Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH2:27]C)[S:23]([CH3:26])(=[O:25])=[O:24])=[C:14]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]3=[N:12][C:13]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])=[C:14]([CH2:16][CH2:17][CH2:18][C:19]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[C:36]([O:35][CH3:34])=[O:37])=[O:20])[CH:15]=[C:10]3[C:9]=2[C:30](=[O:33])[NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1CCCC(=O)O)S(C)(=O)=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(=O)N3CCC[C@H]3C(=O)OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-ethylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)butanoic acid (15 mg) in DMF (1 ml) is added (S)-methylpyrrolidine-2-carboxylate (4.2 mg), HATU (18.5 mg) and DIPEA (17 μl), and the mixture is stirred at rt for 30 min, and purified by preparative HPLC to afford the title compound. (M+H)+=575.2; Retention time=1.26 min, Method A. 1H NMR (400 MHz, CD3CN) δ ppm 8.18 (m, 1H), 8.06-8.01 (m, 2H), 7.33-7.26 (m, 2H), 6.91 (br s, 1H), 4.33-4.29 (m, 1H), 3.67 (s, 3H), 3.61-3.50 (m, 2H), 3.27 (s, 3H), 3.16 (s, 3H), 2.98-2.90 (m, 2H), 2.92 (d, 3H), 2.51-2.36 (m, 2H), 2.32-1.78 (m, 6H)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:31](=[O:32])[CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)CN1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CN3CCOCC3)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and 2-morpholinoacetic acid as a yellow solid (37%). MS 445 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[N:10]=1>>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([NH:16][C:11]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:10]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: Oc1cccnc1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccnc3)n2)ccc1-n1cnc(C)c1
Yield: 53 %

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 3-hydroxy-pyridine and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 53% yield as a pale-yellow solid after purification by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[N:25]1[CH:24]=[CH:23][C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate saturated with gaseous HCl (50 ml) was added to a solution of 1-tert-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (1.65 g) in ethyl acetate (25 ml) and the resulting suspension stirred at ambient temperature for 3 hours. Solvent was evaporated to give 4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine trihydrochloride (1.60 g) as a colourless foam.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>>[Cl:18][C:19]1[N:20]=[N:21][C:22]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]([F:1])([F:16])[F:17])[CH2:7][CH2:8]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Product: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1

Procedure:
The title compound was prepared in the same manner as described for Example 1 Step 3 from 4-[2-(trifluoromethyl)phenoxy]piperidine and 3,6-dichloropyridazine. 1H NMR (400 MHz, acetone-d6): δ 1.89-1.99 (m, 2H), 2.11-2.23 (m, 3H), 3.78-3.84 (m, 2H), 3.91-3.97 (m, 2H), 4.98-5.04 (m, 1H), 7.12 (t, 1H), 7.41 (q, 3H), 7.61-7.67 (m, 2H). MS (+ESI) m/z 358 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30]([CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:29](=[O:40])[CH2:28]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:49]([CH3:48])(=[O:51])=[O:50])[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:32])(=[O:33])[N:30]([CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:29](=[O:40])[CH2:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3S(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-{2-benzyloxy-4-[(E)-(S)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.12 g, 0.21 mmol) in CH2Cl2 (2 mL) is added triethylamine (0.15 mL, 1.0 mmol), followed by methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture is stirred at RT for 1.5 h then is diluted with EtOAc (15 mL) and washed with 1N HCl (2×15 mL) and brine (1×15 mL). The organic layer is dried over Na2SO4, concentrated in vacuo and used directly in the next step without further purification.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:13]([CH2:19][CH2:20][N:21]=4)[C:14]([NH2:18])=[N:15][C:16]=3[CH:17]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:18][C:14]2[N:13]3[CH2:19][CH2:20][N:21]=[C:12]3[C:11]3[CH:10]=[CH:9][C:8]([N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[CH:17][C:16]=3[N:15]=2)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23]
Reactant: NC1=Nc2cc(N3CCOCC3)ccc2C2=NCCN12
Reactant: CC(=O)Nc1ccc(C(=O)O)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C(=O)NC2=Nc3cc(N4CCOCC4)ccc3C3=NCCN23)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a mixture of 8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide 105.7 mg (0.30 mmol), 6-(acetamido)nicotinic acid 81.1 mg (0.45 mmol) and N,N-diisopropylethylamine 0.26 mL (1.50 mmol) in N,N-dimethylformamide 2 mL was added PyBOP((1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)-phosphonium hexafluorophosphate) 234.2 mg (0.45 mmol) and stirred at 90° C. for 16 hours. After cooling to room temperature, saturated NaHCO3 solution was added. The precipitate was collected and washed with water, methanol, and diethyl ether to give the title compound 41.1 mg as yellow solid. Yield 31.6%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[N:5][N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: Cn1nnnc1CCl
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3nnnn3C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 5-chloromethyl-1-methyl-1H-tetrazole [57235-84-4] and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=443.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.ClCCl>[CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluoro-benzoic acid and 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF was added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccsc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccsc2)C1=O
Yield: 5 %

Procedure:
200 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 100 mg of thiophene-3-boronic acid according to a procedure similar to the synthetic procedure in Example 2 to yield 10 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(3-thienyl)-3(2H)-furanone as a solid. NMR: δ1.56 (s, 6H), 3.09 (s, 3H), 6.92-6.93 (m, 1H), 7.32-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.90-7.93 (m, 2H), 7.97-8.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: BrCCCCBr
Product: COc1ccc2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 5-methoxy-1H-indole and 1,4-dibromobutane.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:25]3[N:24]4[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19](=[O:26])[C:18]=3[S:17][CH:16]=2)=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1.Br.O>C(O)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:25]3[N:24]4[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19](=[O:26])[C:18]=3[S:17][CH:16]=2)=[CH:11][C:10]=1[O:27][CH3:28]
Reactant: COc1cc(-c2csc3c2-n2cccc2C3=O)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(-c2csc3c2-n2cccc2C3=O)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1mmol of the compound of Example 23 dissolved in an excess of hydrobromic acid in 33% acetic acid is stirred for 30 minutes at ambient temperature. After adding 100 ml of water, a precipitate is formed, which is filtered off and then dried. Chromatography on silica gel (ethyl acetate/hexane:1/2) allows the expected product to be isolated.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17D, 5 g, 21.52 mmol) and solvent 2,2,2-trifluoroethanol (50 mL) were added to 20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of the above crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g, 7 mmol) and triethylamine (1.13 g, 11.2 mmol) in dichloromethane (40 mL) was slowly added a solution of 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.712 g, 7 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 4 hours. The solution was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:8][CH:7]=1.C(O)C.[ClH:21]>O>[ClH:21].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:10][CH:11]=1)[NH2:1]
Reactant: CN(C)C(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)Cc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An ice cold solution of sodium nitrite (1.088 g) in water (6 ml) was added to a stirred solution of 2-(4-aminophenyl)-N,N-dimethylacetamide (2.67 g) in concentrated hydrochloric acid (10 ml) at -5° C. After stirring the yellow solid for 15 min, it was added to a stirred solution of stannous chloride (16.88 g) in concentrated hydrochloric acid (10 ml) at -10° C. When the addition was complete, the mixture was stirred at room temperature for a further 30 min and poured into ethanol (100 ml). The mixture was evaporated to dryness under reduced pressure, basified using 2N sodium hydroxide (350 ml) and extracted with ethyl acetate (3×200 ml). Evaporation of the dried (Na2SO4) solvent gave a pale yellow gum which was dried under high vacuum. This was dissolved in ethyl acetate (50 ml) and ethereal hydrogen chloride was added until no more solid deposited. Collection of the solid by filtration and washing with ether gave the title compound as a white powder (1.45 g) which was 82.6% pure and was used in the next stage without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(O)=[O:2].S([O-])([O-])(=O)=O.[Na+].[Na+].ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>O.CCOCC.C(N(CC)CC)C>[N:34]([C:1]([CH2:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:2])=[N+:35]=[N-:36]
Reactant: COc1cccc(C2(CCC(=O)O)CCCCC2=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C2(CCC(=O)N=[N+]=[N-])CCCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
About 225 g. of 2-(β-carboxyethyl)-2-(m-methoxyphenyl)cyclohexanone were mixed with 125 g. of triethylamine and about 20 g. of sodium sulfate. A solution of 99 g. of ethyl chloroformate in 3250 ml. of anhydrous ether was added in dropwise fashion, thus converting the carboxyethyl group to an acid chloride. The reaction mixture was stirred for about 1 hour at about 0° C. at which point 89 g. of sodium azide in 350 ml. of water were added in dropwise fashion. After the addition had been completed, the reaction mixture was stirred for an additional 2 hours at 0° C. The organic layer was separated. 2-(β-Azidoformylethyl)-2-(m-methoxyphenyl)cyclohexanone formed in the above reaction was isolated as an oil by evaporation of the ether in vacuo. The residual oil was dissolved in 3.5 l. of benzene, and the solution heated at refluxing temperature for about 1.5 hours. The benzene was removed by evaporation in vacuo. By this procedure the azidoformyl group was rearranged under Curtius conditions to yield the corresponding isocyanate. The benzene was removed by evaporation in vacuo. The residual isocyanate was next hydrolyzed to the cyclic imine by heating overnight in a mixture containing 1200 ml. of water, 1200 ml. of glacial acetic acid and 1200 ml. of 12N aqueous hydrochloric acid. The hydrolysis mixture was cooled and then made strongly basic with 50 percent aqueous sodium hydroxide. 3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole thus produced was extracted into ether, and the ether layer separated, washed with water and dried. Evaporation of the ether layer to dryness yielded 153.2 g. of 3a-(-m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole, distilling at about 140° C. at 0.07 mm/g. (For comparison, see Langlois et al., Tetrahedron, 27, 5641 (1971) compound 10 and page 5647, table 4, compound 42).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([C:8](=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.CC(O)=O>CCO.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:23][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=C(O)c1ccc(F)cc1)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
Iron powder (710 mg, 13 mmol) was added to a stirred solution of ethyl 2-(5-bromo-2-nitrophenyl)-3-(4-fluorophenyl)-3-hydroxyacrylate (1.0 g, 2.4 mmol) in EtOH (20 mL)/AcOH (16 mL) in a 250 mL round bottomed flask. The flask was immediated placed in a preheated (100° C.) oil bath under an air condenser and the slurry was stirred vigorously. After 1.5 h, the reaction was cooled to r.t., diluted with EtOAc (200 mL), and the solids were removed by filtration. The filtrate was washed with water repeatedly until the organic phase was no longer red. The organic phase was then washed with sat'd NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated (PhMe azeotrope to remove residual AcOH) to give an off-white solid. The crude product was triturated with 1:1 CH2Cl2/hexanes and the filtrate purified by silica gel chromatography with a Biotage 40+M cartridge (gradient elution 10% to 40% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm). The off-white ppt. from above was further triturated with CH2Cl2 to give a white solid, and the filtrate was concentrated to give an off-white solid. Both ppt. and filtrate were chromatographed separately with the same method as above, but with fraction collection at λ=320 nm. Each of the three columns afforded two major peaks. The combined first peaks elute were concentrated to give the title compound (335 mg, 38% yield). 1H NMR (300 MHz, CDCl3) δ ppm 8.67 (br. s., 1H) 8.36 (br. s., 1H) 7.54-7.70 (m, 2H) 7.36 (d, J=7.68 Hz, 1H) 7.25 (t, J=7.68 Hz, 1H) 7.11 (t, J=8.23 Hz, 2H) 4.31 (q, J=6.83 Hz, 2H) 1.33 (t, J=7.14 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.73, (ES+) m/z (MH+)=362, 364 (1:1 ratio).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:24]([C:23]2[CH:27]=[CH:28][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Yield: 50 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using 4-nitro-benzoic acid instead of o-toluic acid to the title compound (1.59 mg, 50%) which was obtained as an off-white solid. MS: m/e=349.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 400 mg (1.02 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 360 mg (1.14 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 70° C. for 2 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography to give 441 mg of a black powder (yield: 62.8%; mp: 177-179° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 44 %

Procedure:
Solid N-[3-[(3-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 12.84 g (0.038 mole) was heated in glass at 210°-20° C. in a Wood's metal bath for 7 minutes. The residue was dissolved in methylene chloride, treated with charcoal, and filtered through a Celite pad. The orange filtrate was treated with Florisil® to give a pink filtrate. The filtrate was evaporated to give a solid, which was recrystallized from tetrahydrofuran-petroleum ether. The solid was collected, washed with petroleum ether, and dried under high vacuum at 50° C. for 5 hours to give 5.3 g (44%) of title compound, mp 98°-99.8° C.