Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.N1CCCCC1.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:2]2[C:1](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:10])=[CH:20][CH:19]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: O=Cc1ccncc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccncc2)C(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of indane-1,3-dione (5.85 g), piperidine (0.46 ml) and pyridine-4-carboxaldehyde (4.31 g) was stirred in IMS (40 ml) at ambient temperature for 50 minutes. The mixture was cooled in an ice-bath but no crystallization occurred. The solution was allowed to warm to ambient temperature and then the solvent was removed under reduced pressure to give a residue which was partially purified by flash column chromatography on silica using 10% industrial methylated spirit in dichloromethane followed by 20% industrial methylated spirit in dichloromethane as the mobile phases. The leading fractions were collected, combined and evaporated to give a solid which was triturated with ice-cold diethyl ether and filtered to give 2-(4-pyridylmethylene) indan-1,3-dione, m.p. 152-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:28]=1)=O)C>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:28]=3)=[O:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CCOC(=O)c1cnn(CCN2CCCC2)c1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnn(CCN4CCCC4)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester, the title compound was obtained as white solid (13% yield). MS: m/e=457(M+H+), mp 190-192° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.[OH-].[Na+]>O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1ccccc1
Yield: 1223 %

Procedure:
3-Phenylpropanol (3.00 g) and 1,6-dibromohexane hydrogen sulphate (0.5 g) and 12.5 M aqueous NaOH (16 ml) for 30 h. The mixture was diluted with H2O (80 ml), extracted with ER (3×100 ml), and the combined organic extracts were washed consecutively with H2O (80 ml) and BR (80 ml). The dried extracts were evaporated and the residual oil purified by [FCS], eluting with CX (one columnful), followed by EA-CX (1:20) to give the title compound (5.35 g) as a colourless oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:15]([CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](OC)=[O:20])(=O)[CH3:16].C[O-].[Na+].S(Cl)(Cl)=O>CO.CC(C)=O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:18]1[C:19]([OH:20])=[N:14][C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[N:13][C:15]=1[CH3:16]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethanimidamide hydrochloride (0.22 g, 1.0 mmol), dimethyl acetyl-succinate (0.19 g, 1.0 mmol), and sodium methoxide (0.07 g, 1.3 mmol) in MeOH (10 mL) was refluxed for 15 hours. After cooling to room temperature, the separated solids were collected by suction and added to a pre-formed solution of thionyl chloride (0.65 mL, 8.9 mmol) in MeOH (7.5 mL). The resulting mixture was refluxed for 16 hours and then cooled to room temperature. Acetone was added and the precipitated solids were collected by suction, rinsed with acetone and dried under high vacuum for 4 hours to give methyl[4-hydroxy-6-methyl-2-(4-nitrobenzyl)-pyrimidin-5-yl]acetate (0.12 g, 38% yield) as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2].[I:18][CH2:19][CH3:20]>CC#N>[I-:18].[CH2:19]([N+:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[NH:3][CH:1]=[O:2])[CH3:20]
Reactant: O=CNc1ccccc1CCc1ccccn1
Reactant: CCI
Solvent: CC#N
Product: CC[n+]1ccccc1CCc1ccccc1NC=O
Product: [I-]

Procedure:
A solution of 2-(o-formamidophenethyl)pyridine (36.1 g., 0.159 mole) and iodoethane (30.0 g., 0.191 mole) in CH3CN (450 ml.) heated at reflux for 18 hr., cooled and diluted to incipient turbidity provides 1-ethyl-2-(o-formamidophenethyl)pyridinium iodide, yield 44.8 g. (74%), m.p. 155° - 157° C.
Reaction SMILES: Cl.C(O[C@H](C)C([N:13]1[C:21]2[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH3:23])=O)C1C=CC=CC=1>C(O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH:14]([CH3:23])[NH:13]2
Reactant: CC1Cc2c(F)cccc2N1C(=O)[C@@H](C)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(F)cccc2N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 62.4 %

Procedure:
8 ml of concentrated hydrochloric acid are added to a solution of 1.66 g of (R)-2-benzyloxy-1-(4-fluoro-2-methyl-2,3-dihydroindol-1-yl)propan-1-one diastereoisomer (A) in 200 ml of absolute ethanol. The reaction mixture is refluxed with stirring for 40 hours and is then cooled to ambient temperature and concentrated to dryness under reduced pressure. The residue is taken up in 250 ml of water, alkalinized with concentrated sodium hydroxide to pH 14, and then the mixture is extracted with 3×200 ml of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure heptane and then with a 95/5 heptane/ethyl acetate mixture at a flow rate of 50 ml/min, and then on a 70 g cartridge of 15-40 μm silica, elution being carried out with pure cyclohexane and then with a 70/30 cyclohexane/dichloromethane mixture, at a flow rate of 50 ml/min. 0.50 g of (+)-4-fluoro-2-methylindoline is thus obtained in the form of a colorless oil, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].C(O[CH:6]([O:10][CH2:11][CH3:12])[C:7]([NH2:9])=[O:8])C.[Br:13][C:14]1[C:18]([CH2:19]Br)=[CH:17][S:16][CH:15]=1.[I-].[Na+].C1[CH2:27][O:26][CH2:25]C1>>[Br:13][C:14]1[C:18]([CH2:19][NH:9][C:7](=[O:8])[CH:6]([O:10][CH2:11][CH3:12])[CH2:25][O:26][CH3:27])=[CH:17][S:16][CH:15]=1
Reactant: CCOC(OCC)C(N)=O
Reactant: BrCc1cscc1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CCOC(COC)C(=O)NCc1cscc1Br
Yield: 35 %

Procedure:
To a suspension of sodium hydride (162 mg, 6.74 mmol) in THF (14 mL, 170 mmol) was added 2,2-diethoxyacetamide (949 mg, 6.45 mmol) in portions, followed by 3-bromo-4-(bromomethyl)thiophene (1.50 g, 5.86 mmol) dropwise as a solution in THF (3 mL) and sodium iodide (87.8 mg, 0.586 mmol). The reaction mixture was heated to reflux for 18 h and then concentrated. The residue was then partitioned between water (40 mL) and ethyl acetate (40 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (2×30 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (5 to 30% ethyl acetate:heptane) afforded 729 mg (35%) of the title compound as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.26-7.29 (m, 1 H), 7.23-7.25 (m, 1 H), 6.99 (br. s., 1 H), 4.83 (s, 1 H), 4.44 (dd, J=6.1, 0.8 Hz, 2 H), 3.21-3.98 (m, 4 H), 1.25 (t, J=6.9 Hz, 6 H); MS (ESI): 322.17, 324.15 [M+H]+; HPLC tR=3.26 min (ZQ3, polar—4 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:17][CH2:18][CH2:19][C:4]3=[C:3]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=3)[CH:8]=2)[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cc(Cl)cc(Cl)c3)nc3c2CCC3)cc1
Yield: 45.2 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.065 g, 65%) as a light yellow solid. MW=435.77. 1H NMR (DMSO-d6, 300 MHz) δ 14.15 (s, 1H), 9.69 (s, 1H), 7.88 (d, J=1.8 Hz, 2H), 7.87-7.83 (m, 1H), 7.33 (s, 4H), 7.07 (s, 1H), 3.64 (t, J=6.9, 2H), 3.13 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.28-2.17 (m, 2H); APCI MS m/z 399 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH2:37]([C:39]1([OH:43])[CH2:42][NH:41][CH2:40]1)[CH3:38]>>[CH2:37]([C:39]1([OH:43])[CH2:42][N:41]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:22][C:23]=2[CH3:29])[CH2:40]1)[CH3:38]
Reactant: CCC1(O)CNC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2C)C1
Yield: 41 %

Procedure:
Using a similar protocol as described in Example 70 employing 73C and 70A as starting materials afforded 100 mg (41%) of 73 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.98 (t, 3H), 1.80 (q, 2H), 2.30 (s, 3H), 2.98 (m, 2H), 3.33 (d, 2H), 3.57 (s, 2H), 3.89 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.73 (m, 1H), 5.05 (m, 1H), 5.11 (m, 1H), 6.54 (d, 1H), 6.59 (s, 1H), 7.03 (d, 2H), 7.16 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 479 [M+H]+, LC purity: 96%.
Reaction SMILES: [C:1]([NH:6][C:7](=O)[O:8]CC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[CH3:13]>C1(C=CC(O)=CC=1)O>[C:1]([NH:6][C:7](=[O:8])[O:16][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCC(CC)CO
Reactant: C=C(C)C(=O)NC(=O)OCC
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)NC(=O)OCC(CC)CCCC
Temperature: 120 °C
Yield: 72.2 %

Procedure:
A reaction vessel was charged with 15.7 g of ethyl N-methacryloylcarbamate and 52 g of 2-ethylhexyl alcohol, to which 0.1 g of hydroquinone was added and heated at 120° C. for one hour. The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 17.4 g of 2-ethylhexyl N-methacryloylcarbamate having a viscosity of 800 cp.
Reaction SMILES: [CH2:1]([C:8]([OH:26])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]=[C:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][I:28]>>[I-:28].[CH2:19]([C:8]([OH:26])([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=[C:10]1[CH2:16][CH:15]2[N+:17]([CH3:27])([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CI
Reactant: CN1C2CCC1CC(=CC(O)(Cc1ccccc1)Cc1ccccc1)C2
Product: C[N+]1(C)C2CCC1CC(=CC(O)(Cc1ccccc1)Cc1ccccc1)C2
Product: [I-]

Procedure:
The title compound was prepared from 2-benzyl-1-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-3-phenyl-propan-2-ol and methyliodide by following the experimental procedures in Example 4 (85% yield): LCMS (ES) m/z 346 (M+H)+; 1H-NMR(CDCl3) δ 0.80 (m, 1H), 1.48 (m, 1H), 1.84 (m, 1H), 1.99 (m, 1H), 2.09 (m, 2H), 2.87 (m, 1H), 2.95 (m, 5H), 3.16 (s, 3H), 3.26 (s, 3H), 4.16 (m, 1H), 4.18 (m, 1H), 5.42 (s, 1H), 7.26 (m, 10H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N1CCCCC1>C(O)C>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(NC(C)=O)cc1
Yield: 41.3 %

Procedure:
A mixture of 33.9 g (0.3 mol) of ethyl cyanoacetate and 59.1 g (0.3 mol) of 4-acetamidobenzaldehyde in 300 ml of ethanol in the presence of 5 ml of piperidine is refluxed for 3 hours. The very viscous medium is diluted with 800 ml of hot ethanol. It is filtered while hot. The yellow solid obtained is washed with hot ethanol. After filtration and drying, 32 g (41% yield) of ethyl 3-(4-acetylaminophenyl)-2-cyanoacrylate are obtained in the form of a pale yellow powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:25]([NH:26][CH2:27][CH2:28][NH:29][C:30](=O)[C:31]2[CH:36]=CC([N+]([O-])=O)=CC=2)=[CH:24][C:23](=[O:41])[N:22]([CH3:42])[C:21]1=[O:43].[C:44]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:45]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:19][N:20]1[C:25]([N:26]2[CH2:27][CH2:28][N:29]([CH2:30][CH2:31][CH2:36][O:18][C:10]3[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=3[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:45][CH2:44]2)=[CH:24][C:23](=[O:41])[N:22]([CH3:42])[C:21]1=[O:43]
Reactant: O=[N+]([O-])c1ccc(O)c(NCc2ccccc2)c1
Reactant: Cn1c(NCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3NCc3ccccc3)CC2)cc(=O)n(C)c1=O
Yield: 79.4 %

Procedure:
0.7 g of 2-benzylamino-4-nitrophenol, 0.8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 0.9 g of triphenylphosphine were suspended in 20 ml of anhydrous tetrahydrofuran, followed by the addition of 0.65 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 0.93 g of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy)propyl]piperazin-1yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([C:26]([OH:28])=O)[CH2:20][CH2:19]2.[NH4+].[OH-]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([C:26]([NH2:3])=[O:28])[CH2:20][CH2:19]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)CCC(C(=O)O)C2
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCC(C(N)=O)C2
Temperature: -10 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A solution of triethylamine (2.7 ml, 0.019 mol) and ethyl chloroformate (2 ml, 0.021 mol) in acetone (40 ml) is added to a solution of the acid obtained in step (i) (3 g, 0.014 mol) in acetone (50 ml) cooled to -10° C. After 1,5 hours at -10° C., concentrated NH4OH (4.5 ml, 0.036 mol) is added dropwise and the reaction mixture is allowed to stand at -10° C. for 1 hour and at room temperature overnight. The solution is concentrated under vacuum, ethyl acetate (150 ml) is added to the obtained residue and the solution is washed sequentially with water, a saturated sodium bicarbonate solution, 6N hydrochloric acid, and water, then it is dried and concentrated to dryness. The residue is triturated with isopropyl ether and filtered thus affording 1.7 g of the above indicated amide; m.p. 136°-138° C.; [α]=+40.2° (c= 1.4%, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:15]([C:14]([F:13])([F:23])[F:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][C:8]=2[CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=Cc2cc([N+](=O)[O-])ccc2OC1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 5-nitrosalicylaldehyde (4.80 g, 28.7 mmol) and ethyl 4,4,4-trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was warmed to 60° C. and treated with anhydrous K2CO3 (3.90 g, 28.9 mol). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford an oil. The oil was dissolved in diethyl ether (5 mL). Hexanes was added until the solution became cloudy. Upon standing at room temperature overnight the ester was obtained as yellow crystals (0.856 g, 7% yield). This material was of sufficient purity to be used in subsequent steps without further purification. 1H NMR (CDCl3/300 MHz) 8.15–8.19 (m, 2H), 7.74 (s, 1H), 7.09 (d, 1H, J=8.9 Hz), 5.81 (q, 1H, J=5.8 Hz), 4.29–4.39 (m, 2H), 1.35 (t, 3H, J=6.0 Hz),
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)NNC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccc(Cl)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), 4-chloro-N′-isopropylbenzohydrazide (222.07 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) and dried so that ivory ((E)-tert-butyl 3-(3-(2-(4-chlorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (165.6 mg, 49%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[N:7]=1)=[O:5])C.[Li+].[OH-].O.Cl>C1COCC1>[CH:12]1([C:8]2[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cccc(C2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C2CC2)n1

Procedure:
1.00 g (5.23 mmol) 6-cyclopropyl-pyridine-2-carboxylic acid ethyl ester was suspended in 10 mL THF and treated with 350 mg (14.6 mmol) LiOH and 5 mL water at RT for 2.5 h. The reaction mixture was acidified with 4 M aqueous hydrochlorid acid and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14]C)=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:16][S:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)cc2c1NCCC2
Product: CS(=O)(=O)Nc1cc2c(c(C(=O)O)c1)NCCC2
Yield: 79.9 %

Procedure:
The title compound was prepared (79.9% yield) from methyl 6-amino-1,2,3,4-tetrahydroquinoline-8-carboxylate by the same procedure as in Example 32 by using methanesulfonyl chloride instead of p-toluenesulfonyl chloride. This compound was recrystallized form ethanol to give yellow crystals, mp 244° C.
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([CH3:24])=[C:18]2[C:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[S:28](=[O:36])(=[O:35])[NH:27][N:26]=1.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CC#N.O.C(Cl)Cl>[C:42]([O:41][C:39](=[O:40])[CH2:38][N:20]1[C:21]2[C:17](=[CH:16][C:15]([F:14])=[CH:23][CH:22]=2)[C:18]([C:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28](=[O:35])(=[O:36])[N:27]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:26]=2)=[C:19]1[CH3:24])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1c(C2=NN(C3CCCCC3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Cyclohexyl bromide (8 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1.[C@H:39]12[CH2:45][C@H:42]([CH2:43][CH2:44]1)[C@@H:41]([CH2:46][NH:47][C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])[NH:40]2.CCN(C(C)C)C(C)C>CN(C=O)C.CC(OC)(C)C>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([N:40]2[C@H:41]([CH2:46][NH:47][C:48](=[O:53])[C:49]([F:51])([F:52])[F:50])[C@@H:42]3[CH2:45][C@H:39]2[CH2:44][CH2:43]3)=[O:31])[N:28]=1
Reactant: O=C(NC[C@H]1N[C@@H]2CC[C@H]1C2)C(F)(F)F
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Nc1nc(C(=O)N2[C@@H]3CC[C@@H](C3)[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(F)c2)s1

Procedure:
TBTU (1.70 mmol, 1.10 eq) is added to a solution of 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (1.62 mmol, 1.05 eq), N-[(1R,3S,4S)-1-(2-Aza-bicyclo[2.2.1]hept-3-yl)methyl]-2,2,2-trifluoro-acetamide (1.55 mmol, 1.0 eq) and DIPEA (5.41 mmol, 3.5 eq) in DMF (10 mL). After 90 min the mixture is diluted with TBME (50 mL) and washed three times with an aq. NaOH solution (0.5 M, 50 mL each). The combined aq. layers are extracted twice with TBME (30 mL each). The organic layers are combined, washed with water (3×30 mL) and brine (30 mL), dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.82 min; [M+H]+=442.9.