Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1.O.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH:25]([C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1)=[CH2:26]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cnc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a mixture of 1100 mg of tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 1062 mg of a 2,4,6-trivinylboroxine/pyridine complex, 1020 mg of potassium carbonate, 3 mL of 1,4-dioxane/water (4/1) was added 215 mg of tetrakis(triphenylphosphine)palladium. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture were added water and ethyl acetate and the aqueous layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 783 mg of tert-butyl 5-vinyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:15].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]1)[C:9]2=[O:15]
Reactant: O=c1[nH]ccc2c(Cl)c(Cl)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3c(Cl)c(Cl)ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Sodium hydride (95% dispersion in mineral oil, 0.026 g) was added to a room temperature suspension of the compound prepared in Example 75 (0.07 g) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for one hour and then tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.14 g) added to the system. The reaction mixture was heated at 80° C. overnight, then cooled to room temperature, diluted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution, water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to obtain the title compound (0.05 g) having the following physical data.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: C1CCNC1
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (2.28 mmoles, 0.54 g-see Example 35) and pyrrolidine (5.26 mmole, 0.375 g.) were dissolved in THF and stirred at room temperature. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and concentrated to yield 0.583 g of 5-(2-Cyanophenyl)-2(1-pyrroidinomethyl)-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[I:22]I>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:22])=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)cc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A RBF was charged with 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (577.6 mg, 2.441 mmol) and THF (8135 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (1.8M in hexanes) (1627 μl, 2.93 mmol) was added dropwise. After 30 min, a solution of iodine (929 mg, 3.66 mmol) in THF (3 mL) was added dropwise. TLC after 5 min showed conversion to a slightly lower spot. The mixture was diluted with saturated aq. sodium thiosulfate solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Ultra SNAP column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (687 mg, 1.895 mmol, 78% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) □=7.87 (td, J=1.0, 1.8 Hz, 1 H), 7.74 (td, J=1.8, 7.0 Hz, 1 H), 7.55-7.43 (m, 2 H), 7.25 (dd, J=1.8, 9.1 Hz, 1 H), 7.14-7.07 (m, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)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:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:24]4[S:25][CH:26]=[CH:27][N:28]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Yield: 84.1 %

Procedure:
5-cyano-1-(3-(2thiazolyl)phenyl)benzimidazole was synthesized as described in Example 34 by using (31) (2.0 g, 5.9 mmol) instead of 5-acetyl-1-(3-bromophenyl)benzimidazole, (PPh3)2PdCl2 (100 mg, 0.14 mmol) and 2-(tributylstannyl)thiazole (3.6 g, 9.7 mmol). The reaction gave 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (1.5 g, 86%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCCCC1

Procedure:
The title compound was prepared from piperidine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (br s, 1H), 8.55 (s, 2H), 7.85 (d, 1H), 7.04 (d, 1H), 4.20 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.90-2.30 (br, 6H), 1.75-1.35 (m, 12H); MS (ESI): 505.9.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:9][N:10]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[CH:12][C:11]=12)=O.S(O)(O)(=O)=O.[NH2:35][C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:8]2[C:7]([C:5]3[CH:4]=[CH:3][N:35]=[C:36]([NH2:38])[N:37]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:26][CH:25]=1
Reactant: N=C(N)N
Reactant: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2-c2ccnc(N)n2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one (500 mg, 1.28 mmol) in dimethylformamide (10 mL) was added guanidine sulfate (277 mg, 1.28 mmol), followed by potassium carbonate (195 mg, 1.41 mmol). The resulting solution was heated at reflux for 6 hours. After cooling to room temperature, ethyl acetate and water were added. The phases were separated and aqueous phase extracted with additional ethyl acetate. The combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to give 4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (440 mg, 89%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1H), 7.80 (d, 1H), 7.56 (dd, 2H), 7.20 (t, 1H), 6.92 (d, 2H), 6.43 (d, 1H), 6.05 (d, 1H), 4.95 (b, 2H), 3.83 (s, 3H), 3.74–3.70 (m, 4H), 2.01–1.98 (m, 4H); MS m/z 387 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:12]C(=O)C)(=O)[CH3:10].[N+:16]([O-])([OH:18])=[O:17]>O>[C:9]([NH:4][C:3]1[C:5]([N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=[CH:8][C:2]=1[Br:1])(=[O:12])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Br
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Temperature: 6 °C
Reaction time: 18 h

Procedure:
2-Bromoaniline (15 g, 87.2 mmol) was dissolved in acetic anhydride (76 mL, 0.610 mol) and cooled to 6° C. HNO3 (11 mL, 0.174 mol) was added dropwise and reaction mixture was stirred for 18 hours at 6° C. The reaction mixture was poured into H2O and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOAc—hexane, to yield the above-titled compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[C:32](=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.42 g of fluorene (8.52 mmol) was dissolved in 60 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 5.6 ml of n-butyl lithium/hexane solution (1.58M: 8.85 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 2.99 g of 3-tert-butyl-1-methyl-6,6-di(4-chloro-phenyl)fulvene (8.08 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution (1N) set in an ice bath, and stirred briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a red solid. The solid was purified with a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (3.16 mmol) as a pale yellow solid (yield: 39%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:41]=[CH:40][C:11]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3([CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20][CH2:19]3)[N:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[O:18]=[C:17]1[C:16]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][N:13]1[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Yield: 99.5 %

Procedure:
Benzyl 3-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (4.90 g, 8.82 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W,) in ethyl acetate (50 mL) and methanol (50 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as foam (3.70 g, 99%); 1H NMR (DMSO-d6); δ1.53 (s, 9H); 2.35-2.48 (m, 2H); 2.85-2.92 (m, 2H); 3.17-3.23 (m, 2H); 3.23-3.43 (m, 2H); 4.58 (s, 2H), 4.62 (s, 2H); 6.74 (t, J=6.8 Hz, 1H); 6.87 (d, J=8.4 Hz, 2H); 7.20 (dd, J=7.6 Hz and 8.8 Hz, 2H); 7.40 (d, J=8.4 Hz, 2H); 7.90 (m, 2H); MS for C25H31N3O3 m/z 422 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CCCCCC.ClCCl.C(COC)OC>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 60 °C

Procedure:
To a stirred solution of 2,6-di(t-butyl)phenol in 150 ml. of glyme under nitrogen is added 52 ml. of 2.04 M n-butyl lithium in hexane. The reaction causes an exotherm and the product is heated to 60° C. About 20 g. of 4-nitrobenzoyl chloride is added, and the resulting solution is stirred without heating for about 16 hours. The mixture is then acidified with 10 percent hydrochloric acid and washed with dichloromethane, then with 10 percent sodium hydroxide solution and finally with water. The solution is then reacted in ethanol with 50 percent sodium hydroxide solution by heating at reflux for about two hours, mixed with dichloromethane, then washed several times with water. The organic layer is separated, dried and evaporated to provide an orange oil which solidifies in cold hexane. This solid is recrystallized from a benzene-hexane mixture to provide 4-(4-nitrobenzoyl)-2,6-di(t-butyl)phenol, m.p. 178°-179.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH2:21][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C1COc2c(C(=O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2N1
Product: O=C1COc2c(C(O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2N1
Reaction time: 4 h
Yield: 56.4 %

Procedure:
A solution of 5-(benzyloxy)-8-(dihydroxyacetyl)-2H-1,4-benzoxazin-3(4H)-one (DE 3134590 A1) (150 mg) in dry DCM (2 ml) was treated with acetic acid and N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (320 mg) (Tetrahedron Letters. 1994, 35, 9375) and stirred for 4 hr. Sodium triacetoxyborohydride (216 mg) was added and the reaction mixture stirred at room temperature for 3 days. Sodium borohydride (35 mg) in methanol (2 ml) was added and stirring continued for a further 2 h. The reaction mixture was quenched with water and partitioned between water and DCM. The organic phase was dried and concentrated in vacuo. The residue was purified by chromatography (Hexane-EtOAc, SPE) to give the title compound as a mixture with 5-(benzyloxy)-8-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-2H-1,4-benzoxazin-3(4H)-one (81.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:2]([NH:1][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[CH:18][CH:17]=[CH:16][C:15]=1[S:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1NC(=O)c1c(NS(=O)(=O)c2ccccc2)cccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in azabenzene (40 mL) at room temperature. To this mixture was added benzenesulfonyl chloride (1.2 equiv.). After being stirred for 10 Hours at room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted ethyl acetate (50 mL), washed with water (3×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a white solid. 67% yield;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(Cl)Cl>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)c2c(n1)N(CCCCl)c1ccccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.47 gm of 6,11-dihydro-2,4,6-trimethyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one were dissolved in 15 ml of dimethyl formamide, 0.76 gm of 50% sodium hydride in mineral oil was added, and the mixture was stirred at room temperature for one hour. Then, 1.7 ml of 1-bromo-3-chloro-propane were added, and the mixture was stirred at room temperature for 5 hours. After standing overnight, 100 ml of methylene chloride were added and the reaction mixture was washed three times with water. The organic phase was dried over sodium sulfate and evaporated in vacuo at room temperature. The crystalline residue was digested with a mixture of 7 ml of chloroform and 7 ml of ethyl acetate, and the mixture was suction-filtered. The filter cake was recrystallized from absolute ethanol, yielding 52% of theory of 11-(3-chloro-propyl)-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one having a melting point of 161°-163° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:49][NH:50][CH3:51]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:50]([CH3:51])[CH3:49])=[O:33])(=[O:29])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)N(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.6 %

Procedure:
Prepared using General Procedure 19: To a stirred solution of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 71 (48 mg, 0.1 mmol) in DMF (0.4 mL) was added N-hydroxybenzotriazole (46 mg, 0.3 mmol) and EDC (57 mg, 0.3 mmol). After 5 min, dimethylamine (40 wt % solution in water, 34 μL, 0.3 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The reaction was added dropwise to water (20 mL) and the solid was filtered. The crude material was purified by column chromatography (MeOH/DCM) to give 36 mg (70%) of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 195. LCMS-ESI (m/z) calculated for C25H27N5O5S: 509.2; found 532.2 [M+Na]+, tR=8.99 min (Method 2). (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 194 was synthesized in an analogous fashion from (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid.