Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[NH:6][C:7]([NH2:16])=[C:8]2[C:12]([N:13]=1)=[N:11][C:10]([O:14][CH3:15])=[N:9]2)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CN(C=O)C.ClCCl>[NH2:16][C:7]1[N:6]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine (37 mg, 0.166 mmol) in DMF (0.5 ml) was added potassium carbonate (55 mg, 0.398 mmol) followed by a solution of 1,1-dimethylethyl 4-(4-bromobutyl)-1-piperidinecarboxylate (58 mg, 0.181 mmol) in DMF (0.2 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane (5 ml) and washed with water (5 ml). The layers were separated using a hydrophobic frit, the aqueous layer was extracted again with dichloromethane (5 ml) and the combined organic extracts were evaporated. The residue was dissolved in methanol (0.6 ml) and purified by MDAP (Method A). The appropriate fractions were combined and evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a colourless gum (32 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCC[C@H]2CO)(=O)=O)=CC=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:11]([CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:29][CH:28]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=S(=O)(NC1CC2CCC1C2O)c1ccc(Cl)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1CC2CCC1C2O
Yield: 72.4 %

Procedure:
The title compound was synthesized from 2-(4-chlorophenylsulfonamido)bicyclo[2.2.1]heptan-7-ol (302 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and 1-bromo-4-(bromomethyl)benzene (300 mg, 1.2 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 2) to give N-(4-bromobenzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (341 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 7.65-7.72 (2H, m), 7.40-7.46 (2H, m), 7.37 (2H, d, J=8.56 Hz), 7.18 (2H, d, J=8.56 Hz), 4.68 (2H, dd, J=38.27, 17.12 Hz), 3.97 (1H, t, J=7.30 Hz), 3.77 (1H, s), 1.94 (1H, hr. s.), 1.79-1.88 (3H, m), 1.36-1.62 (3H, m), 1.00-1.12 (2H, m). LC/MS R.T.=2.33 min; [M+H]+=470.03. HRMS [M+H]+ calc'd 470.0192, found 470.0202.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43]Cl>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:43][CH2:42][N:41]([CH3:45])[CH3:40])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OCCN(C)C)cc2n1Cc1ccccc1
Yield: 50.7 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-dimethylamino ethyl chloride hydrochloride (20 mg, 0.20 mmol) to yield the title compound (10 mg, 53%).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([N:13]=[C:14]=[S:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>CCCCC>[C:1]([N:5]=[N:6][C:7]([NH:13][C:14]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[S:15])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCN
Reactant: CC(C)CC(C)(N=C=S)N=NC(C)(C)C
Solvent: CCCCC
Product: CCCCNC(=S)NC(C)(CC(C)C)N=NC(C)(C)C
Temperature: 30 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To 22.65 grams (0.1 mole) of 2-t-butylazo-2-isothiocyanato-4-methylpentane stirred with a magnetic stirrer in a 125 ml erlenmeyer flask was slowly added 7.7 grams (0.105 mole) of n-butylamine. After the addition was complete, the reaction mixture was stirred for 3 hours at 30° C., dissolved in pentane, transferred to a round bottom flask and the pentane evaporated under reduced pressure. The residue was then stripped under high vacuum to remove any low boilers. The residue weighed 30 grams (100% yield) and its infrared spectrum contained peaks around 1500-1550 cm-1 which appears to be due to the ##STR56## group and NH peaks around 3350 cm-1. The isothiocyano band around 2040 cm-1 had disappeared.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B(O)O)[CH:38]=2)[C:33]([CH3:43])=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:39]4[C:34]([C:33]([CH3:43])=[N:32][N:31]4[CH3:30])=[CH:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nn(C)c2cc(B(O)O)ccc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1,3-dimethyl-1H-indazol-6-ylboronic acid (76 mg, 0.4 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (1.6 mL) and water (0.4 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 30% EtOAc in hexanes) to give the product. LCMS-ESI+: calc'd for C31H33ClN3O3S: 562.2 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCCN1CC(O)=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]3[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=3)[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.[F:49][C:50]([F:62])([F:61])[C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][NH:57][CH2:58]2)=[CH:53][CH:52]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[O:39]=[C:38]([N:57]1[CH2:56][CH2:55][C:54]2[C:59](=[CH:60][C:51]([C:50]([F:49])([F:62])[F:61])=[CH:52][CH:53]=2)[CH2:58]1)[CH2:37][N:33]1[CH2:34][CH2:35][CH2:36][C:31]([C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:32]1=[O:41]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.43 (d, J=9.3, 2H), 7.36-7.15 (m, 11H), 4.74 (d, J=40.6, 2H), 4.31 (s, 2H), 3.88 (t, J=5.9, 1H), 3.70 (t, J=5.9, 1H), 3.54 (t, J=6.4, 2H), 2.93 (t, J=5.8, 2H), 2.72-2.56 (m, 2H), 1.93-1.81 (m, 2H); MS (DCI) m/z 493.1 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19])C.[NH2:24][CH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH2:35])=[N:31][NH:32]2)=[CH:28][CH:27]=1>>[NH2:35][C:30]1[C:29]2[C:33](=[CH:34][C:26]([CH2:25][NH:24][C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]3=[O:19])=[CH:27][CH:28]=2)[NH:32][N:31]=1
Reactant: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Reactant: NCc1ccc2c(N)n[nH]c2c1
Product: CCOC(C(=O)NCc1ccc2c(N)n[nH]c2c1)n1cccc(Nc2ccccc2)c1=O

Procedure:
Using similar procedures as described in example 25, (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (example 21.1) was hydrolyzed according to general procedure B. The corresponding acid was reacted according to general procedure C with 6-aminomethyl-1H-indazol-3-ylamine (CAS 368426-75-9) to give (RS)-N-(3-amino-1H-indazol-6-ylmethyl)-2-ethoxy-2-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetamide. Off-white solid. MS 433.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1.Cl>[OH-].[Na+].C1COCC1.CO>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)propanoate (from Example 66) in 1 N NaOH, THF and methanol (1:5:2, 0.1 N) was heated at 60° C. for 3 hours. After cooling to room temperature the reaction mixture was neutralized with 1 N HCl to pH 7, and was concentrated to give a crude residue which was purified by chromatography (silica gel, 0-20% methanol in dichloromethane) to afford (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate as a white solid. 1H NMR: (methanol-d4): δ 8.73 (d, 1H), 8.54 (d, 1H), 8.20 (d, 1H), 7.45 (s, 1H), 7.37 (d, 1H), 7.00-6.97 (m, 2H), 6.92 (d, 1H), 3.19 (t, 2H), 3.04 (t, 2H), 2.81 (t, 2H), 2.53 (t, 2H), 2.50 (s, 3H), 2.25 (s, 3H). LRMS [M+H]=400.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>Cl.O1CCOCC1.ClCCl>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(Nc3ccncc3)c2c1

Procedure:
To a vial was added 4-chloro-6-iodo-quinazoline (100 mg; 0.34 mmol, commercially available), pyridin-4-amine (3 equiv., 1.03 mmol, 97.19 mg, commercially available), and 2 drops of 4M HCl/dioxane. The reaction vial was heated until solids melted. LCMS of resultant solution showed clean product formation. Upon cooling the product re-solidified. The solid was suspended in dichloromethane:water, and collected by filtration. 95 mg of 6-iodo-N-(4-pyridyl)quinazolin-4-amine was recovered as an orange solid, which was carried on directly to the Suzuki step. LCMS M/Z (M+H)=350.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([Cl:1])=[N:3][CH:4]=[CH:5]3)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Oc1ccc2c(Cl)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(Cl)nccc3c2)C1
Temperature: 120 °C
Yield: 29.2 %

Procedure:
The 1-chloro-6-methoxyisoquinoline was prepared as described in WO 00/24718 (Akzo Nobel N.V.). Alternatively it can be prepared from 3-methoxybenzaldehyde using the same procedure as in Example 15A (for the synthesis of 1-chloro-6-methoxy-7-methyl-isoquinoline). The 1-chloro-6-methoxyisoquinoline is demethylated according to the procedure described in WO 00/24718 to afford 1-chloro-6-hydroxyisoquinoline. A suspension of 1-chloro-6-hydroxyisoquinoline (0.18 g, 1 mmol), 3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (336 mg, 1.2 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (500 mg, ˜2.2mmol/g loading) in acetonitrile (4 ml) were heated at 120° C. over a period of 900 seconds using the microwave. The excess supported reagent was removed by filtration, washing with methanol, and the filtrate evaporated to dryness under reduced pressure. Since the reaction had not gone to completion, the above procedure was repeated. Purification of the crude material was achieved by chromatography on silica (eluent: 0-25% ethyl acetate in heptane) to afford 3-(1-chloroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (106 mg), El-MS: m/z=363.7 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([Br:9])([CH3:8])[CH3:7].[O:11]=[C:12]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19][C:20](O)=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[O:11]=[C:12]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19][C:20]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([Br:9])([CH3:8])[CH3:7])=[O:21]
Reactant: CC(C)(Br)C(=O)OCCO
Reactant: O=C(O)CCN1C(=O)C=CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(Br)C(=O)OCCOC(=O)CCN1C(=O)C=CC1=O
Reaction time: 24 h
Yield: 84 %

Procedure:
2-Hydroxyethyl-2-bromo-2-methylpropionate (initiator 9) (0.187 g, 0.887 mmol) and 3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (0.300 g, 1.77 mmol) were dissolved in dichloromethane (10 ml) under nitrogen in a 25 ml round-bottomed flask. Then N,N′-Dicyclohexylcarbodiimide (DCC) (0.366 g, 1.77 mmol) was added to the solution. After one day at room temperature, very low conversion was observed and 0.5 ml (9.50×10−3 mmol) of a solution of 4-dimethylaminopyridine (DMAP) in dichloromethane (Conc.DMAP=19 mmol/l) was added. Total conversion was then achieved in 12 hours and the solvent was removed under reduced pressure. The solid residue was extracted with 3×50 ml of petroleum ether and the petroleum ether was removed by evaporation under vacuum in order to isolate a colourless oil (0.270 g, 0.745 mmol, 84%). The pale pink residue was extracted with 3×50 ml of diethylether, but TLC (CH2Cl2/AcOEt 9:1) revealed that only traces of the ester were present. An analytical pure sample was obtained by flash chromatography (cc, SiO2, Pet. Ether/Et2O 3:1).
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccc(Cl)cc2Cl)n1)C(=O)O

Procedure:
Seven g of the compound of Example 2 was refluxed for 3 hours with 2.4 g of potassium hydroxide in 100 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from toluene to obtain 2.3 g of the desired product, m.p. 151°-153°.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=3)[C:19](OC)=[O:20])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[C:17]([CH2:25][OH:26])[CH:16]=3)=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(c2ccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC1(c2ccc(COc3ccc(CO)c(CO)c3)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.7 g (31.5 mmol) of dimethyl 4-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]phthalate are dissolved in 500 mL of anhydrous ethyl ether. 2.87 g (75.7 mmol) of lithium aluminium hydride are added and the reaction medium is stirred at 0° C. for 1 hour. 2.9 mL of water are then added slowly, followed by 2.9 mL of aqueous 15% sodium hydroxide, and then 8.7 mL of water are also added slowly. After stirring for 20 minutes, the medium is then filtered. The filtrate is concentrated under reduced pressure and the residue obtained is then purified by chromatography on a column of silica. A white solid (m.p.: 78-80° C.) is obtained (m=8 g; Y=72%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6](=[O:24])[C@@H:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br)[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CN(C)C=O.[C:38](O)(=[S:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.ClCCl>[CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6](=[O:24])[C@H:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:38](=[S:40])[CH3:39])[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(O)=S
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCc1ccccc1Br)NC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCc1ccccc1C(C)=S)NC(=O)CC(C)C
Reaction time: 18 h

Procedure:
Combine (R)-2-bromo-3-methylbutyroyl-(L)-homophenylalanyl-(L)-phenylalanine N-methyl amide (0.466 g, 0.93 mmol) and dimethylformamide (3 mL). Add thioacetic acid (0.066 mL, 0.93 mmol) and cesium carbonate (0.151 g, 0.46 mmol). After 18 hours, partition the reaction mixture between ethyl acetate and an aqueous 2 M hydrochloric acid solution. separate the layers, extract the organic layer with water and a saturated aqueous sodium bicarbonate solution, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% acetone/dichloromethane, 15% acetone/dichloromethane, and then 20% acetone/dichloromethane to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[CH:13]12[CH:20]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]([CH2:18][CH2:19]1)[CH2:16][NH:15][CH2:14]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][N:15]2[CH2:14][CH:13]3[CH:20]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:17]([CH2:18][CH2:19]3)[CH2:16]2)=[CH:6][CH:7]=1)#[N:10]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Reactant: N#Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(CCOc1ccc(C#N)cc1)C2
Yield: 75.1 %

Procedure:
A mixture of 4-(2-bromoethoxy)benzonitrile (see step (i) above; 0.94 g, 4.2 mmol), tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 0.91 g, 3.8 mmol) and K2CO3 (0.79 g, 5.7 mmol) in 15 mL of dry DMF was stirred at 90° C. overnight before additional K2CO3 (1 g) was added. The mixture was diluted with 300 mL of DCM, and the mixture was washed with water. The organic layer was separated, dried with Na2SO4 and then evaporated. The crude product was purified by flash chromatography on silica gel, eluting with DCM:MeOH (10:1) containing 0.1% TEA, to yield 1.1 g (76%) of the sub-tide compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1N

Procedure:
The title compound was prepared from (4-chloro-2-nitro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example C8) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a red solid (4.80 g).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[O:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]1(/[CH:28]=[CH:29]/[C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.O>[C:22]1(/[CH:28]=[CH:29]/[C:30]2[CH2:35][CH2:34][N:33]([CH2:6][C:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[O:10][CH:11]=3)[CH2:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1coc2ccccc12
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2coc3ccccc23)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.2 %

Procedure:
Thionyl chloride (0.25 ml 3.4 mmol) was added to a solution of 3-hydroxymethylbenzo[b]furan (0.4515 g, 3.05 mmol) in anhydrous ether (10 ml), the mixture was stirred at room temperature for 2.5 hours and evaporated to dryness. The residue was dissolved in anhydrous dimethylformamide (10 ml), potassium carbonate (1.05 g, 7.60 mmol) and (E)-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine (0.68 g, 3.67 mmol) was added and the mixture stirred at room temperature, under nitrogen, overnight (20 hours). The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (2×50 ml). The extracts were washed with saturated brine (50 ml), combined and dried (magnesium sulfate). The residue after evaporation of the solvent was purified by flash chromatography, eluting with 20% then 25% ethyl acetateetrol (60°-80°), to afford the title compound (0.4734 g, 49%). Recrystallisation from ethyl acetate/petrol (60°-80°) gave pale yellow needles, m.p. 122°-123° C.; (Found: C, 8.29; H, 6.58; N, 4.36. C22H21NO.0.1H2O requires C, 83.30; H, 6.74; N, 4.42%); δH (CDCl3) 2.43 (2H, br s, tetrahydropyridinyl CH2), 2.73 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.21 (2H, d, J 2.7 Hz, tetrahydropyridinyl CH2), 3.76 (2H, s, ArCH2N), 5.82 (1H, br s, tetrahydropyridinyl CH), 6.44 (1H, d, J 16.1 Hz, C H=CHPh), 6.79 (1H, d, J 16.1 Hz, CH=C HPh), 7.17-7.32 (5H, m, ArH), 7.39 (2H, m, ArH), 7.48 (1H, m, ArH), 7.58 (1H, s, 2-H), 7.73 (1H, m, ArH); m (ES+) 316 (M+1)+.