Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CC2)c(F)c1
Reaction time: 16 h
Yield: 23.9 %

Procedure:
According to general procedure B, 4-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (176 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonamide (45 mg, 24%) was provided after purification. MS (ESI) m/z 319. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1>CCO>[Cl:16][C:14]1[C:13]([O:17][CH3:18])=[CH:12][C:11]([CH:19]([CH3:21])[CH3:20])=[C:10]([CH:15]=1)[CH2:9][C:8]1[C:3]([NH2:1])=[N:4][C:5]([S:22][CH3:23])=[N:6][CH:7]=1
Reactant: N
Reactant: COc1cc(C(C)C)c(Cc2cnc(SC)nc2Cl)cc1Cl
Solvent: CCO
Product: COc1cc(C(C)C)c(Cc2cnc(SC)nc2N)cc1Cl
Temperature: 85 °C
Yield: 92 %

Procedure:
To 25 ml of saturated NH3 in EtOH was added 4-Chloro-5-(5-chloro-2-isopropyl-4-methoxy-benzyl)-2-methylsulfanyl-pyrimidine (0.580 g, 1.6 mmol). The solution was warmed to 85° C. in a sealed reaction vessel. After 3 days the solution was cooled, concentrated in vacuo and suspended in CH2Cl2. The precipitate was filtered and the mother liquor was concentrated in vacuo. Purification via flash chromatography (7:3 hexane/ethyl acetate) afforded 5-(5-chloro-2-isopropyl-4-methoxy-benzyl)-2-methylsulfanyl-pyrimidin-4-ylamine (0.504 g, 92%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][C:58]=1[NH2:59])[C:54]#[N:55]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:59][C:58]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][C:51]=2[NH2:50])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C#N)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (14.1 g, 0.061 mol) in DMF (282 mL) was added HBTU (27.76 g, 0.073 mol), DMAP (10.2 g, 0.084 mol) and diisopropylethyl amine (24.2 mL). The reaction mixture was stirred for 30 minutes at rt before 3,4-diaminobenzonitrile (8 g, 0.059 mol) was added. The mixture was stirred overnight at rt before the reaction was quenched by pouring into water (2 L). The mixture was extracted with CH2Cl2 and the organic phase washed successively with 1M aq. HCl solution and 10% aq. Na2CO3 solution, dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel afforded the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].CO>>[ClH:34].[CH3:33][O:32][C:17]1[C:18]2[N:19]=[C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[S:21][C:22]=2[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)c2sc(NC(=O)N3CCOCC3)nc12
Yield: 67 %

Procedure:
0.45 g (0.094 mMol) 4-{4-Methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 2 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 5 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 26 mg (67%) morpholine-4-carboxylic acid (4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-amide hydrochloride (1:1) as a white solid. F.p.: 314-315° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[CH:9][C:10]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:13])=[O:4].[Li+].[OH-]>C1COCC1>[C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:13])=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1NC(=O)OCc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccccc2)cc1C(=O)O)OCc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a solution of 4-(biphenyl-4-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid methyl ester (0.51 g, 1.179 mmol) in THF (5 mL) was added at room temperature 1.0 M LiOH (2.42 mL, 2.42 mmol) and the mixture was stirred for 3 h. The solvent was evaporated, water was added, followed by 2N HCl to adjust the pH to 1-2, and the product was extracted with ethyl acetate. The extract was washed with water, then brine, and dried over magnesium sulfate, concentrated to dryness and purified by chromatography to yield 0.317 g of 4-(biphenyl-4-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid 601, mp: 234.5-235.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1)[S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.S(C1C=CC(C)=CC=1)(O[CH2:43][CH2:44][Cl:45])(=O)=O.[H-].[Na+]>CC(=O)CC>[Cl:45][CH2:44][CH2:43][O:36][C:34]1[CH:35]=[C:30]([CH:21]([S:22][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCCl)c1)CC2
Temperature: 25 °C

Procedure:
To a stirred solution of 5.57 g of 5-[7-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-1-[(4-methylphenyl)thio]heptyl]-2-methoxyphenol and 2.0 mL of 2-chloroethyl tosylate in 50 mL of 2-butanone is added 0.44 g of 60% sodium hydride in oil. The solution is heated to reflux for 48 hours and then cooled to room temperature. The solution is partitioned between chloroform and brine and the organic layer dried. The solvent is removed at reduced pressure and the residue chromatographed on silica gel with a gradient elution going from hexane to chloroform to methyl alcohol. The desired fractions are concentrated, dissolved in diethyl ether and passed through a short hydrous magnesium silicate pad. The solvent is removed at reduced pressure to afford 1.6 g of the desired product as a light tan gum.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]1=[O:28])#[N:2].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[C:1]([CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:24])[C:5]1=[O:28])#[N:2]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Yield: 40 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (33 mg, 0.087 mmol) and [2-(methyloxy)ethyl]amine (0.05 mL) was prepared 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (14 mg, 40% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.95 (s, 1 H), 8.62 (s, 1 H), 7.38 (s, 1 H), 7.18-7.15 (m, 2 H), 7.05-7.01 (m, 2 H), 5.12 (s, 2 H), 4.17 (s, 2 H), 3.63 (m, 2 H), 3.57 (m, 2 H), 3.41 (s, 3 H); MS m/z 411 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[NH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3CCCc4ccccc43)cn2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 1,2,3,4-tetrahydroquinoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.76 (2H, t, J=5.5 Hz), 2.64 (2H, t, J=6.2 Hz), 3.08 (2H, t, J=5.5 Hz), 3.62 (2H, t, J=6.2 Hz), 4.20 (2H, t, J=6.2 Hz), 6.48 (1H, t, J=7.1 Hz), 6.61 (1H, d, J=8.1 Hz), 6.86 (1H, d, J=6.6 Hz), 6.95 (1H, t, J=7.7 Hz), 7.53 (1H, d, J=3.6 Hz), 7.71 (1H, s), 7.84 (1H, s), 8.25 (1H, s), 8.53 (1H, d, J=5.0 Hz). [M+H] Calc'd for C20H20N4O2, 349. Found, 349.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:21][CH2:22][OH:23].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:17][CH2:21][CH2:22][OH:23])([CH3:15])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(-c2cncc(Br)c2)cc1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(NCCO)c1ccc(-c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(5-bromo-pyridin-3-yl)-phenyl]-1-methyl-ethylamine (Intermediate 229) (1 eq, 1.72 mmol, 500 mg) in DMF (10 ml) is added NaH (1.2 eq, 2.06 mmol, 82 mg) and the resulting mixture is stirred for 30 min at r.t. Then 2-bromoethanol (Sigma-Aldrich, St. Louis, USA) (2 eq, 3.43 mmol, 0.24 ml) is added, and the mixture is heated at 100° C. for 4 h. 2 M aqueous NaOH is added, and the mixture is extracted with DCM.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:24]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:23]=[C:22]([CH3:34])[CH:21]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:23]=[C:22]([CH3:34])[CH:21]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(CCCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(3-phenylpropyl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as colorless oil which was used in the next step without further purification. MS (ESI): m/z=486.2 [M−H]−.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[OH-].[K+].Cl.NO.I[C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.C(N)C.CO>[C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC#CI
Reactant: C#CCCCCCCCCC(=O)O
Agent: CCN
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O

Procedure:
10-Undecynoic acid (21.8 g, 0.120 mol) was neutralized with a solution of 57 mL 10 percent KOH in water and hydroxylamine hydrochloride (0.380 g) was added. Then a catalyst consisting of a solution of 1.9 g cuprous chloride in 16 g 70 percent aqueous ethylamine was added. A yellow precipitate formed immediately. A solution of the crude 1-iodo-1-dodecyne in 40 mL methanol was then added dropwise with stirring. The suspension was stirred for one hour after the addition. The reaction mixture was acidified by the addition of 2.5N HCl, filtered, and the filtrate and precipitate washed with ether. The ether layers were washed with water, thiosulfate solution, water and saturated sodium chloride. After drying Na2SO4) the solvents were removed under reduced pressure. The residue was induced to crystallize by scratching under petroleum ether. The crystals of the diyne acid (26.4 g, 74%) exhibited m.p. 57°-58° after recrystallization from acetonitrile.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11](=[O:16])[NH:10][C@@H:9]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@H:8]3[C:7]=2[CH:6]=1)[CH3:4].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>C1COCC1>[CH2:3]([C:5]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11](=[O:16])[N:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C@@H:9]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:19][C@H:8]3[C:7]=2[CH:6]=1)[CH3:4]
Reactant: COC(=O)CBr
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CC(=O)OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of sodium hydride (33 mg of 60% dispersion in mineral oil, hexane-washed, 0.87 mmol) in 4 mL of THF was added (±)-trans-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 74, Part A (191 mg, 0.58 mmol) in 10 mL of THF. The resulting mixture was stirred at ambient temperature for 30 min, at which time gas evolution has ceased. Then there was added methyl bromoacetate (0.082 mL, 0.87 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction was quenched with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 15-25% EtOAc/hexane) to afford 180 mg (77%) of the title compound. LRMS (ESI): 403.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:13]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([N:28]=NC2C=CC(OC)=CC=2)[CH:18]=1)(=[O:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:50]([NH:53][C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N:65]=[N:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[C:62]=2[OH:64])[C:57]([S:75](Cl)(=[O:77])=[O:76])=[CH:56][CH:55]=1)(=[O:52])[CH3:51]>O1CCCC1>[C:50]([NH:53][C:54]1[C:63]2[C:58](=[CH:59][CH:60]=[C:61]([N:65]=[N:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[C:62]=2[OH:64])[C:57]([S:75]([NH:28][C:19]2[CH:18]=[C:17]([S:14](=[O:16])(=[O:15])[N:13]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[OH:27])(=[O:77])=[O:76])=[CH:56][CH:55]=1)(=[O:52])[CH3:51]
Reactant: COc1ccccc1N=Nc1ccc2c(S(=O)(=O)Cl)ccc(NC(C)=O)c2c1O
Reactant: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1cc(N=Nc2ccc(OC)cc2)c(O)c2ccccc12
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1cc(NS(=O)(=O)c2ccc(NC(C)=O)c3c(O)c(N=Nc4ccccc4OC)ccc23)c(O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.47 g (0.0050 mole) 4-(N,N-didodecylsulfamyl)-2-(p-methoxyphenylazo)-1-naphthol in 50 ml tetrahydrofuran containing 0.5 g 5% palladium/carbon catalyst was hydrogenated at low pressure and room temperature for 2 hr. The mixture was filtered and poured into water, then extracted with ether. The extract was concentrated to a gum which was dissolved in 50 ml pyridine. The solution was cooled in an ice bath, and 2.17 g (0.005 mole) 4-acetamido-5-hydroxy-6-(o-methoxyphenylazo)naphthalene-1-sulfonyl chloride was added. The mixture was stirred overnight at room temperature, then poured into ice-water containing 50 ml concentrated hydrochloric acid. The purple solid was recrystallized from dichloroethane and ethyl acetate to give, after drying under vacuum, an amorphous solid (Compound No. 14), m.p. 200°-202° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][OH:33])[CH:30]=1.Cl>CC(O)C>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:25][C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][OH:33])[CH:30]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Nc1cnn(CCO)c1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2C1
Temperature: 140 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (633.5 mg, 1.70 mmol) and 2-(4-amino-1H-pyrazol-1-yl)ethanol (249.1 mg, 1.99 mmol) in i-PrOH (8 mL) was added a solution of HCl in EtOAC ((1 mL, 4 mmol)). The reaction mixture was stirred at 140° C. under microwave radiation for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a yellow solid (0.50 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[C:24]([F:32])[C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[C:27]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:25]=[C:24]([F:32])[C:20]=1[C:21]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1)=[O:22]
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1

Procedure:
This compound was prepared in analogy to example 5 from 1-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH+, 67%)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][S:7]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>O>[CH3:6][S:7]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(=[O:8])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: CS(=O)(=O)n1c(N)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)n1c(N)nc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 9.5 mL (20 eq., 142 mmol) of well stirred chlorosulfonic acid at ˜25° C. was added N-methanesulfonyl-2-aminobenzimidazole (1.5 g, 7.1 mmol) in small portions over 1C minutes with slight exotherming. The solution was stirred at ˜25° C. for 3.5 hours, then was added dropwise to a well stirred mixture of ice and water. The aqueous solution was slowly basified to pH ˜7.5 with solid sodium bicarbonate and extracted with EtOAc. A precipitate formed in the organic phase which was filtered off and was washed with H20 and dried on the filter to yield 1.23 g of N-methanesulfonyl-5-chlorosulfonyl-2-aminobenzimidazole. HPLC, single peak, ret. time=7.61 min. MS: Obs. M +H@ 310.0 amu.
Reaction SMILES: CN1CCCCC1.[CH:8]1([O:14][C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC(C)C)=O.[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[CH:37][CH:36]=1)#[N:34]>C(Cl)Cl.O>[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH3:42])=[CH:37][CH:36]=1)#[N:34]
Reactant: CC(C)[C@H](NC(=O)OC1CCCCC1)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Solvent: O
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC1CCCCC1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
0.8 g of N-methylpiperidine was added to a solution containing 2.0 g of N-cyclohexyloxycarbonyl-L-valine dissolved in 150 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 1.1 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 1.5 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of light brown powder (yield: 16%).