Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][NH:7]1)=[O:5])C.[OH-].[K+].Cl>CO.O>[CH3:12][CH:11]1[O:10][CH2:9][CH2:8][NH:7][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1NCCOC1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1OCCNC1C(=O)O
Temperature: 75 °C

Procedure:
To a solution of 2-methyl-morpholine-3-carboxylic acid ethyl ester (Comp. No. 27) (0.180 g, 1.039 mmol) in methanol (4 ml) was added water (2 ml) and potassium hydroxide (0.291 g, 5.195 mmol). The resulting mixture was heated to 75° C. until the color turned to red. The mixture was allowed to cool to room temperature, diluted with water and acidified to pH=1 with aqueous hydrochloric acid (2 M). The solution was washed with a mixture of dichloromethane and isopropanol (3:1) and freeze-dried. The resulting white solid was used in the next step without further purification. LC/MS (method 7): Rt=0.11 min; m/z=146.20 (M+H+).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:28]/[NH:27][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)c1ccccc1
Product: CCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.98 (br s, 1H).
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C@H:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39](O)=[O:40])[S:36][C:35]=2[CH:42]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39]([NH:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]3)=[O:40])[S:36][C:35]=2[CH:42]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CN1CCC(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1
Agent: Cl
Product: CN1CCC(C[C@@H](NC(=O)c2cc3ccc(Cl)cc3s2)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(1-methylpiperidin-4-yl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (52%).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:18](Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH:13]1([C:18]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc2oc(C3CCCC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide (300 mg, 1.28 mmol) in dichloromethane (8 mL) was added cyclopentane carbonyl chloride (0.16 mL, 1.28 mmol). The resulting reaction mixture was stirred at room temperature for 10 min, then triethylamine (0.71 mL, 5.13 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted in dichloromethane (30 mL) and quenched with aqueous 2 N HCl (10 mL) until the solution reached pH 1. The aqueous layer was further extracted with dichloromethane (2×30 mL). The organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to an orange solid. The amide product was directly re-dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol). The reaction mixture was then heated to reflux for 3 h. The reaction was cooled to room temperature and the toluene was evaporated. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-cyclopentylbenzoxazole-4-carboxylic acid (179 mg, 75%) as a pale orange solid: 1H NMR (500 MHz, DMSO-d6) δ 7.85-7.72 (m, 2H), 7.39-7.29 (m, 1H), 2.05-1.50 (m, 9H); MS (ESI+) m/z 232 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:26]([OH:28])[CH3:27])[C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[OH:28][C@@H:26]([CH3:27])[C@@H:13]([NH:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[O:15][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.4 %

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.69 g, 1.75 mmol) in THF (100 mL) were added PS-BEMP (2.39 g, 5.27 mmol, ˜2.2 mmol/g) and p-TsCl (353 mg, 1.85 mmol) at room temperature. The mixture was stirred at room temperature for 14 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (167 mg, 25%) as a foam and the dehydration product 4-(1-(5-phenyl-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (33 mg, 5%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51˜7.57 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.22 (dd, J=4.7, 8.4 Hz, 1H), 4.80 (b, 1H), 4.65 (m, 1H), 1.42 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.05 (m, 2H), 7.95 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.55˜7.62 (m, 4H) 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(O)CCO.CC1C=CC(S(OCC(CC2C=CC([N+]([O-])=O)=CC=2)COS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.[N+:41]([C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1)([O-:43])=[O:42].[C:52]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:41]([C:44]1[CH:51]=[CH:50][C:47]([CH2:48][CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:52]([O:60][CH2:61][CH3:62])=[O:59])=[CH:46][CH:45]=1)([O-:43])=[O:42]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: OCCCO
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Yield: 88 %

Procedure:
Although PCB-TE2A is a good chelator having an octahedral coordination site with metals like Cu, one of its two pendant arms has to be sacrificed whenever it is conjugated with biomolecules. To keep intact the octahedral coordination structure while allowing further conjugation with biomolecules, introduction of an extra functional group in the backbone is necessary. For this purpose, the inventors have synthesized a suitably tailored nitro-derivative of ditosyl ester of 1,3-propanediol, 25. The precursor was used for the construction of propylene bridge having one extra functionality. The inventors have designed the compound 25 and performed synthesis by condensation of 1 equiv. of 4-nitrobenzyl bromide with 7 equivalent of diethyl malonate in the presence of K2CO3 in acetone to give 23 in 88% yield (Scheme 6). In this reaction a mild base rather than metal alkoxide and excess of diethyl malonate were used in order to prevent the formation of dialkylate product. The diethyl-2-[(4-nitrophenyl)methyl]propanedioate 23 was reduced with sodium borohydride to afford the diol compound 24 in 85% yield. The diol 24 was tosylated by tosyl chloride in pyridine to afford the precursor 25 in 89% yield. According to Scheme 6,2-[(4-nitrophenyl)methyl]propan-1,3-diol bis(4-methylbenzene-sulfonate) (25) was prepared in high overall yield (66%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19](O)=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)[C:15]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:10][CH:9]=1.[CH3:36][N:37]([CH:39]=O)[CH3:38].C(N(CC)CC)C.Cl.[CH3:49][NH:50][O:51][CH3:52]>ClCCl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]([N:50]([O:51][CH3:52])[CH3:49])=[O:20])=[C:16]([C:22]3[CH:23]=[CH:24][C:25]([S:28](=[O:30])(=[O:31])[N:29]=[CH:39][N:37]([CH3:36])[CH3:38])=[CH:26][CH:27]=3)[C:15]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:10][CH:9]=1
Reactant: CN(C)Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNOC
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
Oxalyl chloride (0.39 g, 0.26 ml, 3.1 mmol) was added drop wise at 0° C. to a solution of 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid (compound 35d, 0.7 g, 1.55 mmol) in a mixture of dichloromethane (25 ml) and DMF (0.27 g, 0.24 ml, 3.10 mmol). The mixture so obtained was allowed to come at room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (25 ml), cooled to 0° C. and to this was added triethylamine (0.94 g, 1.3 ml, 9.31 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.3 g, 3.1 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and washed with water (2×25 ml), the organic layer so obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 6% methanol in DCM as an eluent to obtain the title compound (0.45 g, 52.81%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[ClH:20]>C(O)C>[Cl:20][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH:2]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([OH:11])=[CH:13][CH:14]=1
Reactant: Cl
Reactant: O=C(CCl)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)c1ccccc1Cl
Reaction time: 72 h

Procedure:
20 g of 2-chloro acetophenone and 15.8 g 4-hydroxy benzaldehyde were dissolved in 100 ml ethanol saturated with gaseous hydrochloric acid and the mixture was left at ambient temperature for 3 days. The ethanol was concentrated in vacuo. The residue was dissolved in 200 ml isopropanol, after which 500 ml water was added with agitation and the precipitate was filtered. The yield after recrystallization from isopropanol was 25.4 g of the expected chalcone.
Reaction SMILES: C(Cl)CCl.[CH:5]1[CH:6]=[CH:7][C:8]2[N:13](O)N=[N:11][C:9]=2[CH:10]=1.[C:15]([C:19]1[CH:20]=[CH:21][C:22]([O:36][CH3:37])=[C:23]([CH:35]=1)[C:24]([NH:26][C:27]1[C:28]([C:32](O)=[O:33])=[N:29][NH:30][CH:31]=1)=[O:25])([CH3:18])([CH3:17])[CH3:16].C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[NH:11][C:32]([C:28]1[C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:35]=[C:19]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:20]=[CH:21][C:22]=2[O:36][CH3:37])=[CH:31][NH:30][N:29]=1)=[O:33]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1C(=O)O
Agent: Nc1ccccc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To a solution of EDC (720 mg, 3.8 mmol), HOBt (510 mg, 3.8 mmol) and 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (1 g, 3.16 mmol) in DMF (25 ml) was added benzene-1,2-diamine (375 mg, 3.5 mmol) and the mixture stirred at room temperature for 5 hours. The mixture was reduced in vacuo and the residue partitioned between EtOAc (50 ml) and brine (2×50 ml). Undissolved precipitate was removed by filtration, the organic portions washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (2-amino-phenyl)-amide as a pale yellow powder (848 mg, 66%). (LC/MS (acidic method): Rt 3.21 min, [M+H]+ 408).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: NCC(=O)O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(Cc1ccccn1)Cc1ccccn1

Procedure:
2-Chloromethylpyridine hydrochloride (9.2 g, 8.53 mmol) and glycin (2 g, 26.6 mmol) were dissolved in water (30 mL) and stirred at room temperature for five days, with addition of 5 mol aqueous NaOH solution at intervals to maintain the pH at 8-10. The resulting dark red solution was extracted with ethyl acetate, neutralized with HCl and concentrated. The residue was dissolved in dichloromethane, and the insoluble sodium chloride was filtered. Pale yellow crystals formed from the filtrate, which were collected and dried under vacuum. Yield (2.87 g) (11.2 mmol, 42%). 1H NMR (CDCl3), 300 MHz): 3.39 (s, 2H), 3.98 (s, 4H), 7.06 (t, 2H), 7.30 (d, 2h), 7.56 (t, 2H), 8.36 (d, 2H). 13C NMR (CD3OD, 300 MHz): 57.36 (C, CH2), 59.77 (2C, PyCH2), 124.77 (2CH, Py), 125.15 (2CH, Py), 139.00 (C, CH2), 149.76 (2CH, Py), 156.10 (2C, Py), 173.05 (C, CO2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC.C(OCC)(=O)C>CN(C=O)C>[CH:19]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1)=[CH2:20]
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 90.8 %

Procedure:
5-Bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (2.0 g, 0.0066 mole), tributylvinyltin (2.3 g, 0.00726 mole) and Pd(PhCH2)Cl(Ph3P)2 (0.1 g, 0.000132 mole) were heated at 100° C. in DMF (75 mL) for 1 hour. The mixture was then poured into ethyl acetate and extracted 2×200 mL with aqueous KF, brine, dried (MgSO4), filtered through a pad of silica gel with ethyl acetate and evaporated in vacuo. The crude oil was purified by silica gel chromatography to give 5-ethenyl-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.62 g, 91% yield) as an off-white solid.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]([NH2:15])=[O:14].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[CH:19][N:18]=1>C1COCC1>[ClH:16].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[C:12]([C:17]1[N:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[C:20]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[CH:19][N:18]=1)[C:13]([NH2:15])=[O:14]
Reactant: CN1CCN(C(=O)c2cnc(Cl)nc2C(F)(F)F)CC1
Reactant: NC(=O)Cc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cnc(C(C(N)=O)=C3Nc4ccccc4S3)nc2C(F)(F)F)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
Sodium hydride 99% (50.8 mg, 2.1 mmol) was added to a suspension of 2-(benzothiazol-2-yl)acetamide (103 mg, 0.53 mmol) in THF (2 mL), and the resulting yellow suspension was stirred at room temperature for 15 min. The mixture was cooled to 0° C. and (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone (0.18 g, 0.53 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was then removed under reduced pressure. The residue was suspended in water and the pH adjusted to 7 with 1N hydrochloric acid. The solid was collected by filtration and partitioned between EA and water. The EA phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The resulting material was purified by reverse phase preparative HPLC to give 2-[benzothiazol-2(3H)-ylidene]-2-[5-(4-methylpiperazine-1-carbonyl)-4-trifluoromethylpyrimidin-2-yl]acetamide hydrochloride (87 mg, 33% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([NH:38][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 587.1 [(M+H)+]; mp 274° C.
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].[ClH:7].N[C:9]1([CH2:12][S:13][C:14]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:11][CH2:10]1.[C:30](=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[ClH:7].[CH3:30][N:4]([CH3:3])[C:9]1([CH2:12][S:13][C:14]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:11][CH2:10]1
Reactant: NC1(CSc2nc3ccccc3cc2-c2ccccc2)CC1
Reactant: [BH3-]C#N
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)C1(CSc2nc3ccccc3cc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Formaldehyde (37% w/w solution in water, 0.82 ml.), glacial acetic acid (0.82 ml.) and sodium cyanoborohydride (0.70 g.) were added to a solution of 2-[(1-aminocyclopropyl)methylthio]-3-phenylquinoline hydrochloride (1.2 g.) in ethanol (35 ml.). The mixture was stirred at ambient temperature for 4 hr., poured into saturated sodium bicarbonate solution (200 ml.), and extracted with ethyl acetate (3×100 ml.). The ethyl acetate extract was washed with brine (3×20 ml.), dried (Na2SO4), and evaporated in vacuo to dryness. The residual oil was chromatographed on silica gel (Merck Kieselgel 60, Art No. 9385, grain size 0.040-0.063 mm., 230-400 mesh ASTM; 180 g.) using chloroform as eluant. The relevant fraction was evaporated in vacuo to dryness, the residual oil (1.1 g.) was dissolved in methanol (20 ml.), and concentrated hydrochloric acid (0.3 ml.) was added. The resulting solution was evaporated in vacuo to dryness, and the residue was crystallised from a mixture of ethanol and diethyl ether, to yield 2-[(1-dimethylaminocyclopropyl)methylthio]-3-phenylquinoline hydrochloride, m.p. 219°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH3:17]I>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:17])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Reactant: CI
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 13 h
Yield: 104.7 %

Procedure:
Two hundred L of THF was added to a reactor, and 24.6 kg of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was added. Then 35 kg of methyl iodide was added, rinsed in with 10 L of THF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15-25°, rinsed in with 40 L of THF. The mixture was stirred at 36-39° for 13 hours, and was then cooled to 15-25°. The layers were allowed to separate, and the water/THF phase was neutralized to pH 7 with hydrochloric acid and heated to reflux. Distillate was removed until the temperature reached 77°. A total of 154 kg of water was added from time to time. The solution was cooled over 3 hours to 3-10°, and was then stirred vigorously at that temperature until solids began to form. Then the slurry was stirred gently at constant temperature for 3 hours. The slurry was filtered, and the vessel and filter cake were washed with cold water. The cake was air dried at 25-35° for 75 hours to obtain 27.3 kg of the desired product, potency 85.1% by liquid chromatographic analysis.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH:13][C:27]([NH:26][C:20]2[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)=[O:28])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1ccc(CC#N)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(CC#N)ccc2OC)n1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a suspension of 0.3 g of the compound from Example 3 and 0.37 g 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 15 ml of dry acetonitrile was added 0.198 ml DBU. After being stirred overnight the clear solution was diluted with 50 ml of water, acidified with 1N HCl and the precipitate was filtered off. The residue was washed with water and triturated with ether to give 0.44 g solid, m.p. 168°-171° C. (dec.).