Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][CH2:29][CH2:30][N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=3)[CH2:39]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCCC(Br)CCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1ccc(C(C#N)(CCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 20041 %

Procedure:
The procedure of Example 3 is repeated using 0,836 g of α-(5-bromooctyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 0.675 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 0,422 g of the desired product as a brown gum.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:3]1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].Cl>ClCCCl>[C:46]([NH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:17][C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:3]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ccco2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-amino-5-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (70 mg) in 1,2-dichloroethane (3 ml) were successively added triethylamine (55 μl) and acetic anhydride (35 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (50:50:0-85:0:15) was concentrated under reduced pressure to give the object compound (28.5 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:24][C:25]([O:27]CC)=[O:26])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:24][C:25]([OH:27])=[O:26])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)OCC)cc3c2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)O)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl {5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-2H-indazol-2-yl}acetate (Example 120, 90 mg; 0.20 mmol) in ethanol (10 ml) was treated with 10% NaOH solution (5 ml). After stirring at RT for 2 hours the solvent was reduced in vacuo to one quarter of its original volume and water (20 ml) added. The mixture was acidified with dilute HCl and the solid removed by filtration, washed with water and dried to give the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[N:23]=[CH:24][N:25]([CH3:28])[C:26]=1Cl)(=[O:21])=[O:20])(=[O:10])=[O:9]>[OH-].[Na+].[Pd]>[CH3:28][N:25]1[CH:26]=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:8]([C:3]2[N:4]=[CH:5][N:6]([CH3:7])[CH:2]=2)(=[O:9])=[O:10])(=[O:20])=[O:21])[N:23]=[CH:24]1
Reactant: Cn1cnc(S(=O)(=O)NCCCCCCNS(=O)(=O)c2ncn(C)c2Cl)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cn1cnc(S(=O)(=O)NCCCCCCNS(=O)(=O)c2cn(C)cn2)c1

Procedure:
13 g (27 mmol) of 1,6-bis(5-chloro-1-methyl-4-imidazolesulfonamido)hexane from Example 47 in 250 ml of 1N sodium hydroxide solution are hydrogenated over 3 g of 10% strength Pd/C catalyst while shaking at an initial pressure of 3.45 bar until absorption of hydrogen is complete. After separating off the catalyst, the filtrate is evaporated in vacuo. The residue was recrystallized from water/methanol in order to give the title compound as colorless crystals of melting point 153°-154° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20](C(OC)=O)=[CH:19][CH:18]=1>>[CH3:12][O:13][C:14](=[O:28])[C:22]1([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[O:28]
Reactant: COC(=O)CC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(C)Oc1ccc(N)cc1
Product: COC(=O)C=CC1C=CC=CC1(Nc1ccc(OC(C)C)cc1)C(=O)OC

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 1 from p-isopropoxyaniline and 4-methoxycarbonylbenzoyl acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:24]#N)[CH2:8][CH2:7][CH:6]([CH:9]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[C:27]1([Mg]Cl)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:22]([O:21][CH:19]([O:18][CH:9]([CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:26])[CH3:1])([C:24]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC(COc1ccccc1)C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile (871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (3.6 ml, 7.3 mmol), while cooling with ice. The mixture was stirred at room temperature overnight and saturated ammonium chloride solution and water (5 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [OH:1][CH:2]([CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:25]I.[H-].[Na+].O>CN(C)C=O>[CH3:25][O:1][CH:2]([CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To 2 g of ethyl 2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate dissolved in 30 ml of anhydrous dimethylformamide, CH3I (0.78 ml) was added at 3° C., then, in two additions, at the same temperature, NaH 50% (0.3 g) was added too. The whole was stirred at 3° C. for one hour and at room temperature for one hour, after which it was poured into 300 ml of water, extracted with ethyl ether which, after washing with NaCl saturated water and dehydration with sodium sulphate, was evaporated to dryness under reduced pressure. There was obtained 2 g (96%) of ethyl 2-methoxy-3-phenyl-3-(2-nitro-phenoxy)-propionate as an oil.
Reaction SMILES: Br[Zn][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[CH2:11]([C:13]1[C:17](I)=[C:16]([CH:19]=[O:20])[NH:15][C:14]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:12]>C1COCC1.CN1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:11]([C:13]1[C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)=[C:16]([CH:19]=[O:20])[NH:15][C:14]=1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH3:12]
Reactant: COc1cccc([Zn]Br)n1
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1-c1cccc(OC)n1
Temperature: 100 °C

Procedure:
Tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate was obtained following the procedures described in Example 1. To a solution of bromo(6-methoxypyridin-2-yl)zinc (0.076 g, 0.30 mmol) in THF (0.6 mL) and N-methylpyrrolidine (0.44 mL) under argon was added Pd(Pt-Bu3)2 (0.002 g, 0.0032 mmol) and tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate (0.070 g, 0.20 mmol). The reaction was heated to 100° C. and refluxed for 20 h under argon. After cooling to ambient temperature, the reaction was filtered through a pad of silica gel and concentrated. The resultant residue purified by normal phase flash chromatography (5-15% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.86 (s, 1H); 7.66 (t, J=7.8 Hz, 1H); 7.02 (d, J=7.1 Hz, 1H); 6.76 (d, J=8.3 Hz, 1H); 3.95 (s, 3H); 2.90 (q, J=7.3 Hz, 2H); 1.61 (s, 9H); 1.23 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C18H23N2O4 (M+H+): 331.1656. Found 331.1656.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:17][N:18]=2)[N:15]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: OCC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: FC(F)(F)Oc1cccc(-c2cnc3ccc(OCC4CCOCC4)nn23)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 7.4 %

Procedure:
To the solution of compound (tetrahydro-2H-pyran-4-yl)methanol (100 mg, 0.86 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (270 mg, 0.86 mmol) in 10 mL dioxane was added t-BuOK (200 mg, 1.78 mmol). The mixture was stirred at 70° C. for 4 hrs. Then the mixture was purified by Pre-HPLC to afford the compound 6-((tetrahydro-2H-pyran-4-yl)methoxy)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (25 mg, 12%) as a white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:39])[CH2:8][C:9](=[O:38])[C:10]([CH3:37])([CH3:36])[C:11](=[O:35])[CH:12]([CH3:34])[CH:13]([O:25][C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27])[CH:14]([CH3:24])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:5])([CH3:4])[CH3:3]>CO>[C:2]([O:6][C:7](=[O:39])[CH2:8][CH:9]([OH:38])[C:10]([CH3:37])([CH3:36])[C:11](=[O:35])[CH:12]([CH3:34])[CH:13]([O:25][C:26]([O:28][CH2:29][C:30]([Cl:32])([Cl:31])[Cl:33])=[O:27])[CH:14]([CH3:24])[CH2:15][O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C(=O)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C(O)CC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 79.6 %

Procedure:
A bomb liner was charged with (R)-RuBINAP catalyst (16.8 mg, 10.0 μmol). HCl (555 μL, 0.2N in MeOH) was added and the mixture was then sonicated for 15 sec. Then a solution of 69 (59.4 mg, 0.1 mmol) in MeOH (555 μL) was added and the mixture transferred to a Parr apparatus. The vessel was purged with H2 for 5 min and then pressurized to 1200 psi. After 17 h, the reaction was returned to atmospheric pressure and poured into a sat NaHCO3 aq solution. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 88:12) to give 70 (dr>20:1 as judged by 1H NMR analysis) (47.6 mg, 80%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 1.06 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.14 (s, 3H), 1.18 (s, 3H), 1.47 (s, 9H), 2.05-2.12 (m, 1H), 2.35-2.40 (m, 1H), 3.31-3.37 (m, 2H), 3.51-3.54 (m, 2H), 4.11-4.14 (m, 1H), 4.46 (s, 2H), 4.72 (d, J=11.9 Hz, 1H), 4.80 (d, J=11.9 Hz, 1H), 5.05 (dd, J=5.0 and 6.7 Hz, 1H), 7.27-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 12.0, 15.0, 19.3, 21.7, 28.0, 35.6, 37.5, 41.7, 51.8, 71.3, 73.0, 73.3, 80.6, 81.3, 94.7, 127.5, 127.7, 128.3, 138.2, 154.1, 172.4, 216; IR (film, NaCl, cm−1) 3849, 2974, 2879, 1758, 1701, 1454, 1368, 1248, 1152, 926, 734; LRMS (ESI) calcd for C27H39O8Cl3Na [M+Na+] 619.1, found 619.2; [α]23D=−13.0 (c=0.4, CHCl3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].[O:18]1CCOC[CH2:19]1>>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[NH:2][C:19](=[O:18])[N:11]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CNc1cc(Cl)ccc1C(N)=O
Reactant: C1COCCO1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-(2-carbamoyl-5-chlorophenyl)aminoacetate (357 g) and N,N'-carbonyldiimidazole (451 g) were dissolved in 1,4-dioxane (1.5 l) and 1,4-dioxane was concentrated to a bout 0.5 l by distillation. The resulting mixture was stirred at 150° C. for 30 minutes. After cooling, the precipitated crystals were collected by filtration and washed with ethanol to give ethyl 2-(7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (353 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 31.4 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (695.2 mg) and ethyl 4-aminophenylacetate (380 mg) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (509.5 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (321.5 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=[CH:10][CH:9]=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Yield: 62 %

Procedure:
To a suspension of 1.08 g (60% reagent, 27 mmol) of sodium hydride in 20 ml of tetrahydrofuran (THF), stirred in an ice bath, was added dropwise 6 ml (6.7 g, 27 mmol) of triethyl 4-phosphonocrotonate. The resulting mixture was stirred for an additional 1 hour in the cooling bath and a solution of 4.2 g (18 mmol) of 1-benzylindol-3-carboxaldehyde in 25 ml of water. This mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layer was washed with two 25 ml portions of brine, dried (magnesium sulfate) and concentrated on a rotary evaporator to give an oil. Purification on a dry column (25% ethyl acetate in hexane) followed by crystallization (acetone-ether) gave 3.7 g of product as orange crystals, m.p. 110-112. MS (EI): 331 (M+), 240 (M+--C7H7), 167 (M+--C7H7 --CO2C2H5). NMR spectrum (CDCl3) shows a triplet centered at δ1.26 (J=7 Hz), a singlet at δ5.21, a doublet centered at δ5.8 which is the signal of the olefinic proton adjacent to the carbonyl group. The remainder of the proton signals cluster around 7.25 ppm.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]1[O:18][C@@H:17]1[CH2:19]Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C@H:17]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: ClC[C@@H]1CO1
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [K:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:25](O)(=[O:27])[CH3:26].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[K:1].[C:25]([O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-hydroxy-5-[2-(4-sulfophenyl)ethenyl]benzoate potassium salt (57.5 g, 0.15 mol), acetic acid (35 ml) and acetic anhydride (142 ml) were refluxed until the major part of the solids had dissolved, and then more acetic anhydride (142 ml) and sulfuric acid (1 ml) were added. After boiling for 1.5 h, the mixture was cooled to room temperature and diethyl ether was added to complete precipitation. After filtration and drying, the yield was 43.4 g (69%).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[N:9][CH:10]=1.[H-].[Na+]>>[CH3:15][CH:2]1[NH:1][C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC(N)CCc1ccc(CCCN)nc1
Agent: [H-]
Agent: [Na+]
Product: CC1CCc2ccc(CCCN)nc2N1
Temperature: 100 °C

Procedure:
A solution of the diamine 9-3 (1.87 g, 9.05 mmol) in xylenes (100 mL) was degassed with nitrogen gas then treated with NaH (1.3 g, 54.3 mmol) and then heated to 100° C. for 16 hours. Mass spectrum indicated desired product formed. The mixture was cooled, EtOH added then poured into water and extracted with EtOAc. The organic layer was washed with water, brine dried (MgSO4) and concentrated. Purification of the residue on silica gel (2%-5% MeOH/CHCl3) gave a solid which was shown to be the N-acetate of the desired compound by mass spectrum and nm. Treatment with aqueous NaOH/THF/MeOH at reflux for 72 hours then afforded the hydrolysed product. The THF/MeOH was removed in vacuo, the residue was partitioned between water and CH2Cl2, washed with brine and dried over MgSO4. Removal of the solvent afforded the title compound 9-4.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[C:10]([Br:20])[CH:11]=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]=2[CH3:15])[CH:8]=[CH:7][N:6]=1)(=O)C.[OH-].[Na+]>CO>[Br:20][C:10]1[CH:11]=[C:12]([O:16][CH:17]([CH3:18])[CH3:19])[C:13]([CH3:15])=[C:14]2[C:9]=1[CH:8]=[CH:7][NH:6][C:5]2=[O:4]
Reactant: CC(=O)Oc1nccc2c(Br)cc(OC(C)C)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OC(C)C)cc(Br)c2cc[nH]c(=O)c12
Yield: 85.4 %

Procedure:
To a solution of 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinolin-1-yl acetate (108 g, 0.28 g, 0.83 mmol) in MeOH (2 mL) was added 1M NaOH (2 mL). The reaction mixture was refluxed for 1 hour, then concentrated under vacuum. The residue was diluted in water and the pH was adjusted to 4-5 with 1M HCl. The solution was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108h, 0.21 g, 86%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:29])=[O:28]
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.85 mmol) and (3-bromo-propyl)-benzene (0.085 mmol). Stirred at 35° C. for 1.5 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with TFA (2 mL) at rt→45° C. for 1.5 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.