Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:15]([CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=3[C:10]3[CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=CC(B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O.CO[CH2:42][CH2:43]OC>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>[CH3:23][N:20]1[CH2:21][CH2:22][C:9]2[N:8]([C:4]3[CH:3]=[CH:43][CH:42]=[C:6]([C:7]4[CH:26]=[CH:25][N:24]=[CH:29][CH:2]=4)[CH:5]=3)[C:16]3[C:15]([CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=3[C:10]=2[CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C)c2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: COCCOC
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
Product: Cc1cc(C)c2c(c1)c1c(n2-c2cccc(-c3ccncc3)c2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (80 mg, 0.217 mmol), pyridine-4-boronic acid (53 mg, 0.431 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (12 mg, 0.013 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,6,8-trimethyl-5-(3-(pyridin-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.78 (d, 2H), 8.1 (m, 3H), 7.9 (m, 1H), 7.8 (t, 1H), 7.6 (m, 1H), 7.2 (s, 1H), 6.8 (s, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.1 (s, 3H), 2.8-3.03 (m, 2H), 2.4 (s, 3H), 1.93 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11]/[C:10](/[C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[N:21]\[O:22][CH3:23])=[CH:14][CH:15]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc2c(c1)CCC2
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc2c(c1)CCC2
Yield: 38.4 %

Procedure:
Compound 103 was synthesized from (4-{[(2Z)-2-(2,3-dihydro-1H-inden-5-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.25 g, 0.8 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.214 g, 1.04 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 38.4%); Purity: 95.42%.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].O.[N+:13]([O-])([OH:15])=[O:14].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:2]1[CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(I)ccc2c1CCC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)c(O)c2c1CCC2

Procedure:
To a solution of 5-iodoindan-4-ol (358 mg) in acetic acid (3 mL) was added water (0.5 mL). To the solution was added nitric acid (60%, 0.105 mL) in small portions under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. After adding water (10 mL) and aqueous sodium sulfite (1.5 g/10 mL) successively, the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a small amount of dichloromethane and hexane to give the title compound (70 mg).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.C(=O)([O-])[O-].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO>[CH2:36]([O:35][C:33]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:27])[CH3:26])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:10]1)=[O:34])[CH3:37]
Reactant: CC(O)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-naphthalene-1-sulfonic acid piperidin-4-ylamide acetic acid salt 37 (290 mg, 0.74 mmol) in MeOH (10 mL) was added MP-Carbonate (1.45 g, 3.69 mmol, 2.54 mmol/g). After shaking at 25° C. for lh, the solution was filtered. To the resultant solution was added ethyl chloroformate (120 mg, 1.11 mmol). After stirred for another 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The crude material was purified by Flash column chromatography (CH2Cl2: MeOH) to provide 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38. LC/MS showed m/z 407 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>ClCCl.C(O)CCC>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCO
Product: O=S(=O)(Nc1cccc(C(F)(F)F)c1)c1ccc2c(c1)CNCC2

Procedure:
2-Acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3-trifluoromethylaniline in dichloromethane according to the method generally described in EP No. 0038177-A. The resulting product was deacetylated by heating with aqueous hydrochloric acid in butanol to give 7-(3-trifluoromethylphenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccccc1
Product: CCOc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with ethanol to form p-ethoxyaniline.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[CH:10]=[CH:9][C:8]=1[CH2:22][C:23](Cl)=[N:24][OH:25].[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[CH:10]=[CH:9][C:8]=1[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)cc1F
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2F)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (2-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 96-1-4 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was devaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (32.0 mg, 23.9%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:49]1([NH2:52])[CH2:51][CH2:50]1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:19]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:12]=[C:13]([C:14](=[O:15])[NH:52][CH:49]3[CH2:51][CH2:50]3)[CH:17]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: NC1CC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CC3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and cyclopropylamine.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]=[O:19].[H-].[Na+].[CH3:22][CH:23]([SH:25])[CH3:24]>CN(C)C=O.O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:25][CH:23]([CH3:24])[CH3:22])=[C:3]([CH:18]=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)S
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)c(C=O)sc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C=O)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrinidine-6-carboxaldehyde (Example 50 step b; 2 g) in dimethylformamide (20 ml) was added sodium hydride (0.3 g of 60% dispersion) followed by the addition of 2-propanethiol (0.6 g). The mixture was stirred for 24 hours at ambient temperature then the reaction was diluted with water (100 ml) and extracted thrice with ethyl acetate (3×100 ml). The organic phase was washed with water (100 ml), then with brine (100 ml) and then dried, filtered and evaporated to leave the subtitle compound as a pale yellow solid (2.24 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C[Si]([C:30]#[CH:31])(C)C.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:30]([C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1)#[CH:31]
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (435 mg, 1.1 mmol), trimethylsilylacetylene (0.47 ml, 3.3 mmol) and triethylamine (1.0 mL) in DMF (11 mL) was added bis(triphenylphosphine)palladium(II)chloride (17 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 24 h. The mixture was cooled to ambient temperature, filtered through a pad of celite then the solvent concentrated at reduced pressure. The product was dissolved in DMF (8 mL), MeOH (8 mL) cesium fluroide (370 mg, 2.4 mmol) added and the mixture stirred at ambient temperature 24 h. The solvent was concentrated at reduced pressure to give a dark solid. Purification by column chromatography (silica gel, EtOAc:MeOH; 10:1, Rf =0.53) give 30 mg of a tan solid. The compound was further purified by preparative TLC (silica gel, EtOAc:hexane; 3:1) to give Compound I-36 as a tan solid, mp>300° C. 1H NMR (DMSO-d6, 300 MHz): d 4.2 (s, 2H), 5.0 (s, 2H), 7.38-7.46 (m, 3H), 7.58-7.75 (m,4H), 8.15 (s, 1H), 9.42 (d, 1H, J=9 Hz), 12.19 (s, 1H; MS m/e=335 (m+).
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].Br[CH2:22]CCCC=C>>[CH2:16]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:22]
Reactant: C=CCCCCBr
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Product: C=CCCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C

Procedure:
N-{[Hex-5-en-1-yl(isopropyl)amino]carbonyl}-3-methyl-L-valine was prepared according to the procedure described for N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using 6-bromo-1-hexene in Step 1. LRMS (ESI) m/z 299 [(M+H)+; calcd for C16H31N2O3; 299.2].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:20](O)[CH2:21][CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Yield: 96.1 %

Procedure:
To a cooled (0° C.) solution of 0.815 g (2.37 mmol) 3-(3-bromophenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 0.51 mL (7.12 mmol) of 1,3-propanediol and 1.20 g (4.75 mmol) of 1,1'-(azodicarbonyl)dipiperidine in 15 mL of anhydrous tetrahydrofuran was added 1.18 mL (4.75 mmol) of tri-n-butylphosphine dropwise over 8 min. Dichloromethane (10 mL) was added to aid stirring. After stirring at ambient temperature for 5.5 h, the reaction mixture was diluted with 100 mL of diethyl ether. The resulting mixture was stirred for 30 min, filtered and the filtrate concentrated to give a pale yellow semisolid. This residue was flash chromatographed on 80 g of silica gel with 25-50% ethyl acetate-hexane to afford 0.914 g (96% yield) of the title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 8.01 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.42 (t, 1H, J=8.0 Hz), 6.64 (s, 1H), 6.41 (s, 1H), 6.37 (t, 1H, J=2.2 Hz), 4.01 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=5.6 Hz), 2.26 (s, 3H) and 2.00 (m, 2H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(N1CCCO[CH:19]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)C1C=CC=CC=1.C(Cl)(=[O:35])CC.[OH-].[Na+]>C(Cl)Cl>[C:26]1([NH:25][C:24](=[O:35])[CH2:19][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
iPr2EtN (4.72 mL, 27.1 mmol) was added to a solution of (4-benzyl-1,4-oxazepan-2-ylmethyl) phenyl amine (80) (27.1 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then propionyl chloride (5.17 mL, 59.6 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature, with stirring, overnight. CH2Cl2 and 10% aqueous NaOH was added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by silica gel chromatography (97:1:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (81) as a pale yellow oil. 1H NMR (CDCl3, ppm) 7.36–7.19 (8H, m), 6.94 (2H, broad d, J=6.5 Hz), 3.89–3.38 (5H, m), 3.65 (1H, d, J=13.3 Hz), 3.54 (1H, d, J=13.3 Hz), 2.88–2.75 (2H, m), 2.55 (1H, ddd, J=12.5, 8.9, 4.2 Hz), 2.34 (1H, dd, J=13.5, 8.9 Hz), 1.98–1.68 (4H, m), 0.98 (3H, t, J=7.5 Hz). 13C NMR (CDCl3) 174.05, 143.19, 139.64, 129.60, 129.15, 128.46, 128.35, 127.79, 127.10, 76.80, 67.25, 62.61, 59.05, 54.43, 51.64, 30.42, 27.91, 9.70 ppm. LRMS: 352.72.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
173 mg (0.70 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylidenacetic acid, 130 mg (0.75 mmol) of t-butyl N-(3-aminopropyl)carbamate, 149 mg (0.78 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3) to obtain the title compound.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:48]1[C:56]2[C:51](=[CH:52][C:53](O)=[CH:54][CH:55]=2)[CH:50]=[N:49]1>O1CCCC1>[CH:1]1([O:6][C:53]2[CH:52]=[C:51]3[C:56](=[CH:55][CH:54]=2)[NH:48][N:49]=[CH:50]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OC1CCCC1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
Cyclopentanol (0.068 ml, 0.745 mmol), triphenylphosphine (221 mg, 0.820 mmol) and dibenzyl azodicarboxylate (267 mg, 0.895 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure and a 1M-aqueous sodium hydroxide solution (4 ml) and chloroform (3 ml) were added to the resulting residue. After removing the aqueous layer, water (2 ml) was added to the residue. The aqueous layer was removed and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol, hexane/ethyl acetate) to obtain 5-(cyclopentyloxy)-1H-indazole (24 mg, 16%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(O[C:15]([CH3:18])([CH3:17])[CH3:16])=O.N[C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29](N)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:10][C:3]1([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[N:2]1[O:1][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:1][N:2]3[C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][CH2:18][C:15]3([CH3:16])[CH3:17])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: CC1(C)CCCC(C)(C)N1O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(C(=O)c2ccc(ON3C(C)(C)CCCC3(C)C)cc2)cc1
Yield: 19.5 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 6.19 g (60 mmol) of tert-butyl nitrite, 7.6 mg (0.0125 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 80 mL of pyridine and 5.30 g (25 mmol) of 4,4′-diaminobenzophenone at 70° C. The crude product obtained is purified by vacuum flash chromatography (1% ethyl acetate in heptane) to give 0.6 g of the title compound as a yellow solid in 9.17% yield. The structure is confirmed by 1Hnmr and mass spectrographic analysis.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].I[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:27]1([CH2:26][CH:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)[C:22]([OH:24])=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of diisopropylamine (13.36 mL, 101.89 mmol) in tetrahydrofuran (250 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.0M solution of n-butyllithium in hexanes (51 mL, 101.89 mmol). The reaction mixture was stirred at −78° C. for 15 min, at which time, a solution of 3,4-dichlorophenyl acetic acid (9.08 g, 44.3 mmol) in tetrahydrofuran (60 mL) and hexamethylphosphoramide (20 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (11.17 g, 53.2 mmol) in hexamethylphosphoramide (10 mL) was added via a cannula. The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 14 h. The reaction mixture was then acidified to pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, chloroform then 99/1 chloroform/methanol) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (10.28 g, 81%) as a white solid: mp 74.5–76.9° C.; EI-HRMS m/e calcd for C14H16Cl2O2 (M+) 286.0527, found 286.0534.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Yield: 69.6 %

Procedure:
A mixture of 2-(4-bromophenyl)acetic acid (50 g, 0.23 mol), benzyl alcohol (26 mL, 0.25 mol) and p-toluenesulfonic acid (0.3 g) in 200 ml toluene were heated at reflux with the azeotropic removal of water (15 h). The yellow solution was washed with water (250 mL), saturated aqueous sodium bicarbonate (250 mL) and then dried (MgSO4). Concentration provided a light yellow solid that was recrystallized from cold hexanes to give benzyl 2-(4-bromophenyl)acetate (48.5 g, 0.16 mol) in 69% yield, mp. 47.5°-48° C.