro-propane (170 mg, 1.19 mmol). Stir the mixture at ambient temperature for 19.5 hours and dilute with EtOAc. Wash with brine, dry over sodium sulfate, filter, and concentrate the organic to residue. Purify the residue by silica gel chromatography (30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-[3-(3-fluoro-propoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (447 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J=7.9 Hz, 1H), 8.01 (dd, J=7.7, 7.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.13 (dd, J=7.9, 7.9 Hz, 1H), 6.82-6.70 (m, 3H), 5.18 (dd, J=9.7, 6.6 Hz, 1H), 4.58 (t, J=5.9 Hz, 1H), 4.46 (t, J=5.9 Hz, 1H), 4.02-3.88 (m, 2H), 3.47-3.39 (m, 1H), 2.96 (d, J=3.5 Hz, 1H), 2.73-2.63 (m, 1H), 2.06-1.92 (m, 2H), 1.63 (dd, J=22.0, 10.5 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z: 584.0 (M+H)+, Tr=3.61 min., method 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@@H:13]([N:17]([CH3:19])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]([CH3:38])=[N:24]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:18][N:17]([CH3:19])[C@@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:26]2[C:25]([CH3:38])=[N:24][N:23]([CH3:22])[C:27]=2[CH3:28])[CH2:12]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)[C@@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@@H](N(C)C)C2
Reaction time: 2 h

Procedure:
(6R)-6-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (2.5 g, 7.731 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (2.10 g, 8.893 mmol) and Pd(PPh3)4 (1.2 g, 1.038 mmol) were added to a solution of K2CO3 (2.15 g, 15.556 mmol) in a mixture of 1,2-dimethoxyethane (60 mL) and H2O (8 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 2 h. It was allowed to reach room temperature, diluted with H2O (200 mL) and extracted with AcOEt (1×400 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (200 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×300 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 1.45 g of the coupling product (Rf=0.2 (10% Et3N/AcOEt), colorless oil, 66% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]>CN(C)C=O.O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][C:18]([Br:1])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]
Reactant: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(NC(N)=O)c(C(N)=O)c2cc1Br
Reaction time: 1.5 h
Yield: 30 %

Procedure:
Under ice-cooling, a solution of N-bromosuccinimide (94 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added to a solution of 2-aminocarbonylamino-6-methoxyindole-3-carboxamide (Compound No.1-1, 126 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) and the mixture was stirred for 1.5 hours. Moreover the whole was stirred for 2 hours at room temperature and stirred for 3 hours at 50° C. After the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (50 mL), the organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the obtained solid was filtered off and washed with a mixed solvent of diethyl ether-chloroform solution (5:1, 24 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (50 mg) as a gray solid (30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[CH:35]=[CH2:36]>CO.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:36][CH2:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (200 mg) in methanol (0.3 mL) and dichloromethane (0.3 mL) was added a solution of t-butyl acrylate (1.80 mL; 1.57 g) in methanol (0.8 mL) and dichloromethane (0.4 mL) in 1 min. The reaction was heated to 70° C. for 24 hr. The reaction was cooled to room temperature and concentrated. The resulting residue was purified by silica column (ISCO) (5% MeOH/CH2Cl2) to yield tert-butyl 3-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)propanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccccc4)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)NCc3ccccc3)C2)n1
Temperature: 150 °C
Yield: 14.9 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(phenylmethyl)-3-piperidinecarboxamide (190 mg, 0.441 mmol), 3 mL of EtOH, Hunig's base (0.308 ml, 1.761 mmol), and hydrazine anhydrous (0.083 ml, 2.64 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and EtOAc was used to triturate, affording the title compound (29 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.31-1.52 (m, 1H), 1.61-1.81 (m, 2H), 1.86-2.04 (m, 1H), 2.29-2.45 (m, 1H), 2.77-3.05 (m, 2H), 4.17-4.25 (m, 1H), 4.31-4.69 (m, 3H), 5.38 (s, 2H), 6.09 (s, 2H), 6.58-6.70 (m, 1H), 7.17-7.39 (m, 5H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.96 (s, 1H), 8.46 (t, J=5.9 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18](O)=[O:19])[CH:11]=[CH:10]2.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18]([Cl:3])=[O:19])[CH:11]=[CH:10]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Yield: 88.7 %

Procedure:
Compound 2 was prepared from the corresponding carboxylic acid. Thionyl chloride (1.24 g, 10.42 mmoles) was added to a solution of (S)-(+)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (Naproxen, 2 g, 8.69 mmoles) in 8.2 mL chloroform in a round bottom flask equipped with magnetic stirring. A drop of DMF was added and the mixture was refluxed for 3 hours. Chloroform and excess thionyl chloride were distilled from the reaction mixture while methylene chloride was added. Evaporation of residual solvent yielded (S)-2-(6-methoxy-naphthalen-2-yl)-propionyl chloride (1.918 g, 88.8% yield). Rf=0.2 (1:1 hexanes:ethyl ether). 1H NMR (400 MHz, CDCl3) δ 9.98 (br, 1H), 7.78 (t, 2H), 7.36 (d, 1H), 7.18 (d, 1H), 7.14 (m, 2H), 4.25 (q, 1H), 3.93 (s, 3H), 1.68 (d, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[Cl:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20]([OH:30])=[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]3=[N:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:30])[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]=3[N:23]([CH2:8][CH3:9])[CH:24]=2)=[O:18])=[CH:31][CH:32]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (0.87 g) and iodoethane (0.5 mL) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (2.0 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (60 mL). The reaction mixture is stirred at room temperature for 18 h. The mixture is diluted with water (150 mL) and filtered. The resulting white powder is washed with water (15 mL) followed by diethyl ether (15 mL) and dried in a vacuum oven to afford 1.64 g of the title compound as a white solid. Physical characteristics. M.p. 169-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.65, 8.74, 7.37, 7.29, 5.81, 4.70, 4.54, 4.32, 1.44. HRMS (FAB) m/z 377.0720 (M+H)+. Anal. Found. C, 56.87; H, 4.77; N, 7.38; Cl, 9.35; S, 8.44.
Reaction SMILES: CC1C=C(C=C(C)C=1)C([N:7](C)[C@:8](C)([C:21]([OH:23])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)=O.Cl.[CH3:31][O:32][C:33](=[O:46])[C@H:34]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH2:35].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:46])[C@H:34]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:35][C:21](=[O:23])[C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:14][CH:15]=1)[NH2:7]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@@](C)(Cc2ccc(-c3ccsc3)cc2)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)Cc1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine (135 mg, 0.33 mmol) in DMF are successively added tryptophan methyl ester hydrochloride (110 ml, 0.43 mmol), 1-Hydroxybenzotriazole (58 mg, 0.43 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.46M solution) 79μ, 0.43 mmol) at 0° C. under nitrogen atomosphere. The reaction mixture is allowed to stir at 0° C. for 2 h, then at room temperature overnight. The mixture is diluted with ethyl acetate and washed with 10% citric acid twice. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica with hexane/ethyl acetate (1:1) to give (D,L)-isomer (55 mg) and (L,L)-isomer (80 mg: including 15% of (D,L)-isomer) (total 67%) of 3-[4-(3-thienyl)phenyl]alanyl-tryptophan methyl ester. Hydrolysis of (D,L)-isomer (55 mg, 0.09 mmol) with lithium hydroxide hydrate (6 mg, 0.14 mmol) affords N-(3,5-Dimethylbenzoyl)-N-methyl-(D)-2-methyl-3-[4-(3-thienyl)phenyl)-alanyl-(L)-tryptophan FAB-MS m/e 592 (M-H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]=[C:19]2[S:20][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: N#Cc1ccc(N=C2NC3(CCCC3)CS2)cc1

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1a to give 2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>ClCCCl>[Cl:23][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cc(Br)cc(-c2cc[nH]n2)c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Clc1c[nH]nc1-c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4 g (0.0132 mol) of 3-(3,5-dibromophenyl)pyrazole and 1 g of pyridine (0.0132 mol) are dissolved, at room temperature and with stirring, in 50 ml of 1,2-dichloroethane. 2 g (0.0145 mol) of sulphuryl chloride in 10 ml of 1,2-dichloroethane are then added dropwise at 50° C. and stirring is then continued for 30 min days at this temperature. After cooling, the precipitate is filtered and recrystallised from 200 ml of 1,2-dichloroethane. 2.9 g (yield: 66%; melting point: 188° C.) of 4-chloro-3-(3,5-dibromophenyl)pyrazole are obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:12]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]1[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCBr
Reactant: Cc1nc(C)c(C)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCn1c(C)nc(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 16.0 g (0.019 mole) of 2,4,5-trimethyl-1H-imidazole hydrochloride in 125 ml dry N,N-dimethylformamide and cool to 0° C. Add 8.75 g (0.218 mole) of sodium hydride (60%), stir at 0° C. for 30 minutes and then heat reaction mixture to 100° C. for one hour. Cool to 0° C. and then add 18.0 ml (0.114 mole) of n-heptyl bromide to reaction mixture. Upon completion of addition, heat to 100° C. for four hours, following the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, cool to room temperature and add 2 ml water. Filter precipitated salts and evaporate solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(C(=O)CCc2cccc(Br)c2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCC(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one (173 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-190) as a pale brown powder (110 mg, 58%).