Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:2].[CH2:20]1[C@@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[S:23][S:22][CH2:21]1>>[CH2:1]([N:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:20][CH2:21][S:22][S:23]1)[CH3:2]
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: CCN(CCCCCCN)Cc1ccccc1OC
Product: CCN(CCCCCCNC(=O)CCCCC1CCSS1)Cc1ccccc1OC
Yield: 43 %

Procedure:
It was synthesized from N1-ethyl-N1-(2-methoxy-benzyl)-hexane-1,6-diamine (patent application PCT/IT03/0227) (300 mg, 1.13 mmol) and lipoic acid (350 mg, 1.70 mmol) following the procedure described for 17, and purified by gravity column. Elution with a gradient of mobile phase petroleum ether/toluene/CH2Cl2/EtOH/aqueous 30% ammonia solution (7:2:1:1:0.05 to 7:1:1:1:0.5) afforded 18 as a waxy solid: 43% yield, 1H NMR (200 MHz, CDCl3) δ 7.42-7.48 (m, 1H); 7.18-7.26 (m, 1H), 6.85-6.99 (m, 2H), 5.43 (br t, 1H, exchangeable with D2O), 3.84 (s, 3H), 3.53-3.64 (m, 1H+s, 2H), 3.08-3.27 (m, 4H), 2.43-2.57 (m, 5H), 2.17 (t, J=7.4 Hz, 2H), 1.82-2.00 (m, 1H), 1.29-1.73 (m, 14H), 1.07 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 453 (M+H)+. Anal. Calculated for C24H40N2O2S2: C, 63.67; H, 8.91; N, 6.19. Found: C, 63.79; H, 8.93, N, 6.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][NH:24][CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([N:24]([CH3:25])[CH3:23])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CNC
Product: CN(C)c1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1

Procedure:
This compound was prepared by a procedure similar to that described in Example 40 starting with 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and dimethylamine gas; mp 256°-258° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+].O>[N:23]([CH2:21][CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4-dibenzyl-2-chloromethyl-piperazine (8.8 g, 0.028 mol) in dimethylformamide (90 mL) under nitrogen was added sodium azide (5.5 g) and the reaction stirred at 50° C. for 18 h. The reaction was cooled and diluted with 10% aqueous sodium bicarbonate (100 mL) and water (250 mL) and the mixture extracted with ethyl acetate (2×200 mL). The organic extracts were washed with 10% sodium bicarbonate, brine, dried over sodium sulfate and concentrated to an oil.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(Br)C1C=CC=CC=1>C(OCC)(=O)C>[C:17]1([CH2:23][N:2]2[CH2:3][CH2:4][C:5]3[N:12]4[C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[N:9]=[C:8]4[S:7][C:6]=3[CH2:1]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCc3c(sc4nc5ccccc5n34)C2)cc1

Procedure:
1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (1.9 g., 0.008 mole) is dissolved in 100 ml. of boiling toluene. Triethylamine (5 ml.) is added at 80°. Benzyl bromide (1.7 g., 0.01 mole) is dissolved in 5 ml. of toluene and added dropwise to the reaction mixture. After the addition, the reaction mixture is refluxed for two hours. It is filtered and concentrated in vacuo to yield 3.6 g. of oil. Ethyl acetate is added and the product, 1,2,3,4-tetrahydro-2-(phenylmethyl)pyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole crystallizes. This is filtered and recrystallized from ethyl acetate:ethanol (10:1) to yield 1.4 g. of analytical product, m.p. 124°-129°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[OH-].[Na+].[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
6.648 g of methylsulphonyl-acetic acid ethyl ester are added dropwise at -30°, within 30 minutes, to 1.745 g of sodium hydroxide dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 15 minutes, then heated and, within 150 minutes, under reflux, 7.4 g of 2-phenylethyl bromide in 10 ml of DMF are added dropwise thereto. The reaction mixture is then stirred for 20 minutes, acidified with 12 ml of glacial acetic acid and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulphate, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant D). 1H-NMR (DMSO-d6): 1.35 ppm (t, 3H), 2.6-2.9 (m, 2H); 3.75 (dxd, 1H); 4.25 (q, 2H)
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40]>C(O)(C)C>[ClH:40].[ClH:40].[ClH:40].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 5 °C
Reaction time: 0.83 h

Procedure:
To a suspension of 0.30 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 1.8 mL of isopropyl alcohol, 0.23 mL of concentrated hydrochloride was added, and the mixture was heated under reflux while stirring for 1 hour 50 minutes. The reaction mixture was cooled to 5° C., and the solid was filtered off to obtain 0.28 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one trihydrochloride as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[CH2:30]CN>>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:30][CH2:1][NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH:33]=[CH:34][CH:35]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 32 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 3-chlorophenethylamine instead of benzylamine and obtained in 32% yield. 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.37 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.33 (t, J=5.5 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.38-7.23 (m, 5H), 6.45 (dd, J=3.3, 1.8 Hz, 1H), 3.55-3.50 (m, 2H), 2.89 (t, J=7.5 Hz, 2H); MS (m/z) 398 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[C@H:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][C@H:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[C@@H](N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@@H](C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2R)-propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.82 (d, J=7.58 Hz, 1 H), 7.70-7.55 (m, 2 H), 7.46-7.37 (m, 2 H), 7.33-7.22 (m, 2 H), 6.10-5.99 (m, 1 H), 5.13 (brs, 2 H), 3.65-3.52 (m, 3 H), 3.37 (m, 2 H), 3.31-3.20 (m, 2 H), 2.41 (s, 3 H), 1.32-1.22 (m, 2 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:9][CH:8]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33].C([O-])(O)=O.[Na+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:33][C:25]3[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=3[F:23])[CH:14]=2)=[N:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 31.2 %

Procedure:
A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g, 35.1 mmol) and NaHCO3 (1.346 g, 16.02 mmol) in Ph2O (7 mL) was heated to 180° C. for 4 hours. The reaction mixture was cooled to RT and diluted with DCM, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc) afforded 41 (2.5 g, 31% yield) as a yellow solid. MS (m/z): 457.1 (M+H).
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:10][C:9]=1[NH:27][C:28](=[O:46])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]2[S:38][CH:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[N:41]=2)[CH:30]=1)[C:4]([OH:6])=O)C.[NH3:47]>>[C:42]([C:40]1[N:41]=[C:37]([CH2:36][O:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:9]2[CH:10]=[C:11]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:12]=[CH:13][C:8]=2[O:7][CH2:3][C:4]([NH2:47])=[O:6])=[O:46])[S:38][CH:39]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: N
Reactant: CCC(Oc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1)C(=O)O
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC(N)=O)c2)n1
Yield: 77 %

Procedure:
Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid (0.30 g, 0.44 mmol) was dissolved in ammonia-saturated methanol (10 ml) and the solution was subjected to 12 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was crystallized from acetonitrile to give 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetamide (0.22 g, 0.34 mmol, 77%) as colorless crystals. Its structure is shown in Table 30.
Reaction SMILES: Cl.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=CC=1.C([Li])CCC.[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40](=[O:45])[C:39]([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)=[C:38]2[CH:51]=O>O1CCCC1>[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40](=[O:45])[C:39]([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)=[C:38]2/[CH:51]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1c(-c2cccs2)c(=O)[nH]c2ccc(Br)cc12
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(/C=C/c2ccccn2)c1-c1cccs1
Reaction time: 0.25 h

Procedure:
To a solution containing triphenyl(2-pyridylmethyl)phosphonium chloride hydrochloride (153 mg, 0.359 mmol) in tetrahydrofuran (2.26 ml) at −78° C. was added n-butyl lithium (2.50 M, 0.685 mmol). This mixture was stirred for 15 min. and then added to a solution containing 6-bromo-2-oxo-3-(thiophen-2-yl)-1,2-dihydroquinoline-4-carbaldehyde (109 mg, 0.326 mmol) in tetrahydrofuran (1 ml) at −78° C. The reaction was allowed to stir for 4 h at room temperature. The reaction was quenched with 1 N hydrochloric acid (10 ml) and then the pH was increased with 1 N sodium hydroxide. This mixture was extracted with ethyl acetate (3×30 ml). The organic layers were combined and extracted with sodium chloride (1×25 ml). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The resulting crude solid was purified by reverse phase chromatography to afford 6-bromo-4-[(E)-2-(pyridine-2-yl)ethenyl]-3-(thiophen-2-yl)quinolin-2(1H)-one as a yellow solid. LCMS (M+H)=410.69. 1H NMR (400 MHz, d6-DMSO) δ 12.28 (s, 1H), 8.63-8.60 (m, 1H), 7.95 (d, 1H), 7.85 (m, 1H), 7.74-7.65 (m, 3H), 7.60 (d, 1H), 7.39-7.33 (m, 3H), 7.09 (dd, 1H), 6.99 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[N:12][OH:13])[CH3:11].C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][OH:13])[CH3:11]
Reactant: CC(Cc1ccc(Cl)cc1Cl)=NO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Cc1ccc(Cl)cc1Cl)NO
Temperature: 23 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-propan-2-one oxime (3.3 g, 15.1 mmol) in acetic acid (30 ml) was treated at 10° C. with sodium cyanoborohydride (1.90 g, 30.3 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 23° C. for 5 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water and pH was adjusted to 10 with 1M NaOH. The aqueous phase was extracted with dichloromethane (3×20 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent (100 mbar; 45° C.), 3.18 g (96.0% of theory) of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamine was obtained in form of a white solid (m.p. 83-86° C.).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH:39]2[CH2:40][CH2:41][CH:35]1[CH2:36][CH:37]([NH2:42])[CH2:38]2.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH:37]5[CH2:38][CH:39]6[N:34]([CH3:33])[CH:35]([CH2:41][CH2:40]6)[CH2:36]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C2CCC1CC(N)C2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CC3CCC(C2)N3C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.031 g (0.22 mmole) of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) to give 0.034 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide (I-50) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH2:14])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1
Reactant: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc2c(s1)-c1nc(NC(=O)c3ccccc3)ncc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To 2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-ylamine (0.2 g, 0.92 mmol) in pyridine (7 mL) was added benzoyl chloride (117 μL, 142 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. Water (100 mL) was added and the product was extracted into EtOAc (3×50 mL). The organic extracts were combined, dried, filtered, and concentrated under vacuum. Flash column chromatography (50% EtOAc:hexane) followed by crystallisation from EtOH afforded the title product as yellow crystals (173 mg, 59%): mp 229-231° C. Anal. RP-HPLC: tR 13.5 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.59 (s, 1H, NH), 8.44 (s, 1H, Py-H), 7.95 (m, 2H, Ph-H), 7.54 (m, 3H, Ph-H), 3.09 (m, 4H, CH2—CH2), 2.77 (s, 3H, CH3). 13C-NMR (CDCl3): δ 170.70, 165.50, 160.05, 158.04, 157.02, 155.77, 134.89, 132.66, 129.15, 128.92, 127.89, 121.44, 25.39, 24.50, 20.31. MS (ESI+): m/z 323.05 (M+H)+. Anal. (C17H14N4OS)C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>ClCCl.C(N(CC)CC)C>[CH3:14][C:5]1[N:6]=[C:7]2[S:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][O:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2n(c(=O)c1CCO)CCS2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2n(c(=O)c1CCOS(C)(=O)=O)CCS2

Procedure:
After dissolving 6-(2-hydroxy-ethyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyrimidin-5-one (CAS 86487-53-8) (225 mg) in dichloromethane (10 ml), triethylamine (0.44 ml) was added, and then methanesulfonyl chloride (0.20 ml) was added dropwise while stirring on ice. After stirring for 10 minutes, ethyl acetate was added to the reaction mixture and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (264 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]=1[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30]>C(Cl)Cl.CC(=O)OCC>[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:16][NH:15][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([CH3:19])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH2:20][CH3:21])[CH:11]=2)=[O:38])=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30]
Reactant: Cc1cc(C(=O)Cl)ccc1OC(C)C
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)NNC(=O)c2ccc(OC(C)C)c(C)c2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
To a suspension of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (1.12 g, 3.95 mmol) in DCM (20 mL), triethylamine (500 mg, 4.94 mmol) is added. The clear solution is cooled to 5° C. before a solution of 4-isopropoxy-3-methyl-benzoic acid chloride (700 mg, 3.29 mmol) in DCM (10 mL) is added dropwise. The suspension is stirred at rt for 1 h before it is diluted with EA, washed with 1 N aq. HCl, followed by water, dried over MgSO4, filtered, concentrated and dried to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(4-isopropoxy-3-methyl-benzoyl)-hydrazide (1.57 g) as a white solid; LC-MS: tR=1.05 min, [M+1]+=461.66.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[K+]>CC(C)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: N#C[S-]
Reactant: CC(=O)C(Cl)CCCl
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(CCCl)SC#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
77.8 g (0.5 moles) of 3,5-dichloro-2-pentanone [prepared according to Acta Chim. Hung. 3, 157 (1953)] are added to the solution of 49.9 g (0.513 moles) of potassium rhodanide in 500 ml of acetone. The solution is boiled under stirring for 4 hours. The reaction mixture is cooled to room temperature and the precipitated potassium chloride is filtered off and washed with acetone. The filtrate is evaporated, the residue is dissolved in benzene and the benzene solution is washed 3 times with water. After drying with sodium sulphate, the benzene is distilled off. 62.2 g (93%) of 3-thiocyanato-5-chloro-2-pentanone are obtained in the form of a red oil. After distilling at a lower pressure a faint yellow oil is obtained, its boiling point is 112° C. at a pressure of 26.6 Pa, nD20 =1.5110. According to infrared spectrum it does not contain any isothiocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]#[N:13].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(Cl)c(C#N)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1cc(C#N)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 28.7 %

Procedure:
N-(4-Chloro-3-cyano-phenyl)-acetamide (3.00 g, 15.4 mmol) was dissolved in conc. sulfuric acid (15 mL) and cooled to 0° C. A solution of potassium nitrate (3.12 g, 30.8 mmol) in conc. sulfuric acid (15 mL) was added drop-wise with stirring. The reaction mixture was kept at 0° C. for 3.5 h, then slowly added to stirred ice/water. The resulting precipitate was collected, dissolved in EtOAc, dried, filtered, and concentrated. The residue was purified (FCC) (10-80% EtOAc/hexanes) to yield the titled compound (1.06 g, 29% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 10.60 (s, 1H), 9.18 (s, 1H), 8.58 (s, 1H), 2.36 (s, 3H).