Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:16][CH2:15][CH2:14][CH2:13][S:12][CH:11]([CH3:17])[C:10]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:16]1[C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:18][C:10]=2[CH:11]([CH3:17])[S:12][CH2:13][CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1SCCCNc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1CCCSC(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4 g of acetyl chloride were added dropwise to a suspension of 11.4 g of 8-chloro-1,3,4,6-tetrahydro-6-methyl-2H-5,1-benzothiazocine and 10 g of potassium carbonate in 100 ml of acetone, whilst keeping the temperature of the mixture below 10° C. The mixture was stirred for 30 minutes, after which it was poured into ice-water and extracted with chloroform. The solvent was evaporated from the extract and the residue was recrystallized from a 3:2 by volume mixture of methylene chloride and n-hexane to give 5 g of 1-acetyl-8-chloro-1,3,4,6-tetrahydro-6-methyl-2H-5,1-benzothiazocine in the form of crystals melting at 132°-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][C:19]=3[C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH:8]=2)[N:3]=1.C(O)=[O:38]>C(Cl)Cl>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:19]([C:30]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[O:31])=[CH:20][CH:21]=[CH:22][C:23]=3[C:24](=[O:38])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)CCc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: O=CO
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1

Procedure:
A solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)phenyl)(pyrrolidin-1-yl)methanone (188 mg, 0.390 mmol, see Example 45) in formic acid (>96%) (10 mL, 265 mmol) was heated to 110° C. After 4 days CH2Cl2 was added and the solution was washed with water and sodium carbonate solution. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a white powder. MS (ESI, pos. ion) m/z: 501 (M+1).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.57 g, 2.9 mmol) and sodium methoxide (0.18 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue thus obtained was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from dichloromethane-diethyl ether to give the title compound (0.37 g, 1.6 mmol, yield: 61%) as colorless needles.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH2:18][CH3:19])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Benzyloxy-3-ethoxy-benzaldehyde (20 g) was dissolved in dichloromethane (100 ml) and a solution of nitric acid in dichloromethane (2M, 200 ml) was gradually added at a temperature under 30° C. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water. The organic phase was washed with 1M sodium hydroxide and water and then it was dried and evaporated.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:27]1[C:30]2([CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][N:28]1[CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH2:44][CH2:45][OH:46])[CH:41]=[CH:42][CH:43]=1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:46][CH2:45][CH2:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][N:28]1[CH2:29][C:30]2([CH2:35][N:34]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:33][CH2:32][O:31]2)[CH2:27]1
Reactant: OCCc1cccc(CCN2CC3(CNCCO3)C2)c1
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCO)c4)C3)C2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.792 g) was added in one portion to a stirred solution at 0° C. of 2-(3-(2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenyl)ethanol 2HCl (0.56 g) (example 176 step e), 2-isopropylthiazole-4-carboxylic acid (0.275 g) and triethylamine (1.117 ml) in DMF (7 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, 5% methanol in ethyl acetate with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.475 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17]Br>>[CH2:12]([O:11][C:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:17][CH2:16][CH2:15]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: BrCCCBr
Product: CCOC(=O)C1(c2ccc(Br)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 6, Step 1 using ethyl 4-bromophenylacetate and 1,3-dibromopropane.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:21][O:22]C1C=CC(B(O)O)=CC=1>>[CH3:21][O:22][C:8]1[CH:7]=[CH:6][C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Product: COc1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
Made by following the procedure described for the preparation of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-amine with 4-methoxyphenyl boronic acid and making non-critical variations.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CCN(C(C)C)C(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].P([O-])([O-])([O-])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:23]([O:9][CH2:8][C@:2]1([CH3:1])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CCC[C@H]1O[C@]1(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H]1O[C@]1(C)CO[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
Alcohol 3 (51.1 mg, 0.3925 mmol) in 3 ml of CH2Cl2 was treated successively with DIPEA (102 μl, 0.5888 mmol, 1.5 eq), DMAP (1 crystal), and TBSCl (77 mg, 0.5103 mmol, 1.3 eq) and refluxed for 12 h. The solution was poured onto 20 ml of 0.2M pH 7 phosphate buffer and 30 ml of low boiling petroleum ether, shaken, and separated. The aqueous phase was extracted with petroleum ether (3×10 ml), washed with pH 7 buffer (1×10 ml), H2O (1×5 ml), brine (1×5 ml), dried over MgSO4, and concentrated to give 86.0 mg of 4 as a clear oil (89.6%). 1H NMR (CDCl3, 360.134 MHz) δ:3.57 (1H, d, J=11.15 Hz), 3.53 (1H, d, J=11.17 Hz), 2.82 (1H, t, J=5.70 Hz), 1.6-1.4 (4H, m), 1.25 (3H,s), 0.95 (3H, t, J=7.13 Hz), 0.87 (9H, s), 0.04 (3H, s), and (3H, s). 13C NMR (CDCl3, 90.55 MHz) δ:68.0, 61.0, 60.8, 30.2, 25.8, 19.7, 18.3, 14.1, 13.9, and -5.4. IR (thin film): 2959 (s), 2930 (s), 2859 (s), 1473 (m), 1464 (m), 1382 (w), 1362 (w), 1253 (m), 1103 (s), 838 (s), 778 (s), and 667 (w) cm-1. [δ]D=+4.9° (c=2.62, CH2Cl2).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].[CH2:14]([NH:17][C:18]1[C:19]2[CH2:27][CH2:26][C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(C)[C:20]=2[N:21]=[C:22](Cl)[N:23]=1)[CH:15]=[CH2:16].OS(O)(=O)=O>CN1CCCC1=O>[CH2:14]([NH:17][C:18]1[C:19]2[CH2:27][CH2:26][CH:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:20]=2[N:21]=[C:22]([NH:13][C:11]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:12]=2)[N:23]=1)[CH:15]=[CH2:16]
Reactant: C=CCOc1cc(N)ccc1C#N
Reactant: C=CCNc1nc(Cl)nc2c1CCC2(C)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Product: C=CCNc1nc(Nc2ccc(C#N)c(OCC=C)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-(allyloxy)-4-aminobenzonitrile (Preparation D, 168 mg, 0.963 mmol), and N-allyl-2-chloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ua, 204 mg, 0.642 mmol) in N-Methyl-2-pyrrolidinone (5135 μL) was added H2SO4 (54.7 μL, 1.027 mmol). The mixture was stirred at 100° C. overnight. The crude reaction mixture was purified by PREP HPLC: (50×250 mm HPLC XTerra C18.15 to 100% A:B over 40 min, 3 min at 100% B (A is 90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). The appropriate fractions were concentrated in vacuo to afford 4-(4-(allylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2-(allyloxy)benzonitrile (74 mg, 25% yield). LC-MS (M+H)+=456.1.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:12]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: Fc1cccc2ccccc12
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c2ccccc12
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.75 mL (5.0 g, 34.25 mmol) 1-fluoronaphthalene and 10 mL carbon tetrachloride, followed by dropwise addition of 1.7 mL (5.5 g., 34.375 mmol) bromine over 3 min. The reaction was heated to 50-60° C. as HBr was evolved for 2 hours, then cooled and concentrated. The residue was dissolved in methanol and kept overnight at 0° C. After filtration with cold methanol, the product, with mp close to room temperature, was 4.62 g (60%) of a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH:10]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[OH-].[Ba+2].[OH-].O>O1CCCC1>[CH3:17][CH:11]([CH:10]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]([OH:1])[CH3:3])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)C(NCc1ccccc1)C(C(=O)OCC)C(C)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O

Procedure:
A mixture (140 mg) of the isomers (10a) and (10b) of diethyl 2-(1-hydroxyethyl)-3-benzylamino-4-methylpentanedioate (10a:10b=5:2) as obtained in Example 14 (2.15 g) was dissolved in tetrahydrofuran (4 ml), barium hydroxide (250 mg) and water (2 ml) were added thereto, and the resultant mixture was stirred vigorously at room temperature of 45 minutes. Insoluble materials were collected by filtration and washed with ethanol. The washing and the filtrate were combined together and concentrated under reduced pressure. The residue was subjected to thin layer chromatography, whereupon a new spot was revealed in addition to the spots corresponding to the starting material and the original point. The product as the new spot was collected and fractionally purified to give (2RS,3RS,4SR,5SR)-2-methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxyhexanoic acid (70 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50]O)[CH:46]([O:52]O)[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.[C:62]([Si:66](Cl)([CH3:68])[CH3:67])([CH3:65])([CH3:64])[CH3:63]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:66]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:68])[CH3:67])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OO)C(OO)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3", 4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 2, 3.01 g) in dry methylene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tertbutyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13]I)[CH2:6][CH2:5]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c(C3(CCCN4CCOCC4)CCc4cc(F)ccc43)c[nH]c12
Yield: 83 %

Procedure:
Combine N-{3-[5-fluoro-1-(3-iodo-propyl)-indan-1-yl]-1H-indol-7-yl}-methane sulfonamide (65 mg, 0.13 mmol) and morpholine (2 ml) in anhydrous tetrahydrofuran (2.5 ml) and stir at room temperature under nitrogen overnight. Remove the volatiles under high vacuum, dissolve the residue in dichloromethane, add solid potassium carbonate, stir for ten minutes, filter, and concentrate in vacuo. Purify the residue on silica eluting with 5 to 10% methanol in dichloromethane over 15 minutes to obtain the title compound as a white solid (50 mg, 83%). LC-MS m/z 472.2 (M++1).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]([CH2:19][C:20](=[O:21])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: O=C(CNc1ccc(Cl)cc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CN(C(=O)Cc1ccccc1)c1ccc(Cl)cc1)c1ccccc1
Reaction time: 2 h

Procedure:
After dissolving compound 12 (2.27 g, 14.7 mmol) in THF, compound 11 (1.5 g, 6.1 mmol) was added thereto. After the agitation for 2 hours at room temperature, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4 and distillation under the reduced pressure was carried out. After the removal of a junk by column chromatography (EA/HX= 1/9), the next reaction was followed as a crude condition.
Reaction SMILES: [N:1]([CH:4]1[C:9]2=[C:10]3[C:19](=[C:20]([O:22][CH3:23])[CH:21]=[C:8]2[O:7][C:6]([CH3:31])([CH3:30])[CH:5]1[OH:32])[C:18](=[O:24])[C:17]1[CH:16]=[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=[CH:13][C:12]=1[N:11]3[CH3:29])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:9]2=[C:10]3[C:19](=[C:20]([O:22][CH3:23])[CH:21]=[C:8]2[O:7][C:6]([CH3:30])([CH3:31])[CH:5]1[OH:32])[C:18](=[O:24])[C:17]1[CH:16]=[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=[CH:13][C:12]=1[N:11]3[CH3:29]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C(N=[N+]=[N-])C(O)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)C(N)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution containing 0.2 g of the compound of Step 1 and 0.09 g of Pd/C in 5 ml of ethanol is stirred at room temperature under an H2 atmosphere for 48 hours. The catalyst is then filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol: 95/5), allowing the desired product to be isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[C:21]([CH2:20][Cl:19])=[N:1]2
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1F
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Yield: 39.6 %

Procedure:
Prepared according to Procedure B with 1k (1.0 g, 3.78 mmol) and chloroacetyl chloride (0.90 mL, 11.3 mmol) in acetic acid (20 mL). Purified by chromatography in CH2Cl2 to afford 484 mg of a pale pink solid (40%). 1H NMR (CDCl3) δ: 7.69 (s, 1H); 7.68 (d, J=3.2 Hz, 1H); 7.56 (d, J=3.0 Hz, 1H); 7.54 (d, J=3.0 Hz, 1H); 7.40-7.47 (m, 1H); 7.35-7.38 (m, 1H); 7.27-7.32 (m, 1H); 4.35 (d, J=12 Hz, 1H); 4.18 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[C:7]([F:17])=[C:8]([F:16])[C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4].[CH3:19]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[C:7]([F:17])=[C:8]([F:16])[C:9]=1[F:15]
Reactant: CO
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Yield: 10 %

Procedure:
The solid 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid (1.47 g, 0.00519 mol) and p-toluenesulfonic acid catalyst (17.1 mg) were dissolved in methanol (125 ml). The stirring mixture was brought to reflux under a nitrogen atmosphere for 51 hours. The reaction mixture was concentrated in vacuo to give a solid. The product was partitioned between diethyl ether (200 ml) and saturated aqueous potassium carbonate (75 ml). The layers were separated and the organic phase was washed with water (75 ml), brine (75 ml), was dried over anhydrous potassium carbonate, and was concentrated in vacuo to afford 0.15 g of an off-white solid; 10% yield; 1H-NMR (400 MHz; CDCl3) δ8.23-8.19 (m, 1H), 3.92 (s, 3H), 2.83 (s, 6H); 19F-NMR (376 MHz; CDCl3) δ−120.79 to −121.02 (m), −153.69 to −153.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:13]=2[CH3:30])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 3-amino-5-bromopyridine (0.13 g, 0.78 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (63.6 mg, 1.59 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (0.25 g, 0.86 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and warmed to 45° C. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:36]2[CH2:35][CH2:34][NH:33][CH:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][OH:22])=[CH:31][CH:30]=3)[CH2:37]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: OCCOc1ccc(C2CNCCN2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(OCCO)cc5)C4)cc3nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A suspension of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.015 g) and (RS)-2-[4-(2-hydroxyethoxy)phenyl]-piperazine (1.7 g) in dimethyl sulphoxide (15 cc) is heated with stirring to a temperature in the region of 100° C. for 2 hours and a half. After cooling to approximately 20° C., the suspension is treated with water (30 cc), drained and washed with water (3×10 cc). After one recrystallization in dimethylformamide (15 cc), (RS)-7-fluoro-8-{3-[4-(2-hydroxyethoxy)phenyl]-1-piperazinyl}-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.2 g)is obtained in the form of a yellow solid, m.p. 276° C.