Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCCN1CCOCC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(3-chloropropyl)morpholine hydrochloride as the alkylating reagent in Step 1. The product was isolated as a white solid (60 mg, 48.1%). LCMS: m/e 657.55 (M+H)+, 2.24 min (method 13). 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 3.97 (m, 4H), 3.30-3.04 (m, 8H), 2.85-2.66 (m, 1H), 2.46-2.24 (m, 2H), 2.24-1.85 (m, 7H), 1.82-1.65 (m, 7H), 1.65-1.45 (m, 7H), 1.45-1.26 (m, 4H), 1.22 (s, 3H), 1.14 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].Cl[Sn]Cl.Cl>Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Nc1ccc(F)cc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)cc1Br
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ6982 (td, J=8.4 Hz, J=2 Hz 1H), δ5.540 (bs, 1H), δ3.590 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([NH:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)=[O:5]
Reactant: NCc1nnn[nH]1
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)NCc3nnn[nH]3)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Yield: 40 %

Procedure:
The title compound was prepared in analogy to Example 38, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid (Example 66) and 5-(aminomethyl)-tetrazole (commercially available, CAS RN 31602-63-8) to provide 47 mg (40%) of the title compound as a light yellow solid. MS (ESI): m/z=579.142 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][OH:40])[CH2:34]1>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][O:36][C@H:35]([CH2:39][OH:40])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:32])[F:30])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Reactant: OCC1CNCCO1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and (2S) Morpholin-2-yl-methanol following General Procedure B.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH2:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1.C([O-])(O)=O.[Na+].[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([O-:42])=[O:41]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:33][S:49]([C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=1)(=[O:50])=[O:51])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
(S)-2-Amino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester hydrochloride (1.2 g) was dissolved in 100 mL EtOAc and 100 mL saturated aqueous NaHCO3 and 1.0 g p-nitrobenzenesulfonyl chloride was added. After stirring at room temperature for 2 hours, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 7:3 hexanes/EtOAc) to give 1.7 g desired product after drying. 1H NMR (400 MHz, CDCl3): 8.27 (m, 2H), 7.89 (m, 2H), 7.54 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.28-7.24 (m, 1H), 7.20 (m, 2H), 6.81 (m, 1H), 6.56 (m, 2H) 5.26 (m, 1H), 5.02 (s, 2H), 4.99 (m, 1H), 4.26 (m, 2H), 3.95 (m, 1H), 3.66 (s, 3H), 3.05-2.85 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](O)=[O:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:16]([C:7]1[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)=[O:17]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: OCCNCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N(CCO)CCO)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
3,5-bis-(1,1-dimetyletyl)-4-hydroxybenzenecarboxylic acid (2.5. g, 0.010 mol) and diethanolamine (1.05 g, 0.010 mol) were dissolved in 30 ml of dry dimethylformamide and dicyclohexylcarbodiimide (2.13 g, 0.0105 mol) in 10 ml of dry dimethylformamide was added over 5 minutes. After stirring overnight, the resulting colorless suspension was filtered, and the filtrate was evaporated, 3×25 ml of benzene was added and reevaporated to yield a white solid which was recrystallised from toluene.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[C:14]([F:17])([F:16])[F:15])C.[OH-].[Na+].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: CCOC(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(CNCC(F)(F)F)OCC
Temperature: 125 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 1 g (7.5 mmol) of 1-amino-2,2-diethoxyethane, 1.26 g (7.9 mmol) of trifluoroacetaldehyde ethyl hemiacetal and 1 pellet of NaOH in 15 ml of toluene was heated at 110° C. with a Dean-Stark trap for 3 hours. The mixture was heated at 125° C. for a further 3 hours. The reaction mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 25 ml of methanol, and 1.13 g (30 mmol) of sodium borohydride were added. The reaction mixture was then heated to 70° C. and stirred overnight, concentrated in vacuo and partitioned between water and ethyl acetate. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 740 mg of the desired amine were obtained as a clear oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27][CH2:28][CH2:29]Br>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH3:29])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 104 %

Procedure:
50% Sodium hydride (650 mg), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (4 g) and n-propyl bromide (3.8 g) were treated in a similar manner to that of Example 14-(6) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]valerate (4.7 g).
Reaction SMILES: [Br-:1].[Br-:2].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1([CH3:33])[CH2:31][C:30]2[NH:29][N:28]=[CH:27][C:26]=2[C:25](=[O:32])[CH2:24]1>C(O)(=O)C>[Br:1][C:24]1([Br:2])[C:23]([CH3:33])([CH3:22])[CH2:31][C:30]2[NH:29][N:28]=[CH:27][C:26]=2[C:25]1=[O:32]
Reactant: CC1(C)CC(=O)c2cn[nH]c2C1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC1(C)Cc2[nH]ncc2C(=O)C1(Br)Br
Yield: 100 %

Procedure:
According to Scheme 2 Step 3: Pyridinium tribromide (15.2 mmol, 4.87 g) was added to a solution of 6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.00 g) in acetic acid (9 mL) and the reaction mixture was heated under reflux for 3 hours. After evaporation of the solvent, the crude residue was partitioned between DCM and a saturated solution of Na2CO3. The organic phase was washed with water, was dried over Na2SO4 and concentrated to yield 5,5-dibromo-6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
1-(3-Hydroxyphenyl)ethanone (1.36 g, 10 mmol) was dissolved in acetone (50 mL), and the resultant mixture was sequentially added with potassium carbonate (2.76 g, 20 mmol) and 1-methylethyl iodide (1.5 mL, 15 mmol), and stirred at 70° C. overnight. The reaction solution was filtered, washed with acetone, and concentrated in vacuo. The resultant residue was added with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-(1-methylethoxy)phenyl)ethanone (1.67 g, yield 94%) was obtained as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[C:1]([N:15]1[CH2:16][CH2:17][CH:12]([Br:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Benzoyl chloride (1.41 g) was added to a solution of 4-bromopiperidine hydrobromide (2.45 g) in THF (30 ml) at 0° C., followed by triethylamine (2.2 g, 2.2 eq). The solution was stirred at room temperature for 1 h, and evaporated and. The residue was dissolved in dichloromethane (100 ml), washed with water, 1M HCl and saturated sodium bicarbonate, dried and evaporated to give the title compound as colourless oil (2.76 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:15][C:14]=1[F:20]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(Cl)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde (1.0 g, 6.25 mmol),)4-chloro-3-fluorophenol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:35][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33](=[O:34])[O:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:3]3[C:4]([CH3:13])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:6]=[C:2]3[NH2:1])=[CH:19][CH:18]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1c(-c2ccccc2)nc(N)n1-c1ccc(CCO)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3c(N)nc(-c4ccccc4)c3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
A mixture of 2-[4-(2-amino-5-methyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethanol (100 mg, 0.34 mmol) and p-toluenesulfonylisocyanate (67 mg, 0.34 mmol) in dichloromethane (5 mL) was stirred at 0° C. for 10 min. It was washed with water and organic phase was dried over Na2SO4. After removal of solvent, the residue was purified by TLC with dichloromethane/methanol (10:1) to afford 8 mg (4.8%) of the title compound as white solids: MS (ESI) m/z 491 [M+H]+, 489 [M−H]−, 1H-NMR (CDCl3) δ 2.27 (s, 3H), 2.87 (2H, t, J=5.9 Hz), 3.50 (3H, s), 4.24 (2H, t, J=5.7 Hz), 7.56-7.15 (11H, m), 7.83-7.80 (2H, m).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2.C(N(CC)CC)C.[C:24]1([C:29](Cl)=[O:30])[S:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][N:2]([C:29]([C:24]1[S:28][CH:27]=[CH:26][CH:25]=1)=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cccc(NC)c2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(N(C)C(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of ethyl 7-(methylamino)-1H-indole-2-carboxylate (54 mg) in tetrahydrofuran (3 mL) were added triethylamine (42 μL) and 2-thenoylchloride (44 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give colorless crystals (71 mg, yield 87%). melting point 193° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].CN(C=O)C.Br[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)=[O:19]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Yield: 55.2 %

Procedure:
To 4.19 g cesium carbonate and 1.37 g methyl 1-hydroxy-2-naphthoate in 25 ml abs. DMF was added 1.62 g 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine and the mixture was reacted for 16 h at 50° C. The reaction was poured unto ice, the resulting precipitate was isolated by filtration, dissolved in ethyl acetate and washed with brine. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to yield 1.31 g of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[C:3]([F:12])[CH:4]=2)[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc(Br)c2occc2c1F
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(F)c(F)c2ccoc12
Yield: 42.4 %

Procedure:
Beginning with 4.0 gm (17.17 mMol) 4,5-difluoro-7-bromobenzofuran and 3.8 gm (18.88 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 2.6 gm (43%) of the desired compound were recovered as a yellow oil essentially as described in EXAMPLE 3.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][O:23][CH3:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+]>C(O)C>[CH2:28]([O:30][N:31]=[C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][O:23][CH3:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:29]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(COC)C(=O)CO3)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(COC)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 40 mL of absolute ethanol were added in sequence 0.90 g (2.5 mmol) of 2-propionyl-3-hydroxy-5-(N-methoxymethyl-3-oxo-(2H)-1,4 benzoxazin-6-yl)-cyclohex-2-en-1-one, 0.31 g (3.2 mmol) of ethoxyamine hydrochloride and 0.26 g (3.2 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was then partitioned between 200 mL of water and 50 mL of dichloromethane. The organic layer was separated, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as an oily residue which crystallized upon standing. The crude solid was triturated in warm ether and the above-named product was isolated by filtration as a white solid which melted at 101°-103° C. in a yield of 0.60 g (60 percent of theoretical). 1H NMR (CDCl3): d1.05-1.52 (m, 6H, both --CH2CH3 's), 2.58-3.65 (m including 2H,OCH2C=0), 5.33 (s, 2H, --NCH2O), 6.85-7.30 (m, 3H, aromatic H's), 15.05 (broad s, 1H, enol H); (Compound 8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Cc2cc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8.9 %

Procedure:
5-bromoindolin-2-one (23.6 mg, 0.111 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (75.0 mg, 0.198 mmol), Fibercat palladium catalyst (Johnson-Matthey, 36.3 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified two times on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (3.8 mg, 9%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
A mixture of 74.9 g. (0.25 mole) of 2,4-dichloro-3,5-dinitrobenzoyl chloride and 200 ml. of concentrated ammonia is placed in a mortar and ground with a pestle for ten minutes. The mixture stands for two hours at room temperature. The yellow precipitate is removed by filtration and washed with water. There is obtained 67.7 gm. (97%) of yellow needles melting at 263°-265°. Recrystallization of 1.00 g. of material from ethanol yields 390 mg. of yellow needles melting at 262°-263°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:6]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[O:17])=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1CC#N
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Yield: 39 %

Procedure:
A solution of 30 g. of 1-methylpyrrole-2-acetonitrile and 60 g of p-toluoyl chloride in 200 ml of o-dichlorobenzene is refluxed under nitrogen for 4 hrs. The mixture is concentrated to near dryness, diluted with 250 ml. of methylene chloride, washed successively with an aqueous solution of dimethylaminopropylamine, dilute hydrochloric acid and potassium carbonate solution. Removal of the organic solvent leaves an oily residue which crystallizes in 80 ml of methanol to give 22.2 g (39%) of 1-methyl-5-(p-toluoyl)-pyrrole-2-acetonitrile. The methanol filtrate is concentrated and the residual oil is hydrolyzed to the amide by brief refluxing with aqueous ethanolic NaOH (10%). The separated solid is collected giving 10.1 g (16.4%) of 1-methyl-5-(p-toluoyl)-pyrrole-2-acetamide. Total yield = 55.4%.