Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[Br:9]Br.C(N(CC)CC)C>CO.O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([Br:9])[C:3]1=[O:8]
Reactant: CN1C(=O)C=CC1=O
Reactant: BrBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
To N-methylmaleimide (0.5 g, 4.5 mmol) in methanol (10 mL) was added bromine (232 μL, 4.5 mmol) dropwise in methanol (5 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and dissolved in tetrahydrofuran (20 mL). Triethylamine (815 μL, 5.9 mmol) in tetrahydrofuran (5 mL) was added over 5 minutes, whereupon a precipitate formed. The reaction mixture was stirred for 24 hours. The solid was filtered off and washed with tetrahydrofuran (50 mL). Purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow powder (563 mg, 2.96 mmol) in 66% yield. δH (500 MHz, CDCl3) 6.90 (s, 1H, H-3), 3.09 (s, 3H, H3-6); δC (125 MHz, CDCl3) 168.6 (C═O), 165.4 (C═O), 131.9 (C3), 131.4 (C2), 24.7 (C6); IR (solid, cm−1) 3106 (s), 1708 (s); MS (CI+) m/z, (relative intensity): 192 ([81M+H], 99), 190([79M+H], 100); Exact mass calcd for [C5H4O2N79Br]+H requires 189.9504 Found 189.9505 (CI+); m.p: 77-79° C.; UV (Acetonitrile) ε209=17100, ε238=13200, ε299=290 cm−1M−1 d3.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([NH:19][CH2:20][CH2:21][CH2:22]2)=[CH:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C=C4NCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NCCC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a solution of 20-tert-butyldimethylsilyloxy-7β-methyl-4-azapregn-5-ene (23.9 gms, 53.6 mmol) in acetic acid (250 mL) was added platinum oxide (1.8 gm). The mixture was stirred overnight under hydrogen (1 atmosphere). The reaction mixture was filtered through a pad of celite filter aid and the filtrate was coevaporated with toluene (3×500 mL) to remove all of the acetic acid. The residue was dissolved in chloroform and filtered again through a pad of celite filter aid to remove residual catalyst. The solvent was removed by rotoevaporation to yield the title compound which was taken directly on to the next step without any further purification.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]3[C:16]([CH:17]=[CH:18][C:3]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[H][H]>[Pd].COCCO>[O:5]1[CH:6]([C:8]([OH:10])=[O:9])[CH2:7][CH2:2][C:3]2[CH:18]=[CH:17][C:16]3[C:11]([C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: O=C(O)c1cc(=O)c2ccc3ccccc3c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: O=C(O)C1CCc2ccc3ccccc3c2O1
Yield: 61.4 %

Procedure:
A mixture of 12 parts of 4-oxo-4H-naphtho[1,2-b]pyran-2-carboxylic acid and 100 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 7 parts (61.4%) of 3,4-dihydro-2H-naphtho[1,2-b]pyran-2-carboxylic acid as a residue (intermediate 19).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-dimethylamino-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example C4) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as an amorphous yellow substance (1.34 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:27]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: Cc1c[nH]cn1
Product: Cc1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Yield: 43 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (25 mg, 0.0786 mmol) is reacted with 4-methyl-1H-imidazole according to the GPB affording 12.6 mg (43%) of a yellowish powder as a 5 to 1 regioisomer mixture. Rt=2.11 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:33][CH2:34]1)[CH3:21]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Product: CCOc1ccccc1N1CCN(CCc2c(C)c3c(OC)cc(OC)cc3oc2=O)CC1
Yield: 31 %

Procedure:
Process B: starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-ethoxyphenyl)piperazine; yield 31% of crude product.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2].[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(O)(=O)C>C(O)C>[C:18](=[N:26][NH2:27])([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.[CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2]
Reactant: NNC(=O)c1cccnc1
Agent: CCOP(=O)(Cc1ccccc1C=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(O)c1cccnc1

Procedure:
2.0 g (8 mmol) of the compound A and 1.07 g (8 mmol) of nicotinic acid hydrazide were dissolved in 30 ml of absolute ethanol. After adding 1 ml of acetic acid, the mixture was boiled under reflux for 8 h. The solvent was removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2 /EtOH 9.5/0.5; Rf =0.45). The product E was obtained in crystalline form. Yield: 2.2 g (73%); m.p.: 136° to 140° C.;
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12]C)[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].B(Br)(Br)Br>ClCCl>[N+:1]([C:4]1[CH:11]=[C:8]([CH:7]=[C:6]([OH:12])[C:5]=1[OH:14])[CH:9]=[O:10])([O-:3])=[O:2]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
35 g of 5-nitro vanillin (commercial) and 1200 ml of dichloromethane were mixed together under nitrogen and the mixture was cooled to 0° C. 533 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for 2 days at abmient temperature and then was concentrated. The residue was taken up cold ice bath+methanol) in 300 ml of 2N hydrochloric acid and the mixture was stirred for two to three hours at this temperature, then left for 16 hours at ambient temperature. Extraction was carried out with ethyl acetate and the organic phase was washed, dried and concentrated to obtain 18 g of the expected product melting at >260° C.
Reaction SMILES: NC1C=C([F:11])C=CC=1C([O-])=O.[C:12]([N:15]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30](Br)[CH:31]=[CH:32][C:17]1=2)(=[O:14])[CH3:13]>>[C:12]([N:15]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30]([F:11])[CH:31]=[CH:32][C:17]1=2)(=[O:14])[CH3:13]
Reactant: Nc1cc(F)ccc1C(=O)[O-]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)ccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 22 by replacement of methyl 2-amino-4-bromobenzoate with 2-amino-4-fluorobenzoate following the procedure of Example 22, Steps 1-6 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. EI MS 535 (M+H).
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].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[CH:53]=[CH:52][O:51][C:50]=1[C:54](O)=[O:55]>>[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:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[O:51][CH:52]=[CH:53][C:49]=2[CH3:48])=[O:55])[CH2:42][CH2:41]1
Reactant: Cc1ccoc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccoc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-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-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methyl-2-furoic acid as starting materials in 51% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:42]([OH:44])=[O:43])[CH2:20][CH2:21][C:22](=[O:41])[NH:23][CH:24]([P:33]([CH2:38][CH:39]=[CH2:40])([CH2:35][CH:36]=[CH2:37])=[O:34])[P:25]([CH2:30][CH:31]=[CH2:32])([CH2:27][CH:28]=[CH2:29])=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH2:30]([P:25]([CH:24]([P:33]([CH2:35][CH:36]=[CH2:37])([CH2:38][CH:39]=[CH2:40])=[O:34])[NH:23][C:22](=[O:41])[CH2:21][CH2:20][C@@H:19]([C:42]([OH:44])=[O:43])[NH2:18])([CH2:27][CH:28]=[CH2:29])=[O:26])[CH:31]=[CH2:32]
Reactant: C=CCP(=O)(CC=C)C(NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)P(=O)(CC=C)CC=C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C=CCP(=O)(CC=C)C(NC(=O)CC[C@H](N)C(=O)O)P(=O)(CC=C)CC=C
Reaction time: 4 h

Procedure:
Fmoc-protected compound 97 (898 mg, 1.18 mmol) was treated with a 5% v/v solution of piperidine in DMF (5.9 mL). After stirring for 4 h, the reaction mixture was concentrated to dryness and purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-5% methanol in CH2Cl2. Compound 98 was obtained as a colorless oil (274 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.72-1.81 (m, 1H), 2.04-2.31 (m, 3H), 2.36-2.43 (m, 1H), 2.46-2.54 (m, 1H), 3.41 (dd, J=9.5, 4.3 Hz, 1H), 4.59-4.67 (m, 8H), 5.15 (dt, J=22.1, 9.1 Hz, 1H), 5.23-5.26 (m, 4H), 5.35-5.39 (m, 4H), 5.88-5.98 (m, 4H), 7.50 (bs, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[NH2:10]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([N:10]=[C:1]=[O:2])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(N=C=O)cc1OC

Procedure:
Phosgene (4 eq) is bubbled at a moderate rate into a 3-neck flask containing a solution of 3,4-dimethoxyaniline (1 eq.), in benzene (2 liters). The flask is cooled in an ice bath for 15 minutes and then the solution is refluxed for 13/4 hours while excess phosgene is added. The reaction mixture is then refluxed overnight and the solvent removed under vacuum. Acetone is added and the solvent is again removed under vacuum leaving a dark brown oily residue which is distilled at 132°-134° C./0.6 mm. Yield: 22.5 g.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:15](=[O:16])[CH2:14][O:13][CH3:12])[N:10]=2)[N:7]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1cn2nc(I)ccc2n1
Yield: 79 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (10 mL) and methoxyacetyl chloride (0.46 g, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (1.01 g, 79%) was obtained as a dark brown powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)=[CH:2][CH3:3].[H][H]>[Pd].C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CC=Cc1cccc(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cccc(O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of Part B (1) compound (3 g, 22.4 mmol) and 10% palladium on carbon (150 mg) in THF (25 mL) was connected a hydrogen balloon. Hydrogenation was maintained at RT overnight. The mixture of reaction was filtered through Celite. The resulting clear solution was evaporated to give the title compound (2.97 g, 100%) as a yellowish oil.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>[Cl-].[Na+].O>[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccccc1
Reactant: OC1CN2CCC1CC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccccc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.2 %

Procedure:
To a 30 ml toluene solution containing 0.70 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate and 0.41 g of 3-quinuclidinol, 0.03 g of sodium hydride (60%) was added. The resulting mixture was stirred at 140° C. for 2 days while removing the ethanol formed. The reaction mixture was cooled to room temperature, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1→chloroform:methanol:28% aqueous ammonia=10:1:0.1), thereby 0.11 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate was obtained as yellow oil. The resulting oil was dissolved in 10 ml of ethanol, followed by the addition of 27 mg of oxalic acid. Then, the solvent was removed under reduced pressure. The resulting solid was recrystallized from isopropanol and isopropyl ether, thereby 0.08 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate monooxalate was obtained as colorless crystals.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[ClH:7].[CH:8]1([C@H:11]([NH:15][CH2:16][C:17]#[N:18])[CH2:12][O:13][CH3:14])[CH2:10][CH2:9]1>O1CCOCC1.C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:15]([C@@H:11]([CH:8]2[CH2:10][CH2:9]2)[CH2:12][O:13][CH3:14])[CH:16]=[C:17]([Cl:7])[N:18]=1
Reactant: Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC[C@@H](NCC#N)C1CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Temperature: 53 °C
Yield: 68.7 %

Procedure:
Oxalyl chloride (54.5 mL, 624 mmol) was added dropwise to a cold (<8° C.) solution of (S)-2-(1-cyclopropyl-2-methoxyethylamino)acetonitrile hydrochloride (23.6 g, 124 mmol) in 1,4 dioxane (300 mL) and methylene chloride (200 mL). The reaction mixture was then heated at 53° C. for 19 h. The reaction mixture was cooled to room temperature and concentrated to a semi-solid then co-evaporated three times with CH2Cl2 (50 mL). The resulting brown solid was purified by column chromatography on silica gel (0→10%→20% ethyl acetate in hexanes) to afford (S)-3,5-dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (22.4 g, 69% yield) as a white solid: Mp 109.8-110.8° C.; [α]25D−88.8 (c 0.513, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 4.12-4.08 (m, 1H), 3.73 (dd, JAB=10.3, JAX=4.5 Hz, 1H), 3.62 (dd, JBA=10.3, JBX=3.0 Hz, 1H), 3.32 (s, 3H), 1.43-1.37 (m, 1H), 0.82-0.76 (m, 1H), 0.65-0.61 (m, 1H), 0.55-0.50 (m, 1H), 0.33-0.27 (m, 1H); LRMS (ESI) m/e 206.3 [(M+H)+, calcd for C10H13N2O2Cl2 263.0]. Anal. calcd. for C10H12N2O2Cl2; C, 45.64, H, 4.59, N, 10.64. Found: C, 45.74, H, 4.62, N, 10.61.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[C@H:11]([CH2:13][CH3:14])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36].[CH:41]1([NH:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.N[C@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)[C@H](CC)C>C(N(CC)CC)C.C(Cl)Cl>[CH:48]1([NH2+:47][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]1.[C:1]([NH:9][C@@H:10]([C:15]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([O-:37])=[O:36])=[O:17])[C@H:11]([CH2:13][CH3:14])[CH3:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[C@@H](C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC[C@H](C)[C@@H](NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)[O-]
Reaction time: 2 h

Procedure:
19.2 g. (81.5 mmoles) of benzoyl-L-isoleucine (F. Ehrlich: Berichte 37, 1809 (1904) and 16.5 g. (80 mmoles) of dicyclohexyl-carbodiimide are dissolved in 150 ml. of methylene chloride cooled to 5° to 10° C. The solution is stirred in an ice bath for two hours, then 2 ml. of triethyl amine and 100 ml. of petroleum ether are added. The precipitated dicyclohexyl-urea is filtered off and washed with petroleum ether (2×20 ml.). The filtrate is extracted with water (2×50 ml.), 5 percent sodium hydrogen carbonate solution (2×50 ml.) and water, dried over sodium sulfate and evaporated at reduced pressure. The residue is dissolved in 80 ml. of pyridine, then 9.2 g. (80 mmoles) of L-proline and 22.4 ml. (160 mmoles) of triethylamine are added to the solution. The reaction mixture is stirred at room temperature for six hours, then is evaporated under reduced pressure. The residue is dissolved in a mixture of water (100 ml.) and ether (50 ml.), the aqueous phase is washed twice with ether (20 ml.), and the combined ether extracts are washed twice with water (20 ml.). The aqueous phases are combined and acidified with 5 N sulfuric acid to pH=2. The separated oil is extracted three times with ethyl acetate (50 ml.), the combined ethyl acetate is washed twice with water (20 ml.), dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 100 ml. of ether, thereafter 16 ml. of dicyclohexyl amine are poured to the solution. The crystals formed are filtered, washed with ether (3×20 ml.) and dried over concentrated sulfuric acid in vacuo. Yield 26.3 g. (64 percent of the theoretical yield) of the named compound. M.p. 117° to 118° C. RF1 =0.36 to 0.46 and 0.13 to 0.23 (dicyclohexylamine). Amino acid analysis: proline: 1.00 (base); allo-isoleucine: 0.92; isoleucine: 0.02.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][NH2:28].C(O)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:28][CH3:27])=[CH:13][CH:12]=1
Reactant: CN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)cc1
Reaction time: 8 h

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. (ESMS): 326.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].[S:25]([NH2:35])(=[O:34])([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(CC)CC>[O:16]=[C:14]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([S:25](=[O:34])(=[O:26])[NH2:35])=[CH:28][CH:29]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)CN(CCCCCC(=O)O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(CCCCCC(=O)Nc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Yield: 31 %

Procedure:
A solution of 6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.6545 g, 1.95 mmol), sulfanilamide (0.362 g, 2.10 mmol) and HATU (0.798 g, 2.10 mmol) in DMF (10 mL) and Et3N (1.0 mL) was stirred at 40° C. overnight. The reaction mixture was purified by flash chromatography over silica gel eluting with MeOH/DCM to give tert-butyl 2-((6-oxo-6-(4-sulfamoylphenylamino)hexyl)(pyridin-2-ylmethyl)amino)acetate (297 mg, 31%). ESMS m/z: 491.3 (M+H)+.