Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18](=[O:25])[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:2]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:55][C:56]([CH3:58])=O>C(Cl)Cl.C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18]([N:19]2[CH2:20][CH2:21][N:22]([CH:56]([CH3:58])[CH3:55])[CH2:23][CH2:24]2)=[O:25])[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2ccccc2cn1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)CC[C@@H](COC(=O)Nc2cc3ccccc3cn2)N(C)C(=O)NCc2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl isoquinolin-3-ylcarbamate (610 mg, 1.07 mmol) in acetone (1 mL) and DCM (1 mL) was added acetic acid (4 drops, ˜0.2 mL). The reaction mixture was stirred at RT for 30 min. To this mixture was added solid NaBH(OAc)3 and the resulting mixture was stirred at RT for 1 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrle and water (0.1% HCOOH buffer). The fractions was collected, concentrated to dryness, and re-dissolved in EtOAc. The organic mixture was washed with Na2CO3, dried over Na2SO4, filtered, and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(4-isopropylpiperazin-1-yl)-5-oxopentyl isoquinolin-3-ylcarbamate (540 mg, 82%) as white solid. LRMS (M+H+) m/z 613.3.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:10][C:9]=2[F:23])[C:3]1=[O:24].[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33](Cl)(=[O:35])=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:10][C:9]=3[F:23])[C:3]2=[O:24])(=[O:35])=[O:34])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1nccn1-c1ccc(N2CCCN(N)C2=O)c(F)c1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(N2CCCN(NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.6 mg (0.046 mmol) of the diHCl salt of 1-amino-3-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-tetrahydropyrimidin-2(1H)-one prepared as above, were dissolved in 3 mL of anhydrous CH2Cl2. To this solution placed under N2 atmosphere were added 50 μL of TEA followed by 11.2 mg (0.046 mmol) of 2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride. The mixture was stirred at room temperature overnight. An additional 3 mL of CH2Cl2 were added, and the mixture was washed twice with 2 mL of saturated NaHCO3 solution. The organic phase was dried and concentrated to yield 17.2 mg of a brown oil. A pure compound was obtained after purification by preparative HPLC. 1H NMR (500 MHz, MeOD) δ 7.53 (t, 1H), 7.49 (s, 1H) 7.41 (d, J=10.4 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.93(d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.1 (m, 1H), 4.45 (q, 2H), 3.5 (m, 2H), 3.14 (m, 1H), 2.86 (s, 6H), 2.0 (m, 2H), ppm. LC-MS (ESI) 556.8 [M+NH4+, tR=4.645 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H25ClFN6O3S2 [M+H]+ 539.1102. found 539.1105
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][CH2:17][C:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH2:17][C:18]3([CH2:21][OH:22])[CH2:20][CH2:19]3)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NCC1(CO)CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)cc2c1NCC1(CO)CC1
Yield: 73.7 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 45 mg, 0.164 mmol), (1-(aminomethyl)cyclopropyl)methanol HCl salt (25.9 mg, 0.189 mmol) and DIPEA (0.072 mL, 0.410 mmol) in NMP (0.5 mL) was heated to 110° C. for 1 hr. The reaction mixture was purified on preparative HPLC to afford the title compound (41 mg, 74%). HPLC (condition G): retention time=2.73 min. LCMS (condition B): m/z 339.1, 341.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH:69]([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72]>CN(C=O)C.O>[CH2:71]([O:70][CH:69]([O:73][CH2:74][CH3:75])[CH2:68][CH2:67][NH:66][C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:31]=[CH:32][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:13][CH:14]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:29])[CH3:72]
Reactant: CCOC(CCN)OCC
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)cc3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 115) (700 mg, 1.64 mmol) in 10 ml of anhydrous DMF were added HATU (684 mg, 1.84 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol). The mixture was stirred at room temperature for another 10 minutes and poured into 150 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 910 mg, 100%.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C(O)C>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[S:31](=[O:32])(=[O:33])[N:34]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)C)c1=O)N2
Temperature: 180 °C
Yield: 45 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-5-methoxy-benzenesulfonamide (Example 2b, 0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.5 mL) and heated to 110° C. for 12 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The crude solid was washed with methanol and dried in vacuo to afford the desired product, 4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.027 g, 0.063 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (6H, d, J=6.4 Hz), 1.69 (1H, m), 1.78 (1H, m), 3.89 (3H, s), 4.39 (2H, t, J=7.6 Hz), 6.60 (1H, dd, J1=4.4 Hz, J2=2.8 Hz), 7.04 (1H, d, J=4.4 Hz), 7.05 (1H, dd, J1=4.8 Hz, J2=2.0 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.39 (1H, d, J=2.0 Hz); LC-MS (ESI) calcd for C19H22N4O5S 430.49, found 431.33 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:31][Mg]Br>O1CCCC1.C(OCC)C>[CH3:31][C:2]1([OH:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[Mg]Br
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(C)(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is suspended in tetrahydrofuran (20 ml), and thereto is added dropwise a 3.0M solution of methyl magnesium bromide in diethyl ether (1.5 ml) at room temperature. The mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (20 ml), and extracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=2:3→1:1), and recrystallized from ethyl acetate/n-hexane to give 5-methyl-5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as white powder, m.p. 204°-205° C.
Reaction SMILES: [N+](C1C=C[N+]([O-])=C2NC=CC=12)([O-])=O.[N+:14]([C:17]1[C:25]2[C:20](=[N+:21]([O-])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([O-:16])=[O:15].CS([Cl:31])(=O)=O>CN(C)C=O>[Cl:31][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[C:25]=12
Reactant: O=[N+]([O-])c1c[nH]c2c1ccc[n+]2[O-]
Reactant: CS(=O)(=O)Cl
Agent: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of a 2:1 mixture (589.8 mg) of 4-nitro-1H-pyrrolo-[2,3-b]pyridine 7-oxide and 3-nitro-1H-pyrrolo[2,3-b]pyridine-7-oxide in N,N-dimethylformamide (6 ml) was added dropwise methanesulfonyl chloride (0.68 ml) at 65° C. The reaction mixture was stirred at 65° C. for 2 hours. The reaction mixture was quenched with water (30 ml) under ice cooling, and neutralized (pH ˜6.5) with 20% NaOH solution. The resulting precipitates were collected by filtration, dried in vacuo at 40° C., and washed with EtOAc to give 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (172.8 mg) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[ClH:19].[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([CH3:35])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2F)c1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5ccccc5F)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 1-(2-fluorobenzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.70(1H,s), 9.45(1H,s), 8.90(1H,s), 8.60(1H,d), 8.20(1H,s), 8.13(1H,s), 7.85(1H,d), 7.70(1H,d), 7.38(1H,m), 7.24 (1H,m), 7.17 (3H,m), 5.76(2H,s), 2.65 (3H,s); m/z (M+1+) 452.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]2[C:16]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[N:15][C:14]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=3)=[N:13][C:12]=12.[OH-].[Na+]>CO.O>[NH2:28][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[N:15]=[C:16]([NH:17][CH:18]3[CH2:19][CH2:20]3)[N:11]3[N:10]=[CH:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[C:12]3[N:13]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCc1cnn2c(NC3CC3)nc(Nc3cccc(N)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(Nc2nc(NC3CC3)n3ncc(CCCCC(=O)O)c3n2)c1
Yield: 87.4 %

Procedure:
To a solution compound (9a) (0.12 g, 0.3 mmol) in 10 mL of MeOH and 0.5 mL of H2O was added NaOH (40 mg, 1 mmol). The reaction mixture was refluxed for 1 h, concentrated to re-move MeOH. The reaction solution was adjusted to pH 4 with HCl and the solid was collected by filtration, washed with water, and dried in vacuum over P2O5 to give 5-[2-(3-amino-phenylamino)-4-cyclopropylamino-pyrazolo[1,5-a][1,3,5]triazin-8-yl]-pentanoic acid (10a) (0.1 g, 90%).
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]([C:11]1([OH:14])[CH2:13][CH2:12]1)=[O:10])[CH3:7].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C(Cl)Cl>[Cl:23][C:21]([O:14][C:11]1([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:13][CH2:12]1)=[O:22]
Reactant: CCOC(=O)C1(O)CC1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(OC(=O)Cl)CC1

Procedure:
Step 81) A THF solution (50 mL) of 1-hydroxy-cyclopropanecarboxylic acid ethyl ester (5 g, 38.4 mmol) and pyridine (3.3 mL, 41 mmol) was added dropwise a phosgen/toleune solution (25 mL, 47.5 mmol) at 0° C. in 5-10 min. the reaction mixture was allowed slowly warm up overnite. The solid was filtered off and the filtration was concentrated in vacuo. The residue was dissolved in hexane, refiltered, and concentrated in vacuo to afford.7.4 g (100%) the product. The product was dissolved in CH2Cl2 (100 mL) as a stack solution: 1H NMR (300 MHz, CHLOROFORM-D) □ ppm 1.25 (t, J=7.14 Hz, 3H), 1.37 (m, 2H), 1.57 (m, 2H), 4.21 (q, J=6.95 Hz, 2H); (ppm) 13.97, 15.75, 62.07, 62.13, 150.54, 168.71.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[O:4].[C:18]([O-:21])(=[S:20])[CH3:19].[Na+].C(O)(=S)C.[Na]>CO>[C:18]([S:20][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:8])=[O:4])(=[O:21])[CH3:19]
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)CCl
Reactant: CC([O-])=S
Agent: CC(O)=S
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(=O)SCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Yield: 88.5 %

Procedure:
The crude chloroacetylglycylglycylglycine product (1.0 g, 0.0037 mol) was suspended in 50 ml of anhydrous methanol under nitrogen. Sodium thioacetate (prepared from 0.58 g (0.0076 mol) of thioacetic acid and dry methanol to which 175 mg (0.0076 mol) of sodium had been added) in methanol was added. The reaction mixture was refluxed for 1.5 hr. After removal of solvent under reduced pressure, 2N HCl was added with stirring. The solid was isolated by filtration and washed with CHCl3. Crystallization from methanol/water gave 1.00 g (90%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[C:25]([F:28])([F:27])[F:26])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1C(OC(C)(C)C)=O)=O.FC(F)(F)C(O)=O.COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1)=O>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[CH:15][C:14]=2[C:25]([F:27])([F:26])[F:28])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester containing (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give a mixture of the title compound and (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as yellow oil. MS (ESI): m/z=436.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:2]1([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 250 g (2.68 mole) of aniline and 233.2 g (2.95 mole) of pyridine in 1.25 L of methylene chloride and 319.6 g (2.79 mole) of methanesulfonyl chloride dropwise. Stir the resulting solution at 0° C. for about 30 minutes then warm to ambient temperature for about 16 hours. Extract the mixture with 2N aqueous sodium hydroxide (4×1 L). Combine the aqueous extracts and wash with 1 L of methylene chloride. Cool the aqueous layer to about 0° C. and acidify with concentrated hydrochloric acid until about pH 1. Collect the precipitate and dry to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:24])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g, 0.0015 mol) (Aldrich Cat. #495484) and triethylamine (0.31 mL, 0.0022 mol) in methylene chloride (2 mL) was added p-nitrophenyl chloroformate (0.33 g, 0.0016 mol) (Acros Organics, Cat. #17080). The mixture was stirred at r.t. for 2 h. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography on a silica gel with ethyl acetate in hexanes (0-20%) to afford the desired product (0.32 g, 58%). Analytic LCMS (M+Na)+: m/z=389.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[CH:26]([C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1)([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:26]([C:29]1[S:33][C:32]([NH:34][S:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[O:10][CH:11]=3)=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1nnc(N)s1
Reactant: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Cl)cc3)co2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Nc4nnc(C(C)C)s4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
580 mg 4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride were added to a stirred solution of 275 mg 5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 ml pyridine. 18 mg 4-Dimethylaminopyridine were added. The reaction mixture was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue coevaporated with 15 ml toluene. The residue was purified by RP-HPLC to obtain 19 mg N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: C[C@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (22 ml of a 2.29M solution, 0.050 mole) was added and the reaction mixture was heated at 45° L C. for two days under nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to a residue which was dissolved in hot isopropyl ether, filtered, and cooled to room temperature. The resulting solid was collected by filtration and dried under high vacuum at 50° C. to give 2.61 g (48%) of title compound, mp 124°-127° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.CS(C)=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2Cl)C1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCCCC2)C1
Temperature: 160 °C
Yield: 180 %

Procedure:
To a mixture of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (91) (0.16 g, 0.50 mmol) and piperidine (0.085 g, 1.0 mmol) was added triethylamine (0.10 g, 1.0 mmol) and DMSO (3 mL). The solution was heated to 160° C. in microwave for 2 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give 3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (92) (0.16 g, 0.90 mmol, 90% yield) as a white solid. ESI-MS (M+1): 369 calc. for C21H28N4O2 368.