Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[O:28]=[C:27]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: C[C@H](NC(=O)c1cccn1N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: C[C@H](NC(=O)c1cccn1NC(=O)CNC(=O)OC(C)(C)C)c1ccccc1
Yield: 97.9 %

Procedure:
The title compound was prepared from (S)-1-amino-N-(1-phenylethyl)-1H-pyrrole-2-carboxamide (3.50 g, 15.3 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (2.67 g, 15.3 mmol) following the experimental procedure described in Preparation 73a. 5.79 g (89% yield) of the desired compound were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([NH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(Cl)=[O:23]>ClCCl>[O:23]=[C:22]1[NH:1][CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[NH:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](N)C1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2NC(=O)NC2C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl cis-3,4-diaminopyrrolidine-1-carboxylate (the product in Intermediate 11, Step C; 140 mg) and triethylamine (0.29 mL) in dichloromethane (10 mL) was added phosgene (20% in benzene, 0.4 mL) at 0° C. and the reaction mixture allowed to warm up to room temperature. The solution was evaporated after stirring for one h and purified on a Biotage Horizon® system (silica gel, 10-20% gradient of methanol containing 10% ammonium hydroxide in dichloromethane). The tert-butyl 2-oxohexahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate obtained was dissolved in trifluoroacetic acid/dichloromethane (2 mL, 1:1) and eluted through Strata-X-C™ ion exchange resin. The desired product was eluted with a solution of concentrated ammonium hydroxide in methanol (5%) and evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 90%). 1H NMR (200 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.78 (m, 3H), 4.13 (s, 4H), 6.75-6.78 (m, 3H), 7.14-7.28 (m, 2H), 7.36 (s, 1H), 7.44-7.51 (dd, J=9.8 and 2.4 Hz, 1H), 7.67-7.74 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F
Reaction time: 3 h
Yield: 61 %

Procedure:
Tert-butyl ({4-fluoro-1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (527 mg) was dissolved in ethyl acetate (5 mL) and 2-propanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added at room temperature. The reaction mixture was stirred for 3 hr and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 255 mg, 61%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]#[N:15])[N:11]=[CH:10]1.NO.Cl.CC[N:23](CC)CC>CCO>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](=[NH:23])[NH2:15])[N:11]=[CH:10]1
Reactant: CCN(CC)CC
Reactant: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Agent: Cl
Agent: NO
Solvent: CCO
Product: N=C(N)c1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A mixture of give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile (694 mg, 1.485 mmol), NH2OH.HCl (258 mg, 3.71 mmol), Et3N (0.6 mL, 4.3 mmol), and dry EtOH (15 mL) was stirred at 55° C. for 5 h under N2. The solvent was removed in vacuo to give N′-hydroxy-1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboximidamide as a white solid, which was used in the next reaction without further purification. MS (ESI) 501 [M+H]+.
Reaction SMILES: [C:1]([N:9]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][CH2:26][C@@H:24]([OH:25])[C@@H:22]([OH:23])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:28]([N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][CH2:26][C@@H:24]([OH:25])[C@@H:22]([OH:23])[C@H:20]1[O:21][C:36](=[O:37])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccccc1)N(C(=O)c1ccccc1)c1ncnc2c1ncn2[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cnc2c(N(C(=O)c3ccccc3)C(=O)c3ccccc3)ncnc21)c1ccccc1
Temperature: -88.5 °C
Reaction time: 60 h
Yield: 72.1 %

Procedure:
26.4 g (55,5 mmol) of 3 were dissolved in 550 ml of anhydrous CH2Cl2 and 55 ml of pyridine (in each case stored over a molecular sieve) under an N2 atmosphere, treated with 0.73 g (5.55 mmol; 0.1 eq.) of DMAP and cooled to −87 to −90° C. 8.58 g (61 mmol; 1.1 eq.) of BzCl in 14 ml of pyridine were added dropwise in the course of 1 h and the mixture was left at −78° C. over a period of 60 h (week-end). The batch was concentrated, treated twice with 100 ml of toluene each time and evaporated in order to remove pyridine. Chromatography on silica gel 60 (20×10 cm) using gradients (AcOEt/heptane, 1:1 to 9:1) yielded 23.2 g of 4.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29]O)([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29][Cl:1])([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CO)O2
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CCl)O2
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
N-Chlorosuccinimide (150 mg) was suspended in dichloromethane (4 ml). After adding dimethyl sulfide (0.1 ml) dropwise at -5° C., the suspension was stirred for 15 min. Subsequently, a solution of 5-acetoxy-4,6-di-tert-butyl-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran (0.4 g) in dichloromethane (1 ml) was added dropwise and the resulting mixture was stirred at -5° C. for 90 min. After the end of the reaction, dichloromethane was distilled off under reduced pressure and the concentrate was purified by silica gel chromatography (25% ethyl acetate in n-hexane) to afford 5-acetoxy-2-(5-chloro-4-methyl-3(E)-pentenyl)-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran [0.3 g (yield, 70%)] as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[CH3:53][C:54]1[O:58][N:57]=[C:56]([C:59](Cl)=[O:60])[CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[CH:55]=[C:54]([CH3:53])[O:58][N:57]=2)=[O:60])[CH2:48][CH2:47]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Clc1cnc2nc1Nc1ccc(OCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(COc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C28H29ClN7O3 (M+H)+: m/z=546.2.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Cl[CH2:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: O=C(CCl)Cc1ccccc1
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)Cc1ccccc1
Yield: 40.5 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.45 g, 6.5 mmoles) and 1-chloro-3-phenyl-2-propanone (1.1 g, 6.5 mmoles) in acetonitrile was stirred for 18 hours at 20°. After removal of the acetonitrile at reduced pressure, the residue was treated with water and extracted with methylene chloride. The residue, after concentration of the extracts, was chromatographed on alumina (grade III) using ethyl acetate for elution. Combination of the appropriate fractions gave 1.1 g of product which was recrystallized from ethyl acetate to give the title compound, mp. 138°-139°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (43 mg, 33%). MS (ISN) 509.0 [(M−H)−]; mp 273-274° C.
Reaction SMILES: C1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])C=CC=CC=1.[C:25]1([CH2:31]S(Cl)(=O)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:31][S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:8])=[O:9])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)Cc2ccccc2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxlyate and phenylmethanesulphonyl chloride.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:22])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:22])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[O:11][CH3:12]
Reactant: CON(CCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(CCc1ccc(F)cc1)OC
Yield: 66 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[2-(4-fluorophenyl)-ethyl]-N-methoxy-acetamide was treated with methanol as described in the preparation Compound 44-D and gave the title ester as a clear oil (66% yield). HRMS (MAB N2) calculated for C14H16FNO5: [M]+: 297.101251. found: 297.101514. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.95 (2H, t, J=7.6 Hz, CH2), 3.73 (3H, s, OCH3), 3.89 (2H, t, J=7.6 Hz, CH2), 3.92 (3H, s, OCH3), 6.44 (1H, s, CH), 7.0 (2H, m, aromatics), 7.19 (2H, m, aromatics).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][C:13]=3[O:12][CH2:11][C:8]2=[CH:9][N:10]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:41])C(=O)C1>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:18]3[CH:17]=[C:16]([Cl:41])[C:15]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][C:13]=3[O:12][CH2:11][C:8]2=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1cc2c(cn1)COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: CC#N
Product: CC(=O)Nc1cc2c(cn1)COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc1-2
Temperature: 25 °C
Yield: 79.1 %

Procedure:
The stirred solution of (S)-tert-butyl (1-((2-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.220 mmol) (prepared as described in Example 18, Part H) and NCS (29.3 mg, 0.220 mmol) in acetonitrile (15 mL) was heated to 80° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (25 mL) and DCM (25 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford (S)-tert-butyl (1-((2-acetamido-9-chloro-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (120 mg, 0.174 mmol, 79% yield) as an off-white solid. The product was used as is for the next step without purification. LCMS (ESI) m/e 490.2 [(M+H)+, calcd for C25H33ClN3O5 490.2]; LC/MS retention time (Method D): tR=1.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][C:7](=[O:26])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:13]=1.Cl.C(OCC)C>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][O:15][CH2:16][CH2:17][NH2:18])[N:13]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-((2-(3-(3,4-dichlorobenzyl)ureido)thiazol-4-yl)methoxy)-ethylcarbamate (Example 77) (350 mg) in 1,4-dioxane (3 mL) was treated with 4N HCl in 1,4-dioxane (4 mL). The mixture was stirred overnight, 5 mL of diethyl ether was added, and the precipitated material was isolated by filtration. 1H-NMR (300 MHz, DMSO-d6): 10.85 (bs, 1H), 7.90 (bs, 2H), 7.60 (d, 1H), 7.50 (s, 1H), 7.27 (d, 1H), 6.97 (s, 1H), 4.43 (s, 2H), 4.30 (d, 2H), 3.60 (m, 2H), 2.98 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:26]OCC)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:30])[C:17](=[CH:26][NH:12][C:11]1[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][CH:10]=1)[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: Nc1ccnn1Cc1ccco1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)c1ccccc1

Procedure:
163 g. of 1-(2-furyl)methyl-5-aminopyrazole (1 mol.) and 248 g. of ethoxymethylene benzoyl acetic acid ethyl ester (1 mol.) are heated at 130° until no more alcohol distils off (approximately 1 hour). The oily residue crystallizes and yields on cooling and recrystallization from hexane 310 g. of [[[1-(2-furyl)methyl-5-pyrazolyl]-amino]methylene]benzoyl acetic acid ethyl ester (85%), m.p. 75°-77°.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C@:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]2)([OH:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A 250 mL three-necked flask was charged with magnesium turnings (2.88 g, 0.12 mol) and a small crystal of iodine in THF (20 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture. After heating under reflux for 1 h, most of magnesium was consumed, the reaction mixture cooled to rt. Another 250 mL three-necked flask was charged with (R)-3-(3-chloro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent derived from 1-chloro-4-methoxybutane (20 mL) was added dropwise. After addition, the mixture was allowed to warm slowly to rt and stirred for 2 h. The mixture was quenched with sat'd aq NH4Cl (100 mL), extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE 10:90) to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (3.0 g, 73%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.52-1.58 (m, 3H), 1.75 (m, 1H), 1.92 (m, 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H), 3.95 (m, 1H), 4.35 (m, 1H), 7.20-7.26 (m, 3H), 7.36 (m, 1H). MS (E/Z): 412 (M+H+).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16](C)[CH2:15]2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1C=CC=CC=1>[CH2:39]([O:38][C:36]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:28])[F:27])=[CH:10][CH:11]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:37])[CH3:40]
Reactant: CN1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 50.2 %

Procedure:
To a solution of 2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline of Example 4 (18.0 g, 0.06 mole) in 200 ml benzene, is added K2CO3 (20 g, 0.145 mole), and, with stirring, a solution of ethyl chloroformate (7.6 g, 0.07 mole) in 50 ml benzene. After refluxing for four hours, the mixture is cooled, washed twice with 100 ml portions of water, thrice with dilute HCl solution (100 ml), twice with water (100 ml), then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent is evaporated to an oil, which solidifies upon cooling, to a solid, 13.7 g (64%), m.p. 84° C. This material is recrystallized from hexanes twice, to yield 11.0 g, m.p. 107°-109° C. of 2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[CH:45][CH:44]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 2.08 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.13 g of methyl 3-(bromomethyl)benzoate are used to obtain the title compound as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.06.
Reaction SMILES: C(OC1C=CC(CCCl)=C([NH:18][C:19]([C:21]2[O:22][C:23]3C=CC(N)=C[C:24]=3[CH:25]=2)=[O:20])C=1)C1C=CC=CC=1.CC[N:33]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:25]([CH2:21][C:19]([NH2:18])=[O:20])[CH2:24][C:23]([NH2:33])=[O:22]
Reactant: Nc1ccc2oc(C(=O)Nc3cc(OCc4ccccc4)ccc3CCCl)cc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCCC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 524.9 %

Procedure:
To the 2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride (0.243 mmol) was added the N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]glutaramide monocarboxylic acid (0.133 g, 0.258 mmol), EDCI (0.093 g, 0.486 mmol) and 1-hydroxybenzotriazole hydrate [HOBT] (0.033 g, 0.244 mmol) which was then dissolved in DMF (15 mL). Dissolution was aided by sonication and the suspension stirred under nitrogen at room temperature for two days with the flask covered with foil. At that time, the DMF was removed via kugelrohr apparatus (0.1 mm Hg, 60° C.). The resulting oil was dissolved in CHCl3, washed with water (1×75 mL), then with brine (1×75 mL) and dried over sodium sulfate. It was then filtered and concentrated under reduced pressure to yield the product N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]-N-[5-(3-benzyloxy-2-(2-chloroethyl)phenyl)benzofuran-2-carboxamido)]glutarodiamide as a brown oil (0.166 g, 68% yield). Rf=0.40 (10% MeOH/CHCl3).