Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][C:23]=1[Cl:32])=[C:8]2[CH3:33]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2Cl)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
A solution of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.50 g), methanol (10 mL), saturated aqueous lithium hydroxide solution (0.5 mL) and water (1.0 mL) was stirred at 40° C. for 3 hours. The methanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried to afford title compound as a white solid, 0.15 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1
Reactant: CI
Reactant: Cc1cccc2c(CO)csc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1csc2c(C)cccc12
Temperature: 50 °C

Procedure:
400 mg of 3-hydroxymethyl-7-methyl-benzo[b]thiophene are dissolved in tetrahydrofuran, mixed with 82 mg of NaH (80%) and after addition of 48 mg of methyl iodide heated for half an hour at 50° C. The reaction mixture is mixed with water, repeatedly extracted and the organic phase washed, dried and concentrated on a rotary evaporator. The residue is chromatographed over silica-gel (eluant: toluene/glacial acetic acid=95:5) to yield the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2.C(N(CC)C(C)C)(C)C.[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:33](Cl)=[O:34])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:33]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]3)=[O:34])=[CH:28][CH:27]=1
Reactant: O=C(Cl)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: COC(=O)C1Cc2cccc(N)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CBr)cc3)C3CCCC3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
235 mg (1.228 mmol) of methyl 4-amino-2,3-dihydro-1H-indene-2-carboxylate (racemic; Example 88A) were dissolved in 10 ml of THF, and 428 mg (4.911 mmol) of N,N-diisopropylethylamine and 388 mg (1.228 mmol) of [4-(bromomethyl)phenyl](cyclopentyl)acetyl chloride were added at 0° C. The mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium bicarbonate solution was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. This gave 577 mg of the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8089 %

Procedure:
To a cooled (−78° C.) solution of (S)-4-benzyloxazolidin-2-one (10.26 g, 58 mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 M, 64 mmol, 1.1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10.0 g, 0.58 mmol, 1.0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with sat'd. aq. NH4Cl, extracted with DCM, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10-20% EtOAc/Hexanes) provided the title compound as a thick oil (14.7 g, 81%). m/z=314.3 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:16][C:17]=1[F:22]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=721 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[CH3:15][N:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[C:19]2[CH:31]=[CH:32][N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]=2[C:17]1=[O:44]>>[CH3:14][O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH:6][CH3:7])[CH:8]=[CH:9][C:2]=1[C:20]1[C:19]2[CH:31]=[CH:32][N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]=2[C:17](=[O:44])[N:16]([CH3:15])[CH:21]=1
Reactant: CNc1ccc(Br)c(OC)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-methoxy-N-methyl-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C23H23N4O6S (M+H)+: m/z=483.1. found: 483.1.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:15]=[C:16]([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=4)[C:10]=3[N:9]=2)[CH2:6][CH2:5][N:4]([C:30]2[N:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][C:31]=2[C:38]([F:41])([F:40])[F:39])[CH2:3]1>O=[Mn]=O>[CH3:1][C@H:2]1[N:7]([C:8]2[NH:9][C:10]3[C:16]([C:17]4[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=4)=[CH:15][C:14]([C:26]([F:29])([F:28])[F:27])=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][N:4]([C:30]2[N:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:31]=2[C:38]([F:41])([F:39])[F:40])[CH2:3]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1c1nc2c(-c3cc(F)c(F)c(F)c3)cc(C(F)(F)F)cc2[nH]1
Agent: O=[Mn]=O
Product: C[C@@H]1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
(6-{(3R)-3-Methyl-4-[6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazol-2-yl]-piperazin-1-yl}-5-trifluoromethyl-pyridin-3-yl)-methanol (1.18 g, 2.0 mmol, Example 183h) reacted with MnO2 (3.48, 40 mmol, Aldrich) under the conditions of Example 154a to give the title compound as a white solid, which was used in the next step without additional purification. MS (ESI, pos. ion) m/e: 588 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[Na+].[C-:21]#[N:22].[K+].O>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:21]#[N:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A slurry of 1-benzyl-4-piperidone (53.3 g, 0.28 mol), sodium bisulfate (38.5 g, 0.32 mol), potassium cyanide (24.5 g, 0.38 mol) and water (200 mL) was stirred 1 hour and then combined with diethyl ether. The mixture was stirred 1 hour and the ether layer was separated, washed with water (2×) and brine (2×), dried (K2CO3), filtered and concentrated. The residue was crystallized from pentane/diethyl ether (3:1, approximately 400 mL) to give 1-benzyl-4-hydroxypiperidine-4-carbonitrile (45 g) as a crude material.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([CH2:10][Br:1])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2)c(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1ccccc1

Procedure:
In this instance one equivalent of Br2 was added dropwise to a refluxing solution of 2-fluoro-4-methylbiphenyl and CCl4 while being irradiated with a sunlamp. NMR analysis showed the ratio of starting material:monobromide:dibromide to be 21:67:12.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCNCC1
Yield: 99.9 %

Procedure:
A solution of 1-benzyl-4-tertbutyloxycarbonylaminomethylpiperidine 8 (4.79 g; 15.7 mmol) in 120 ml of MeOH is poured into a hydrogenation reactor. The 10% Pd/C-based catalyst is added (0.872 g; 0.82 mmol) and the mixture is subjected to a hydrogen pressure of 3.5 bars (50 psi) for 24 hours in a Parr type shaker. After filtration on celite and washing with methanol, the medium is concentrated in order to produce 3.36 g (Yield=100%) of product in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CCOCC.[Br:16]Br>O1CCOCC1>[CH:5]1[C:4]([C:2]([CH2:1][Br:16])=[O:3])=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1

Procedure:
To a stirred, cooled solution of 4-chloroacetophenone (100 g, 0.65 mole), anhydrous ether (650 ml) and dioxane (325 ml) was added bromine (35 ml, 0.65 mole) dropwise over a period of 1.25 hours, keeping the temperature at 20° C. (±5° C.). The solution was then washed with water (3 × 1 l). The collected ether layer was dried over magnesium sulfate and the ether solution was evaporated under reduced pressure to give a solid. The solid was washed with water, collected by filtration, and air-dried to give the α-bromo-4-chloroacetophenone.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=3)[C:19](=[O:24])[CH2:20][CH2:21][C:22]#[CH:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[C:19](=[O:24])[CH2:20][CH2:21][C:22]#[CH:23])=[CH:38][CH:39]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(pent-4-ynoyl)amino]methyl}phenoxy)acetate and NaOH 1N in the presence of MeOH/THF as a yellow oil (87%). 1H NMR (DMSO-d6, 300 MHz) δ 7.49 (m, 4H), 7.25-7.11 (m, 6H), 6.87 (m, 2H), 4.65 (s, 1H), 4.64 (s, 1H), 4.54 (s, 1H), 4.50 (s, 1H), 4.46 (s, 1H), 4.44 (s, 1H) 2.77-2.42 (m, 7H), 1.55 (m, 2H), 1.30 (m, 2H), 0.89 (t, J=7.3 Hz, 3H). M− (ESI): 506.4; M+ (ESI): 508.4. HPLC, Rt: 5.05 min (Purity: 99.1%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Yield: 98.6 %

Procedure:
To 7.3 g (20.2) 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 15 ml CH2Cl2, 10 ml trifluoro acetic acid were added at 0° C. The mixture was stirred at reflux for 3 h and was concentrated in vacuo. Water and 2M NaOH were added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Evaporation yielded 5.2 g (98%) Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine as orange oil, MS: 261 (MH+)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.O[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[C:16]1([CH:12]2[C:4]3[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=3[O:15][C:13]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: Cc1cc(C)c(C)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccccc1
Yield: 37 %

Procedure:
Using 2,3,5-trimethylphenol and hydroxy(phenyl)acetic acid, the title compound was synthesized in the same manner as in Reference Example 2. Yield 37%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COC(CCBr)OC
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(CCn1cc([N+](=O)[O-])cn1)OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (4.50 g, 39.80 mmol) in MeCN (135 mL), 3-bromo-1,1-dimethoxypropane (7.25 mL, 47.76 mmol) and Cs2CO3 (16.30 g, 50.0 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h and allowed to reach rt overnight. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitioned between brine and EtOAc, then the org. layer was separated and the aq. layer was extracted with EtOAc (2×). The comb. org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(3,3-dimethoxypropyl)-4-nitro-1H-pyrazole as a yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.54 min, [M+H]+=no ionization.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:13][C:14]=2[S:15][CH2:16][CH2:17][OH:18].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:12]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:13][C:14]=2[S:15]([CH2:16][CH2:17][OH:18])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Nc2ccc(F)c3c(SCCO)cc(-c4ccc[nH]4)c1c23
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)c3c(S(=O)CCO)cc(-c4ccc[nH]4)c1c23
Reaction time: 0.33 h

Procedure:
A solution of 6-fluoro-5-(2-hydroxy-ethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (from Example 36 above) (15 mg, 0.05 mmol) in THF (approximately 7 mL) was treated with mCPBA (Acros, 14 mg, 0.06 mmol, 75%). After 20 minutes, the reaction mixture was diluted with ethyl acetate and washed with aqueous saturated Na2S2O3 and aqueous saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient), followed by precipitation out of THF with excess pentane to give 6-fluoro-5-(2-hydroxy-ethanesulfinyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 15 mg, 96%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([Cl:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([Cl:18])[C:12]([C:13]#[N:14])=[C:15]([Cl:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile (0.121 g, 0.41 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.063 g, 0.41 mmol), HOBt (0.083 g, 0.615 mmol), DIPEA (0.214 mL, 1.23 mmol) and EDCI (0.118 g, 0.615 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 6.3 mg. 1H NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 2.55 (s, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 6.64 (d, 1H), 7.40 (s, 1H), 7.58 (d, 1H), 7.83 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2cccc(CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a solution of 0.220 g (0.940 mmol) of 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 5 mL of DMF was added 0.156 g (1.034 mmol) of t-butyldimethylsilyl chloride and 0.160 g (2.350 mmol) of imidazole and the reaction was stirred at room temperature for 14 h. The reaction mixture was diluted with water and extracted with ether. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.315 g of 4-tert-butyl(dimethyl)silyloxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.O1[CH2:22][CH2:21]OCC1>CO>[CH2:2]1[C:2]23[C:21]4[C:22](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:5]([CH2:6][C:10]42[C:9]2[C:4]([CH:3]1[C:16]1[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:4]1[C:3]3=[CH:16][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1c2ccccc2cc2ccccc12
Reactant: C1COCCO1
Solvent: CO
Product: c1ccc2c(c1)C1CC34c5ccccc5C(CC23c2ccccc21)c1ccccc14
Reaction time: 0.5 h
Yield: 18 %

Procedure:
9-(bromomethyl)anthracene (4 gm., 14.8 mmoles) was dissolved in 200 ml. of dioxane at 70° C. under nitrogen. With the addition of powdered stannous chloride dihydrate (3.2 gm., 14 mmoles), the solution turned orange brown. Coloration faded in a few minutes and the reaction mixture was allowed to stand at 70° C. for another half hour and then was diluted with an equal volume of methanol. The crude yellow-green precipitate was filtered and then dissolved in methylene chloride and the methylene chloride solution filtered to remove undissolved material. The solution was decolored and the lepidopterene reprecipitated from the methylene chloride solution by the addition of methanol to obtain 1 gm. (2.6 mmoles) of the colorless, crystalline solid (18% yield).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:32])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(Sc3ccccc3)c3ccccc3c2=O)cc1

Procedure:
The product from Example 57B and 2-(4-(methylsulfonyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.34 (dd, J=7.9, 1.1, 1H), 8.08 (d, J=7.7, 1H), 8.03-7.97 (m, 1H), 7.97-7.92 (m, 1H), 7.92-7.87 (m, 2H), 7.60 (d, J=8.3, 2H), 7.45-7.40 (m, 2H), 7.40-7.30 (m, 3H), 3.81 (s, 2H), 3.22 (s, 3H); MS (APCI+) M/Z 466 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:30](=[O:32])[CH3:31])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Product: CC(=O)NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (prepared in analogy to Example 9-3) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.00-7.97 (m, 1 H), 7.81 (d, J=7.2 Hz, 1 H), 7.76-7.64 (m, 2 H), 7.46-7.42 (m, 2 H), 7.30-7.28 (m, 1 H), 5.99 (s, 1 H), 5.14 (s, 2 H), 4.54 (brs, 2 H), 3.58 (t, 2 H), 3.36 (m, 4 H), 2.42 (s, 3 H), 2.00 (s, 3 H), 1.94-1.87 (m, 2 H).