Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1OC)([O-:3])=[O:2].[Cl-].[Cl-].[Ca+2].[CH2:20]([CH:22]([NH2:25])[CH2:23][CH3:24])[CH3:21]>>[CH2:20]([CH:22]([NH:25][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH3:24])[CH3:21]
Reactant: COc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reactant: CCC(N)CC
Agent: [Ca+2]
Agent: [Cl-]
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reaction time: 24 h
Yield: 86.6 %

Procedure:
To a suitable reaction vessel equipment with a thermometer and mechanical stirrer was introduced 24 g 2,6-dinitro-3,4-dimethylanisole 94% (0.1 moles), 0.55 g CaCl2 (0.005 moles), and 43.5 g of (0.5 moles) 1-ethyl propylamine. The reaction mixture was stirred at a temperature of 25°-30° C. The progress of the reaction was followed by periodically withdrawing samples and analyzing for starting product and the new product formed. During 24 hours the starting product disappeared and the N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline is gradually formed. After completion of the reaction as indicated by vapor phase chromatography, the excess of 1-ethyl-propylamine was recovered from the reaction mixture by distillation. The residue was dissolved in dichloromethane and the solution was successively washed with 5% aqueous hydrochloric acid, 5% aqueous sodium hydroxide and then by water to neutral and dried. The solvent is next recovered by distillation leaving an oily product which solidified. (25.2 g 96.6%) with a yield of 86.6 %.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:3][S:4]C.O.BrN1C(=O)CCC1=O.C(=O)([O-])O.[Na+].C(OC[S:37][CH2:38][C:39]([NH:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])([CH3:41])[CH3:40])(=O)C.II.S([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C.CO>[CH2:46]([O:45][C:43]([NH:42][C:39]([CH3:41])([CH3:40])[CH2:38][S:37][S:4][CH2:3][C:2]([NH:7][C:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])([CH3:6])[CH3:1])=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CSCC(C)(C)NC(=O)OCc1ccccc1
Reactant: CC(=O)OCSCC(C)(C)NC(=O)OCc1ccccc1
Agent: II
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)(CSSCC(C)(C)NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of 45.4 g (179 mmol) of benzyl 1,1-dimethyl-2-(methylthio)ethylcarbamate in aqueous methanol (obtained by adding 5.22 g (290 mmol) of water to 150 ml of methanol) was added 33.46 g (188 mmol) of N-bromosuccinimide in small portions with stirring. The reaction was carried out at room temperature for 2 hours, after which the reaction solution was made weakly basic with saturated aqueous sodium hydrogencarbonate solution and then the methanol was distilled off. Water was added to the residue, followed by three runs of extraction with ethyl acetate. The extract solution was washed three times with water and then once with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the thus obtained crude benzyl 1,1-dimethyl-2-(methylsulfinyl)ethylcarbamate was dissolved in acetic anhydride (150 ml), and the reaction was carried out with refluxing for 4 hours. The excess acetic anhydride and acetic acid were distilled off under reduced pressure to obtain a residue containing crude [2-(benzyloxycarbonylamino)-2-methylpropyl]thiomethyl acetate. This residue was dissolved in methanol (300 ml), followed by adding thereto 19.54 g (77 mmol) of iodine, and the reaction was carried out with refluxing for 5 hours. After the reaction mixture was cooled to room temperature, an aqueous sodium hydrogensulfite solution was added thereto to reduce the excess iodine. The reaction solution was made weakly basic with saturated aqueous sodium hydrogencarbonate solution, after which the methanol was distilled off. Water was added to the residue, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 10.0 g (yield 23%) of bis[2-(benzyloxycarbonylamino)-2-methylpropyl]-disulfide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:42]3[CH2:43][CH2:44][N:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCN(c4ccccc4)CC3)cc2F)CC1
Yield: 11.8 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using 1-phenylpiperazine (5.0 g) as an amine to yield the titled compound (237 mg, 12%).
Reaction SMILES: Cl.CC1(C)[C@@H]2CC[C@@]1(CS)[C@H](N1CCOCC1)C2.C([Zn][CH2:22][CH3:23])C.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH4+].[Cl-]>C(OCC)(=O)C>[C:25]1([C@H:24]([OH:31])[CH2:22][CH3:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS)[C@H](N1CCOCC1)C2
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC[C@@H](O)c1ccccc1

Procedure:
After stirring a mixture of (1S,2R,4R)-(7,7-dimethyl-2-morpholinobicyclo[2.2.1]heptan-1-yl)methanethiol hydrochloride (MITH•HCl; (Ib)) (58 mg, 0.20 mmol) and diethylzinc solution (3.2 mmol, 1.0 M in hexanes) at ambient temperature for 30 minutes, neat benzaldehyde (200 μL, 2.0 mmol) was added in one portion at 0° C. Upon completion of the reaction (as judged by TLC analysis), sat. aq. NH4Cl (3 mL) was slowly added to the reaction product mixture followed by ethyl acetate (20 mL). The mixture was washed twice with 1 N aq. HCl (20 mL each) and brine (5 mL), dried over solid Na2SO4, and concentrated to give a colorless oil which was purified by silica gel column chromatography (1:10 ethyl acetate/n-heptane) to give (R)-1-phenyl-propanol as a colorless oil (217 mg; 80%; 96.3% e.e.). The optical purity was determined by normal phase HPLC using a Chiralcel OD-H chiral column (eluted with isocratic IPA/Hexane=2:98, with 1.0 mL/minute flow rate; monitoring at 254 nm).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][NH:33][C:34](=O)OC(C)(C)C)[CH:30]=3)=[CH:13][N:14]2S(C2C=CC=CC=2)(=O)=O)=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][NH:33][CH3:34])[CH:30]=3)=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNCCn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a slurry of LiAlH4 (100 mg; 2.64 mmol) in THF (4 mL) was added a solution of tert-butyl 2-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)ethylcarbamate (Intermediate 18; 300 mg; 0.62 mmol) in THF (6 mL) dropwise under argon. The reaction mixture was stirred at r.t. overnight and then at reflux for 4 hours. The reaction was added sequentially water (0.1 mL), 10% aqueous NaOH (0.2 mL), water (5 mL), filtered and washed with EtOAc. The filtrate was extracted with EtOAc (30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (DCM/MeOH=20/1) to afford the 94 mg (62%) of title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[CH3:13][C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[C:23]([C@@H:27]([NH2:29])[CH3:28])[CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:29][C@H:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:17]2[CH:18]=[N:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:22]=1)[CH3:28])=[O:8]
Reactant: Cc1ccc(Oc2cccc([C@H](C)N)c2)cn1
Reactant: O=C(O)C=Cc1ccccc1F
Product: Cc1ccc(Oc2cccc([C@H](C)NC(=O)C=Cc3ccccc3F)c2)cn1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid following the general procedures as described for Example 1 with the exception that (S)-1-[3-(6-methyl-pyridin-3-yloxy)-phenyl]ethylamine was used.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O>Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 10 °C

Procedure:
To 4,5-dichloro-1,2-phenylenediamine (25 g) was added 3,3,3-trifluoropropionic acid (25 mls) and 4N HCl (90 mL). The resulting mixture was heated to 10° C. overnight. The reaction mixture was quenched with water, basicified with concentrated NH4OH, extracted with EtOAc, and dried over Na2SO4. The crude product was filtered through a plug of silica gel, eluting with 30% EtOAc/hexanes, and collecting the red band. The fractions were concentrated to yield a mixture of the desired title compound and 4,5-dichloro-1,2-phenylenediamine. The crude material was dissolved in small amount of CH2Cl2 and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[S:17][C:16]([CH3:18])=[N:15][CH:14]=2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1.CO.C(Cl)Cl>C1COCC1.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:48]([C:45]2[N:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:40][C:41]3=[N:47][CH:46]=2)=[O:49])[N:4]([CH2:12][C:13]2[S:17][C:16]([CH3:18])=[N:15][CH:14]=2)[N:3]=1
Reactant: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.11 mmol) in anhydrous THF (3 mL) was treated at ambient temperature under a nitrogen atmosphere with lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL). The resulting brown solution was added dropwise to a cooled (ice-water) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (35.9 mg, 0.11 mmol) in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature, and was diluted with water (10 ml). The resulting mixture was extracted thoroughly with ethyl acetate and dichloromethane. The combined organic extracts were dried over sodium sulfate, the solids removed by filtration, and the filtrate was concentrated to afford an oil. The crude oil was subjected to preparative thin-layer chromatography on silica with MeOH/DCM as the eluent to afford 11.6 mg of the desired product.
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:26]([OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>[N+](C)([O-])=O>[CH:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]
Reactant: C=CCCCCCCO
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: C[N+](=O)[O-]
Product: C=CCCCCCC=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
6.1 mg (0.02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.37 g (0.6 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 156 mg (1 mmol) of octa-7-en-1-ol were added to 5 ml of nitromethane, and the mixture was heated at 70° C. while being stirred under a nitrogen for two hours. The later treatment was carried out in the same way as in Example 1, and then octa-7-enal was obtained. The yield of the obtained octa-7-enal was determined and the result is shown in Table 2. (Yield 92%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 100 °C

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), acetic anhydride (0.4 g) and dry pyridine (4 mL) was heated at 100° C. for 3 hours. The reaction mixture was cooled and water (about 35 mL) and sodium bicarbonate (0.6 g) were added. The mixture was chilled in ice and stirred. The resulting white solid was removed by filtration, washed with water and dried to give 6-(4-acetoxypiperidino)-2(1H)-quinolinone. 1/4 hydrate (0.3 g); m.p. 245°-250° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][C:17]1[CH:22]=[N:21][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]3)=[N:19][CH:18]=1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 80.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (300 mg, 1.2 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)pyrrolidin-3-ylcarbamate (380 mg, 1.4 mmol) to afford the desired product (468 mg, 78%) as a yellow-orange solid: 1H NMR (500 MHz, CDCl3) δ 11.72 (s, 2H), 9.09 (s, 2H), 8.21 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.26 (s, 2H), 4.70 (s, 2H), 4.38 (s, 2H), 3.90 (dd, J=11.6, 6.1 Hz, 2H), 3.78-3.66 (m, 4H), 3.52 (dd, J=11.6, 4.3 Hz, 2H), 2.77 (s, 5H), 2.31 (dq, J=13.4, 7.2 Hz, 2H), 1.57 (s, 2H), 1.47 (s, 17H), 1.19 (s, 1H); ESI MS m/z 484 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[OH:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:37]([CH:34]3[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][OH:27])[CH2:32][CH2:33]3)=[O:38])[CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:25][CH:26]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 41.4 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (200 mg) obtained in Example 137a, 1-(hydroxyacetyl)piperidine-4-carboxylic acid (129 mg) and triethylamine (127 μL) in acetonitrile (5 mL) were added WSC.HCl (176 mg) and HOBt (140 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), potassium carbonate (317 mg) was added, and the mixture was stirred at room temperature for 3 hr. The solution was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane) to give 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-{[1-(hydroxyacetyl)piperidin-4-yl]carbonyl}piperidin-4-yl]-N-methylbenzamide (108 mg, 41%) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]3)[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: OB(O)Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cc(Cl)cc(Cl)c3)ccc2C1
Yield: 90.5 %

Procedure:
A solution of 3.81 g of crude tert.-butyl 6-(trifluoromethanesulphonyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate in 40 ml of dimethoxyethane was treated under argon with 2.01 g (0.0105 mol) of 3,5-dichlorophenylboric acid and 13.5 ml (0.027 mol) of an aqueous 2N sodium hydrogen carbonate solution. The mixture was saturated with argon, 0.578 g (0.00050 mol) of tetrakis-(triphenylphosphine)-palladium was added thereto and the mixture was boiled at reflux for 20 hours. The mixture was cooled, poured into 120 ml of an aqueous 2N sodium hydroxide solution and extracted with ethyl acetate. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 9:1 as the eluent. 3.42 g (90%) of tert.-butyl 6-(3,5-dichlorophenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate were obtained as a pale yellow dense oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Cl)cnnc2cc1OCc1nccn1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
The starting material, 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]-cinnoline was obtained by adding potassium carbonate (531 mg, 3.8 mmol) followed by 2-chloromethyl-1-methylimidazole (232 mg, 1.4 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (270 mg, 1.28 mmol), (prepared as described for the starting material in Example 10), in DMF (6 ml). After stirring overnight at 40° C. the mixture was diluted with water and adjusted to pH7. After extraction with ethyl acetate the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/methanol (98/2) as eluent to give 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (111 mg, 29%).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[O:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1.CCN(CC)CC.C(OCC)(=O)C>C(#N)C>[Cl:4][CH2:3][CH2:2][N:12]1[CH2:13][CH2:14][C:9]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: ClCCN1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 48 h
Yield: 6348.2 %

Procedure:
Step 1): 1-Bromo-2-chloroethane (10.0 g, 0.07 mmol) was added by portions to a solution of 1,4-dioxa-8-azaspiro[4,5]decane (1.0 g, 7.0 mmol) and Et3N (0.7 g, 7.0 mmol) in acetonitrile (10 ml) at 0° C. The mixture was stirred at 0° C. for 48 hours, poured into ethyl acetate and washed with water. The organic layer was dried (MgSO4) and concentrated to give 8-(2-chloroetyl)-1,4-dioxa-8-azaspiro-[4,5]decane (0.914 g, 63.5%) as a solid product.
Reaction SMILES: Cl.O[CH:3]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[NH:14][C:15](=[O:17])[CH3:16])[CH2:4][N:5]1[CH2:9][CH2:8][S:7][C:6]1=[NH:10].S(=O)(=O)(O)O.[OH-].[NH4+]>>[S:7]1[CH2:8][CH2:9][N:5]2[CH2:4][CH:3]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[NH:14][C:15](=[O:17])[CH3:16])[N:10]=[C:6]12
Reactant: CC(=O)Nc1cccc(C(O)CN2CCSC2=N)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)Nc1cccc(C2CN3CCSC3=N2)c1
Reaction time: 1 h

Procedure:
Addition of 5.00 g. (0.0158 mole) of 3'-[1-hydroxy-2-(2-imino-3-thiazolidinyl)ethyl]acetanilide hydrochloride (Example 6) to 15 ml. of concentrated sulfuric acid is carried out in small increments over 0.5 hour. The orange solution is stirred an additional 1 hour, poured onto ice and made basic with concentrated ammonium hydroxide. The aqueous base is extracted twice with chloroform and the combined organic layers washed with water, brine, dried (sodium sulfate) and evaporated at reduced pressure to give 3.76 g. of an oil. Crystallization from ether gives 3.32 g. (80% crude yield) of fine white crystals, which on recrystallization from 2-propanol gives the product melting point 164°-166° C. Analysis: Calcd. for C13H15N3OS: Calcd: C, 59.74; H, 5.79; N, 16.08; S, 12.27. Found: C, 59.93; H, 5.85; N, 15.96; S, 12.49.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](F)=[CH:24][CH:25]=2)[C:20]([C:28](=[O:30])[CH3:29])=[CH:19][N:18]=1.[NH4+].[Cl-]>CC(N(C)C)=O>[C:28]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)[CH:22]=2)[C:17]([NH2:16])=[N:18][CH:19]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cnc(N)c2ccc(F)cc12
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1cnc(N)c2ccc(-n3cc(C)c4c3CC(C)(C)CC4=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To 3,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.104 g, 1.2 eq) in dimethylacetamide (3 mL), sodium hydride (14.4 mg, 1.2 eq) is added slowly and stirred at RT for 0.5 h. Then 1-(1-amino-6-fluoro-isoquinolin-4-yl)-ethanone (0.1 g, 1 eq) is added and stirred at 150° C. overnight. The reaction mixture is poured into Sat'd NH4Cl aq. (200 mL), extracted by EtOAc (3×100 mL), dried over Na2SO4, filtered, concentrated to give a crude product. That is purified by Biotage chromatography, eluted by 50-100% EtOAc in Hexanes to give 1-(4-acetyl-1-amino-isoquinolin-6-yl)-3,6,6 trimethyl-1,5,6,7-tetrahydro-indol-4-one (48.1 mg, 27%). LC/MS m/z=362 [M+H]+.