Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]/[CH2:10]Br>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]/[CH2:10][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: CCNCC
Reactant: BrC/C=C/CBr
Solvent: Cc1ccccc1
Product: CCN(CC)C/C=C/CN(CC)CC
Reaction time: 4 h
Yield: 108.9 %

Procedure:
Diethylamine (1.5 g, 20 mmol) in toluene (50 ml) was added to a stirred solution of (E)-1,4-dibromobut-2-ene (2.14 g, 10 mmol) in toluene (50 ml) at room temperature, and the solution was stirred for 4 h. The white precipitate formed was filtered off, washed with ether (2×20 ml), and dissolved in hot aqueous ethanol. The solution was allowed to cool and acetone was added. The white precipitate formed was filtered off and washed with acetone to yield (E)-N,N,N',N'-tetraethyl-1,4-diaminobut-2-ene (TED) dihydrobromide (2.16 g, 60%). δH (90 MHz, D2O) 1.10 (12H, t), 3.15 (8H, q), 3.98 (4H, m) and 5.90 (2H, m).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.10 g, 0.52 mmol), 4-(pyridin-2-ylamino)phenol (0.29 g, 1.55 mmol), and cesium carbonate (0.51 g, 1.55 mmol) were mixed in NMP (1.5 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 360.1 (M+1). IC50 (uM) 0.002.
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[N:23][C:17]=3[N:16]3[CH:24]=[CH:25][CH:26]=[C:15]3[C:14]2=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:27][C:14]1[C:15]2[N:16]([CH:24]=[CH:25][CH:26]=2)[C:17]2[N:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: O=C1c2cccn2-c2ncccc2OC1c1cccc2ccccc12
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2cccc3ccccc23)Oc2cccnc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of potassium hydride (0.281 g, 2.45 mmol, 35% in oil) in anhydrous THF (5.0 mL) was added the the (±)-6-(1-naphthyl)pyrrolo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one (800 mg, 2.45 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.303 g, 2.82 mmol) was slowly added. After stirring for 12 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:3) to give the PBOX-13 in 78% yield. IR (neat) 1725 cm−1; 1HNMR (CDCl3) δ 2.61 (s, 3 H), 2.70 (s, 3 H), 6.44 (m, 2 H), 7.10 (m, 2 H), 7.41-7.59 (m, 4 H), 7.62-7.90 (m, 3 H), 8.12 (m, 1 H), 8.25 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:56])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:55])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:58])[CH3:57])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:54][C:50]1[CH:49]=[C:48]([C:45]2([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:55])([CH2:21][CH2:22]4)[C@@:19]4([CH3:56])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:59])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)[CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3cccc(Cl)c3)CC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3cccc(Cl)c3)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(3-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.241 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (3 mL, 38.9 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated to get the crude product which was purified by preparative-HPLC to get the product (100 mg, 53%) as a light white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 8.78 (s, 1H), 7.38-7.18 (m, 2H), 7.13 (d, J=5.3 Hz, 1H), 7.08-6.96 (m, 1H), 6.65 (d, J=15.8 Hz, 1H), 5.92 (d, J=16.1 Hz, 1H), 4.39 (dd, J=4.8, 11.0 Hz, 1H), 3.31-3.08 (m, 1H), 2.85-2.72 (m, 1H), 2.63-0.58 (m, 53H); LC/MS: m/z calculated 773.4. Found 772.3 (M−1)−.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: Br[CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].[CH2:32]([N:34](CC)[CH2:35]C)C.CNC>C1(C)C=CC=CC=1>[CH3:32][N:34]([CH3:35])[CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(Br)CN1CCN(c2ccc(F)cc2)CC1
Agent: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-{2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g), triethylamine (1.1 cc) and dimethylamine (0.5 cc) in toluene (50 cc) are introduced into a 250 cc bomb apparatus cooled to a temperature of about 0° C. The mixture is stirred and heated for 8 hours to a temperature close to 120° C., then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature, then the reaction mixture is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant. After recrystallization from boiling acetonitrile (15 cc), 2-{2-dimethylamino-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.9 g) is obtained, m.p. 118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7](O)[C:6]=2[CH:16]=1.P(Br)(Br)[Br:18].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br:18][CH:7]1[C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2=[CH:12][CH:13]=[CH:14][N:9]2[CH2:8]1
Reactant: BrP(Br)Br
Reactant: OC1Cn2cccc2Sc2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc2c(c1)C(Br)Cn1cccc1S2
Yield: 48 %

Procedure:
To a solution of 24c (0.17 g 0.71 mmol) in dry ethyl ether (3 ml) was added dropwise a solution of phosphorus tribromide (μL 33.5, 0.36 mmol) in dry ethyl ether (0.7 ml); the reaction mixture was refluxed for 2 hours under argon atmosphere. After cooling to room temperature dry ethanol (μL 143) was added and the resulting solution was heated at reflux for 1 hour. Then 4 ml of aqueous sodium carbonate was added; the organic phase was separated, dried and evaporated. The crude product was chromatographed (50% petroleum ether 40-60° in dichloromethane) to give 0.103 g of pure 25c (48% yield). 1H NMR (CDCl3) δ7.35-7.16 (m, 2H); 6.92-6.82 (m, 2H); 6.39-6.37 (m, 1H); 6.13-6.09 (m, 1H); 5.69-5.64 (m, 1H); 5.10-5.01 (dd, 1H, J=14.57, 2.65 Hz); 4.70-4.59 (dd, 1H, J=14.88, 7.05 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CC(C)=O>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: BrCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCBr
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a stirred solution of 1,7-dibromoheptane (11) (13.90 g, 53.9 mmol) in acetone (100 mL) was added potassium phthalimide (5.00 g, 27.0 mmol). The resulting mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. MPLC purification of the residue (Hexanes:EtOAc/70:30) gave 12 as a colorless oil (6.62 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.83-7.84 (m, 2H), 7.69-7.72 (m, 2H), 3.67 (t, J=7.6 Hz, 2H), 3.39 (t, J=7.2 Hz, 2H), 1.82-1.84 (m, 2H), 1.67 (m, 2H), and 1.35 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 168.55, 134.06, 132.30, 123.32, 38.06, 34.12, 32.85, 28.67, 28.48, 28.19, and 26.83.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[O:1]([C@H:2]([CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@H](O)CC(C)=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](CC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Methyl(3R)-3-hydroxy-5-oxohexanoate (6) (10 g, 0.062 mol) was dissolved in dry DMF (110 mL) and the solution was cooled down to 0° C. Imidazole (8.5 g, 0.124 mol) and tert-butyldimethylsilyl chloride (11.3 g, 0.0744 mol) were added. The reaction mixture was stirred at 25° C. for 12 h and then quenched with a 10% NaHCO3 solution. After the extraction with toluene (3×150 mL), the collected organic phase was dried under vacuum and the resulted oil was purified via by fractional distillation. Methyl(3R)-3-(tert-butyldimethylsiloxy)-5-oxohexanoate was obtained as a yellow oil the compound of formula (II-R, PG=TDBMS, Z=OMe)(11.3 g; molar yield 66%).
Reaction SMILES: Br[C:2]1[C:3]2[S:14][C:13]([CH3:15])=[CH:12][C:4]=2[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.[CH3:17][N:18]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:17]([C:2]1[C:3]2[S:14][C:13]([CH3:15])=[CH:12][C:4]=2[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:18]
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1Br
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.96 g) in N-methylpyrrolidone (10 mL) were added zinc cyanide (1.17 g) and tetrakis(triphenylphosphine)palladium (0.38 g), and the mixture was stirred at 150° C. for 30 minutes using microwave reactor. To the reaction solution was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.64 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=2)=[N:12]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: CO.[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:11])[CH2:5]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:11])[CH2:5]1
Reactant: O=Cc1ccccc1
Reactant: NCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCCCNCc1ccccc1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reaction time: 0.5 h

Procedure:
To a methanol solution of 87 mg of 3-aminopropyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 35 mg of benzaldehyde was added at room temperature, stirred for 30 minutes at the same temperature, sodium borohydride was added, and further stirred for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: chloroform/methanol=50/1), to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[CH:3][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(F)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.00 g (3.60 mmol) of 6-amino-4-(3-fluorophenylamino)quinoline-3-carbonitrile in 12 mL of THF under N2 was chilled in ice. Triethylamine (0.436 g, 4.32 mmol) was added followed by 0.393 g (4.32 mmol) of acryloyl chloride and the reaction was stirred at 25° C. overnight. The solvent was removed and the residue was slurried with water and filtered. The crude product was washed with water, dried, washed with hot ethyl acetate and dried in vacuo (50° C.). This yielded 0.862 g of N-[3-cyano-4-(3-fluorophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): M+H 333.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20](OCC)=[O:21])=[CH:19][C:12]=2[N:11]=1.C[Al](C)C.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][N:34]=[C:33]([NH2:38])[CH:32]=1>CCCCCC.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20]([NH:38][C:33]3[CH:32]=[C:31]([CH3:30])[C:36]([CH3:37])=[CH:35][N:34]=3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F
Reactant: Cc1cnc(N)cc1C
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)n(C)c3cc2F)cc1C

Procedure:
Prepared analogously to example 131f from ethyl 2-(2,6-dichlorophenylamino)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxylate, 2 M trimethyl aluminium solution in hexane and 4,5-dimethylpyridin-2-amine in THF.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Oc1sc3c(c1C(=O)N2)CCCC3
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc2c(c1)Oc1sc3c(c1C(N1CCN(C)CC1)=N2)CCCC3

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[F:13].[CH3:14][N:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[C:18]2[CH:30]=[CH:31][N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:17]=2[C:16]1=[O:41]>>[F:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH:6][CH3:7])[CH:8]=[CH:9][C:2]=1[C:19]1[C:18]2[CH:30]=[CH:31][N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:17]=2[C:16](=[O:41])[N:15]([CH3:14])[CH:20]=1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccn(COCC[Si](C)(C)C)c2c1=O
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C21H28FN4O4Si (M+H)+: m/z=447.2. found: 447.1.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][CH:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:26]3[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH:20]([CH3:21])[CH3:19])[CH2:25]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)NCC1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC(C)C)C3)nc21
Yield: 17.7 %

Procedure:
A near solution of 0.82 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid and 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine in 50 mL of acetonitrile was heated at reflux for one hour. The solvent was removed in vacuo, the residue dissolved in water, filtered through a fiber glass pad to clarify and the filtrate adjusted to pH 2.0 with 6M hydrochloric acid. The resulting clear solution was lyophilized and the residue recrystallized from ethanol to give 200 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[[(1 -methylethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-l,8-naphthyridine-3-carboxylic acid, mp 302°-304° C. as the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:10]1[C:5]2[C:6](=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:8]([C:11]2[CH2:19][CH:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[CH2:13][CH:12]=2)=[CH:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2n1
Product: CC(=O)n1cc(C2=CCN3CCCC3C2)c2nc(N)ccc21
Yield: 72.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)pyrrolo[3,2-b]pyridine and 0.35 μL (0.47 mMol) acetyl chloride, 0.084 gm (73%) of the title compound were recovered by the procedure of Example 19.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14](=[O:19])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[OH-:20].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:19])=[O:20])=[CH:7][N:8]2[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [Na+]
Product: CCCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 1-(6-chloro-1-propyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (277.1 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C., partitioned between water (75 mL) and ethyl acetate (75 mL), and extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-propyl-1H-indole-3-carboxylic acid (141.4 mg, 74%) as a cream-colored solid: mp 179-180° C.; EI-HRMS m/e calcd for C12H12ClNO2 (M+) 237.0556, found 237.0558.