Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[H-].[Na+].Br[C:29]1[CH:30]=[C:31]([CH:52]=[CH:53][N:54]=1)[C:32]([NH:34][C:35]1[S:36][C:37]2[C:43]([CH:44]3[CH2:49][O:48][CH2:47][CH2:46][O:45]3)=[CH:42][CH:41]=[C:40]([O:50][CH3:51])[C:38]=2[N:39]=1)=[O:33]>O1CCOCC1.CN(C=O)C>[O:45]1[CH2:46][CH2:47][O:48][CH2:49][CH:44]1[C:43]1[C:37]2[S:36][C:35]([NH:34][C:32](=[O:33])[C:31]3[CH:52]=[CH:53][N:54]=[C:29]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)[CH:30]=3)=[N:39][C:38]=2[C:40]([O:50][CH3:51])=[CH:41][CH:42]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OCCN1CCOCC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCCN4CCOCC4)c3)nc12
Temperature: 50 °C
Yield: 72.6 %

Procedure:
To a solution of 437 mg (3.33 mmol) N-(2-hydroxyethyl)morpholine and 20 mg (0.09 mmol) 2,6-di-tert-butyl-para-cresol in 5 ml dioxane and 1 ml DMF was added portionwise 194 mg (4.44 mmol) sodium hydride (55% dispersion in oil) and the mixture heated at 50° C. for 30 min. 200 mg (0.44 mmol) (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 80° C. for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (5/95 methanol/ethyl acetate) followed by trituration in ether and hexane afforded 160 mg (72%) (+)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide as a white solid. [α]D20=+51.2° (c=1.04, CHCl3), ES-MS m/e (%): 501 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[N:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:16]([C:18]1[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)#[CH:17].C(N(CC)CC)C>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[O:14][N:13]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CC(Cl)=NO)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Manufacturing Example 70-1-3 and 3-ethynyl-pyridin-2,6-diamine (56.5 mg, 0.424 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (232 μL, 1.66 mmol). This mixture was stirred for 5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (66 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1.CO.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCN(c2ccc(F)cn2)CC1
Yield: 96 %

Procedure:
A solution of tert-butyl (1-(5-fluoropyridin-2-yl)piperidin-4-yl)carbamate (0.36 g, 1.22 mmol) in HCl in Dioxane (4M, 2 mL), THF (2 mL) and MeOH (2 mL) was stirred at rt. After 4 h the reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.31 g, 96%) as a solid. 1H NMR (500 MHz, CD3OD): 8.10-8.02 (m, 2H), 7.52 (dd, 1H), 4.34-4.26 (m, 2H), 3.61-3.50 (m, 1H), 3.38 (dt, 2H), 2.28-2.21 (m, 2H), 1.80 (dq, 2H); 13C NMR (CD3OD): 153.2, 151.2, 151.0, 134.5, 134.3, 123.9, 123.6, 115.0, 114.9, 45.3, 29.1; Mass Spectrum: M+H 196.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C(OC([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=O)[CH2:19][CH2:18]1)=O)(C)(C)C.OP(O)(O)=O.S1(CCCC1)(=O)=O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:24]([CH2:23][CH:20]3[CH2:21][CH2:22][NH:17][CH2:18][CH2:19]3)[S:9][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc(Br)cc1S
Agent: O=P(O)(O)O
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: Brc1ccc2nc(CC3CCNCC3)sc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
2-Amino-5-bromobenzenethiol (326 mg, 1.597 mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (480 mg, 1.973 mmol), PPA (115% as H3PO4) (1637 mg, 6.82 mmol), and sulfolane (3.9 mL) were placed in a microwave vial and heated carefully with vial open to air at 80° C. for 10 min. The vial was then sealed and heated in microwave at 140° C. for 20 min. The mixture was diluted with MeOH, and purified via preparative HPLC (PHENOMENEX® Axia 5u C18 30×100 mm, Flow rate: 40 mL, Solvent A: 90% H2O and 10% MeOH with 0.1% TFA, Solvent B: 90% MeOH and 10% H2O with 0.1% TFA. 20% to 100% B in 10 min gradient, stop at 12 min, the product RT=6.86 min) to afford Compound 41A as an orange solid (380 mg, 76% yield). 1H NMR (400 MHz, methanol-d3) δ 8.16 (d, J=1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.63 (dd, J=8.7, 1.8 Hz, 1H), 3.40 (d, J=12.8 Hz, 2H), 3.14 (d, J=7.1 Hz, 2H), 3.01 (t, J=12.2 Hz, 2H), 2.27 (tdt, J=11.2, 7.3, 3.5 Hz, 1H), 2.02 (d, J=12.6 Hz, 2H), 1.56 (td, J=14.9, 3.7 Hz, 2H). LCMS (m/z)=311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5]N1C2C(=CC=CC=2C(F)(F)F)C2(C(=O)NC(=O)N2)C1=O.[Cl:30]C1C=C(C=CC=1Cl)C[N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[C:44]([F:47])([F:46])[F:45])[C:37](=[O:48])[C:36]1=[O:49]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][Cl:30].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:43]=1[NH:35][C:36](=[O:49])[C:37]2=[O:48]
Reactant: O=C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2c1cccc2C(F)(F)F
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1c(C(F)(F)F)cccc12
Product: ClCc1ccc(Cl)c(Cl)c1
Product: O=C1Nc2c(cccc2C(F)(F)F)C1=O

Procedure:
(Example 4): 1'-(3,4-dichlorobenzyl)-7'-trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, as a solid m.p. 170°-171° C., starting from 1-(3,4-dichlorobenzyl)-7-trifluoromethylindoline-2,3-dione (itself obtained as a syrup of satisfactory purity by NMR, by reaction of 3,4-dichlorobenzyl chloride with 7-trifluoromethylindoline-2,3-dione in an analogous manner to that described for the starting material in Example 1);
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28]>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH2:25][CH2:26][C:27]#[N:28])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: N#CCCCBr
Product: N#CCCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 54.3 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 4-bromobutanenitrile (0.025 mL, 0.252 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0360 g, 54.1%). EI-MS m/z 356 (M+) Rt (1.57 min).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 66.7 %

Procedure:
A solution which contained 19.5 g R-(+)-thioctic acid and 0.5 g S-(-)-thioctic acid in a mixture of 24 ml toluene and 6 ml n-heptane was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 13.0 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 94.5% with a melting range of 45 to 48° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.CS[C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC.[CH3:25][NH2:26]>C(O)C>[CH3:13][N:12]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:26][CH3:25])=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=1)[CH3:14]
Reactant: CN(C)Cc1cc(CSCCN)cs1
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: CCO
Product: CNC(=NS(C)(=O)=O)NCCSCc1csc(CN(C)C)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[[2-(amino)ethyl]thio]methyl-N,N-dimethyl-2-thiophenemethanamine (0.4 g) and S,S'-dimethyl-N- (methylsulphonyl)-dithio-carbonimidic acid (0.35 g) in ethanol (10 ml) was heated at 60° C. for 1 hour. A 33% solution of methylamine in ethanol (10 ml) was added and the mixture was stirred for 20 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica using methanol to give the title compound (0.5 g) as an amber gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11]Cl)[CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloride (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) in ethanol (1000 ml) was heated at reflux for 8 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether. The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111 g, 99%) as an amorphous brown solid which was used in the next step without purification. MS m/e: 273 ([[M+H]]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(S)cc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
324 mg of said di(3-chloro-4-methoxyphenyl)disulfide was dissolved in 10 ml of ethanol, followed by addition of 106 mg of sodium borohydride. The mixture was stirred over 2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with ethyl acetate. The organic layer was washed with saturated salt water and then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column chromatography (hexane: ethyl acetate=15:1), whereby 239 mg of 3-chloro-4-methoxybenzenethiol was obtained. 231 mg of the resulting 3-chloro-4-methoxybenzenethiol was dissolved in 4 ml dichloromethane, followed by cooling to 0° C. 4 ml of boron tribromide in dichloromethane was added dropwise under stirring. The mixture was stirred for 2 hours under cooling on ice and then for 20 hours at room temperature. Subsequently, under cooling on ice, water was added to the solution thus reacted, and the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out, whereby 208 mg of crude 3-chloro-4-hydroxybenzenethiol was obtained.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: Br
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc(-c2ccccc2Br)cc1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 2'-amino-4-biphenylylglycolate suspension in 225 ml. of 40% hydrobromic acid and cooled to 0°C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 2'-bromo-4-biphenylylglycolic acid.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: C#CCCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and CuI (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:43][C:42]3[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc([N+](=O)[O-])cc5)c4=O)CC3)c2cc1OC
Yield: 38 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-nitrobenzyl bromide was used in place of methyl iodide. As a result, 145.0 mg (yield: 38%) of Compound 11 was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:21][O:13][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[CH3:1])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
30 g (114 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid (CAS [43071-45-0]) were suspended in 250 ml of dry CH2Cl2; 20 ml (230 mmol) of oxalyl chloride dissolved in 120 ml of CH2Cl2 were added dropwise and the reaction mixture was stirred at room temperature for 30 min. Two drops of DMF were added and the reaction was stirred for additional 30 min. The solvent was evaporated in vacuo to dryness, the residue was taken up with 100 ml of CH2Cl2 and 100 ml of MeOH, dissolved in 400 ml of CH2Cl2, were added dropwise. After stirring for 18 h the solvent was evaporated in vacuo to dryness, the residue was taken up with CH2Cl2 and washed with 1% NaHCO3; the organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to yield 31.6 g of the title compound as a solid, which was used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[C:33]([CH2:34]Br)=[CH:32][CH2:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[C:33]([CH2:34][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:32][CH2:31][CH2:30]1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2=CCCC2CO)c(=O)[nH]c1=O
Yield: 22.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH2:20][OH:21])[S:16][N:15]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH2:20][O:21][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[S:16][N:15]=1
Reactant: OCc1snc(Cl)c1Cl
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(OCc2snc(Cl)c2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
In 6 ml of acetonitrile were dissolved 0.62 g (3.10 mmol) of 3-chloro-1,2-benzoisothiazole 1,1-dioxide and 0.57 g (3.10 mmol) of the (3,4-dichloroisothiazol-5-yl)methanol. To the resulting solution was dropwise added 0.34 g (3.4 mmol) of triethylamine, followed by stirring at room temperature for 5 hours to give rise to a reaction. After the completion of the reaction, 12 ml of water was added. The resulting crystals were obtained by filtration. The crystals were washed with water and isopropyl alcohol to obtain 0.89 g (yield: 82%) of 3-(3,4-dichloroisothiazol-5-ylmethoxy)-1,2-benzoisothiazole 1,1-dioxide as a colorless powder (melting point: 165 to 167° C.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(NC(CO)CO)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
After triethylamine (10.12 g, 100 mmol) was added dropwise to a solution of serinol (3.64 g, 40 mmol) in a mixture of dioxane (100 ml) and water (200 ml), the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 4-phenoxybenzenesulfonyl chloride (10.75 g, 40 mmol) in dioxane (100 ml) was added dropwise and this was stirred for 3 hours. Most of the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (10.62 g, yield 82%) as a white powder.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.C[N:17]([CH:19]=O)C.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:27][CH:26]=1)=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([N:7]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:27][CH:26]=4)[N:17]=[C:19]3[CH2:23][CH:25]([CH3:30])[CH3:26])=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: O
Product: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC(C)C)n2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5.2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was extracted in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield˜22%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85 %

Procedure:
A solution of N-Boc-piperazine (300 mg, 1.63 mmol), triethylamine (494 mg, 3 equiv), and acetyl chloride (1.5 equiv) in dichloromethane was stirred overnight at rt. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound (˜85% yield) as a solid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.[OH2:41].[NH2:42][NH2:43]>CO>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[C:29]5=[N:42][NH:43][C:31](=[O:32])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH2:11]2)=[O:41])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc1)C(c1ccccc1)N2
Reactant: NN
Reactant: O
Solvent: CO
Product: O=C(c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A mixture of methyl 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (90 mg, 0.16 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (18 mg, yield 22%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.86-0.94 (m, 4H), 2.00 (s, 1H), 3.33-3.82 (m, 8H), 4.41-4.43 (d, J=8.4 Hz, 1H), 4.78-4.80 (d, J=8.4 Hz, 1H), 7.21-7.27 (m, 6H), 7.30-7.35 (m, 4H), 7.58-7.60 (m, 1H), 7.65-7.69 (t, J=8.0 Hz, 4H); LC-MS (ESI) m/z: 520 (M+1)+.