Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:18][CH:19]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[CH:20]([CH3:22])[CH3:21])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:18][CH:19]([O:23][C:24]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:25])[CH:20]([CH3:22])[CH3:21])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCCCC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (700 mg, 4.5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl pentanoate (500 mg, 1.6 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 42 as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.92 (br. m, 11H), 1.17-1.32 (br. m, 5H), 1.45-1.52 (m, 2H), 1.68 (d, J=12 Hz, 2H), 1.85-1.94 (br. m, 3H), 2.04-2.12 (m, 1H), 2.27-2.32 (br. m, 1H), 2.83 (td, J=7.2, 1.6 Hz, 2H), 2.78-2.82 (m, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.38 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 380.16 (M+Na)+; 356.17 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:23])[N:12]2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:6]=1)=[O:4].[NH:40]1[CH2:45][CH2:44]O[CH2:42][CH2:41]1>>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:40]2[CH2:45][CH2:44][N:12]([CH:13]([CH3:14])[CH3:8])[CH2:42][CH2:41]2)[CH:14]=[C:13]2[C:8]=1[CH2:9][NH:10][C:11](=[O:23])[N:12]2[C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: C1COCCN1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CBr)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: CC(C)N1CCN(CC(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1

Procedure:
The title compound was prepared from 7-(bromoacetyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one and using morpholine as an amine as described in EXAMPLE ABA1. 1H NMR (CDCl3, 500MHz): δ 7.53-7.27 (m, 8H); 6.92 (s, 1H); 5.91 (brs, 1H); 4.45 (d, J=15.5 Hz, 1H); 4.28 (d, J=15.5 Hz, 1H); 3.64 (m, 4H); 3.55 (Abq, J=3.7, 15.8 Hz, 2H); 2.44 (m, 4H). Mass spectrum (ESI): 530 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][S:10]([OH:12])=[O:11].CCO.O>CO.C(Cl)Cl>[CH3:9][S:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])(=[O:12])=[O:11]
Reactant: CS(=O)O
Reactant: OCCCCCCBr
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)CCCCCCO
Yield: 47.1 %

Procedure:
The reaction was conducted following the procedure for Example 171: step a, using 6-bromo-hexan-1-ol (0.300 g, 1.660 mmol), methane sulfinic acid, (0.844 g, 8.280 mmol), EtOH [2 mL], H2O, [2 mL]. Chromatography of the residue (1%–5% MeOH/DCM) yielded the title compound (0.141 g 48%). 1H-NMR (CDCl3): δ 3.67 (t, 2H, J=6.2 Hz), 3.03 (t, 2H, J=8.0 Hz), 2.92 (s, 3H), 1.89 (m, 2H), 1.60 (m, 2H), 1.46 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12.[NH4+].[Cl-].Cl>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:13]([CH:14]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:19][CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 17 (59 mmol, 0.29 M) in THF was added dropwise to an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride in THF (120 mL) over a 1 hr period. After the addition was complete, the resulting mixture was stirred for another 30 min at 0° C. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction was then stopped with sat. NH4Cl and the pH adjusted to 2 with concentrated HCl(aq) and then extracted with diethyl ether. The organic layer was washed with water and subsequently extracted with 1 M NaOH. The combined aqueous extract was acidified with concentrated HCl and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over MgSO4, filtered, and concentrated under reduced pressure to afford oil. The oil was dissolved CH2Cl2 and filtered through silica gel to remove the dicarboxylic acid formed during workup. The product was recrystallized from diethyl ether to afford pure product (1.62 g, 10%) as a white solid; mp=109° C.; LRMS ESI [m−H]− cacld for C16H18O5 289, found m/z 289; 1H NMR (CDCl3, 500 MHz): δ 7.60-7.53 (m, 2 H), 6.92 (d, J=8.4 Hz, 1 H), 5.84-5.82 (m, 1 H), 5.71-5.68 (m, 1 H), 4.03-4.00 (m, 1 H), 3.98 (s, 3 H), 3.95 (s, 1 H), 3.10-3.07 (m, 1 H), 2.90-2.84 (m, 1 H), 2.54-2.44 (m, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCCC#Cc1cccc(CC(=O)OCC)c1

Procedure:
heating a mixture of ethyl [3-bromophenyl]acetate and 1-pentyne in the presence of tetrabutylammonium fluoride hydrate and PdCl2(PPh3)2 to provide ethyl [3-[pentyne-1-yl]phenyl]acetate;
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:42]1([CH:45]=O)[CH2:44][CH2:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH:42]1([CH2:45][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH2:44][CH2:43]1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), cyclopropanecarbaldehyde (0.195 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 44 mg (83%) of the title compound as a yellow solid. MS (ESI) m/z 529.4 (M+H)+1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:23])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C:12]1=[O:23]
Reactant: COc1ccc2c(c1)N(CCO[Si](C)(C)C(C)(C)C)C(=O)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)N(CCO)C(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 127, 1.38 g, 4.1 mmol) in tetrahydrofuran (40 mL) was added tetrabutyl ammonium fluoride (1M in tetrahydrofuran (THF), 4.1 mL, 4.1 mmol). The reaction was stirred at room temperature for two hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane, washed with water and dried over magnesium sulfate. Chromatography on silica gel using dichloromethane/methanol (95:5) gave the title compound as a yellow oil (570 mg, 62%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:42]4[CH2:43][CH2:44][N:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:40][CH2:41]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N1CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A flask was charged with (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) and 1-tert-butylpiperazine (33.1 mg, 0.232 mmol). 1,4-Dioxane (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCC3)n2n1)c1cccnc1
Yield: 104.5 %

Procedure:
The title compound was prepared following procedure described for example 84, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 100 mg; 0.3 mmol; 1.0 eq.) and cyclobutylamine (125 μl; 0.150 mmol; 5.0 eq.) at 120° C. for 30 min. under microwave irradiations. Solvents were removed under vacuum to dryness after which the residue was triturated with water, filtered and washed with EtOAc to give the title compound as a white powder (59 mg; 53%). 1H NMR (DMSO-d6) δ 11.4 (s, 1H), 9.15 (d, J=2.2 Hz, 1H), 8.79 (dd, J=1.5, 4.5 Hz, 1H), 8.35 (dt, J=1.8, 7.9 Hz, 1H), 7.63-7.56 (m, 2H), 7.32 (bs, 1H), 6.36 (d, J=1.5 Hz, 1H), 4.32-4.24 (m, 1H), 2.43-2.34 (m, 2H), 2.25-2.18 (m, 2H), 1.79-1.70 (m, 2H). HPLC, Rt: 3.20 min. (purity 94.8%). LC/MS, M+(ESI): 377.0, M−(ESI): 375.0.
Reaction SMILES: [CH3:1][C@@H:2]([NH:9][C:10]([C:12]1[O:13][C:14]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=2[C:16](=[O:18])[CH:17]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][C@@H:2]([NH:9][C:10]([CH:12]1[CH2:17][C:16](=[O:18])[C:15]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:14]=2[O:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](NC(=O)c1cc(=O)c2cc(F)ccc2o1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: C[C@@H](NC(=O)C1CC(=O)c2cc(F)ccc2O1)c1ccccc1
Reaction time: 1 h

Procedure:
Raney nickel (100 mg) was added to a solution of (-)-N-[(R)-α-methylbenzyl]-6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide (1.00 g, 3.21 mmol, obtained in Example 9 or 10) in ethanol (20 ml) and the mixture was hydrogenated for 1 hour at a temperature of 55°-60° C. under H2 atomosphere (1 kg/cm2) with stirring. It was determined that the (+)-isomer/(-)-isomer ratio of the reduction product was 1.4/1 (26% d.e.) by 1H-NMR analysis.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:29])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1csc(N)n1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-(2-amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.16 min; [M+H]+=479.1.
Reaction SMILES: S(=O)(O)[O-].[Na+].[OH-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.N[C:24]1[CH:25]=[C:26]([P:30](=[O:33])([OH:32])[OH:31])[CH:27]=[CH:28][CH:29]=1.Cl.S(=O)=O>>[P:30]([C:26]1[CH:25]=[C:24]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:29]=[CH:28][CH:27]=1)([OH:33])([OH:32])=[O:31]
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: Nc1cccc(P(=O)(O)O)c1
Agent: Cl
Agent: O=S([O-])O
Agent: O=S=O
Product: O=P(O)(O)c1cccc(Nc2cccc3cc(S(=O)(=O)O)ccc23)c1
Temperature: 25 °C

Procedure:
Sodium bisulphite liquor (40% -- 23 parts), sodium hydroxide liquor (70° Tw -- 8.1 parts), salt (1.8 parts), 1-amino-6-sulphonaphtalene (11.2 parts) and 3-aminophenylphosphonic acid (10.4 parts) are heated in a sealed tube for 10 hours at 130° C. After cooling the tube is opened and hydrochloric acid (36% - 13.9 parts) is added until an acid reaction is obtained on Congo Red paper. The suspension is boiled under reflux for 1 hour until evolution of sulphur dioxide has essentially ceased. During this period samples are spotted on to Congo Red paper to confirm acid reaction. The suspension is cooled to room temperature and filtered. The filtrate is set stirring and sodium chloride (8 parts = 20% wt/vol) added. After stirring for 18 hours the suspension is filtered under vacuum and the cake pressed well to remove mothers liquor. The paste (8 parts) is dried in air at 50°-60° C to give 7 parts of 1-(3-phosphonophenylamino)-6-sulphonaphthalene.
Reaction SMILES: N.Br[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:11]([CH3:14])([CH3:13])[CH3:12]>[Zn]>[C:11]([C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[O:7][CH:3]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(C(=O)O)oc1Br
Agent: N
Agent: [Zn]
Product: CC(C)(C)c1coc(C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure as described in Gilman, H., et al., J. Am. Chem. Soc., 1935, Vol. 57, pp 909-912, more particularly, as described on page 910) by treating a dilute aqueous NH3 solution (made by dilution of 1 mL of 29.3% aqueous NH3 with 9 mL of H2O) of 5-bromo-4-tert-butyl-furan-2-carboxylic acid (500 mg, 2.02 mmol, prepared as described in Example K, Step B) with Zn dust (265 mg, 4.05 mmol) to yield the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.40 (d, J=1.0 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H), 1.26 (s, 9H).
Reaction SMILES: Cl[CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C(N(CC)CC)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(CN)OC
Reactant: ClC1CNCCN1
Solvent: CCN(CC)CC
Product: COC(CNc1cnccn1)OC
Reaction time: 48 h
Yield: 6.6 %

Procedure:
To a solution of 2-chloropiperazine (1.0 g in 5 mL dry toluene) was added 2,2-dimethoxyethylamine (1.1 g) followed by 1.2 mL triethylamine and the mixture heated to reflux on an oil bath. After 48 hours, the reaction mixture was applied to a flash chromatography column (silica gel) for purification (ethyl acetate:hexane, 7:3; then 100:0) to give the title compound (101 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH:42]=C)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2].I([O-])(=O)(=O)=[O:47].[Na+].CC(C)=O.C(#N)C>[Os](=O)(=O)(=O)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:47])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3F)c(CCC)n3ncnc32)CC1)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate (0.81 g), sodium periodate (1.4 g), acetone (20 mL), acetonitrile (20 mL), water (20 mL) and osmium tetraoxide (0.24 g, 7% immobilized catalyst) was stirred at room temperature for 14 hr. The precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL). Sodium tetrahydroborate (0.084 g) was added at 0° C., and the mixture was stirred at 0° C. for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The diol of Example 3, 0.27 g, was reduced in MeOH with 60 psi H2 at 60° in 3 hrs using 5% Rh/C catalyst. After filtering, the solvent was stripped off and the 0.27 g of white crystals were recrystallized from CH2Cl2 -hexane to furnish tiny needles of the title compound, 0.19 g, mp 126°-128°; further recrystallization gave mp 128.5°-129.5° Rf (ether): single spot, 0.8.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.O1CCCC1.[AlH4-].[Li+]>>[CH3:33][C:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:35])[F:34])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1)([CH3:32])[CH2:29][NH2:31]
Reactant: CC(C)(C(N)=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.2 %

Procedure:
To a solution of 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide (0.182 g, 0.000361 mol) in tetrahydrofuran (5.864 mL, 0.07229 mol) under N2 at 0° C. was added lithium tetrahydroaluminate (1M in THF, 1.44 mL, 0.00145 mol) dropwise. The reaction was stirred at room temperature for 6 h. The reaction was quenched with saturated Na2SO4 until no more hydrogen evolution was observed. MgSO4 was added and the solution was filtered and rinsed with copious amounts of methylene chloride. The mixture was concentrated and purified by reverse-phase HPLC to give 412 (12.8 mg) as a colorless solid. MS(ESI+) 490.1. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.39 (t, J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50 (s, 6H)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][NH2:13]>C1COCC1>[Cl:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:13][CH3:12])=[O:6]
Reactant: CN
Reactant: O=C(Cl)c1ccncc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a suspension of crude 3-chloroisonicotinoyl chloride hydrochloride in 25 mL of THF was added methylamine solution (2M in THF, 20 mL, 40 mmol, 8.4 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude material was dissolved in EtOAc (75 mL) and water/brine/saturated sodium bicarbonate solution (1/1/1, 75 mL) and phase separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water/brine/saturated sodium bicarbonate solution (1/1/1, 25 mL) and brine (25 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as an off-white solid (321 mg, 39.7%), which was used without further purification. ES/MS m/z 171.0, (MH+), Rt=0.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in THF (10 mL) was added excess methylamine (2M solution in THF). The reaction solution was stirred at room temperature for 1 hr. Water was then added and the product was extracted into chloroform. The combined extracts were washed, dried over sodium sulfate, filtered and evaporation to yield 2.3 g of the crude 4-chloro-N-methyl-3-nitrobenzenesulfonamide as an oil. The crude material was used in the subsequent step without further purification.