Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
70.2 g (409.7 mmol) of a-bromopropionic acid chloride is added in drops at 0° C. to 40 g (341.4 mmol) of valine and 103.7 g (1024 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][N:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][CH2:13][C@H:12]1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)CN[C@H](C(O)=O)CO1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:45](=[C:46]([NH2:48])[CH:47]=1)[NH:44][C:43]1[CH:42]=[N:41][CH:40]=[C:39]([CH3:49])[C:38]2=1.CCN=C=NCCCN(C)C>N1C=CC=CC=1.CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:22])[CH2:10][N:11]1[C@H:12]([C:19](=[O:21])[NH:48][C:46]2[CH:47]=[C:35]([Cl:34])[CH:36]=[C:37]3[C:45]=2[NH:44][C:43]2[CH:42]=[N:41][CH:40]=[C:39]([CH3:49])[C:38]3=2)[CH2:13][O:14][C:15]([CH3:17])([CH3:18])[CH2:16]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Reactant: C[C@@H](CN1CC(C)(C)OC[C@H]1C(=O)O)NC(=O)OC(C)(C)C
Agent: CC1(C)CN[C@H](C(=O)O)CO1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cncc2[nH]c3c(NC(=O)[C@@H]4COC(C)(C)CN4C[C@H](C)NC(=O)OC(C)(C)C)cc(Cl)cc3c12
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A solution of (S)-4-((S)-2-tert-butoxycarbonylamino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (3.316 g, 10.5 mmol) (prepared by reductively alkylating (S)-6,6-dimethyl-morpholine-3-carboxylic acid with N-(tert-butoxycarbonyl)-L-alanal) in anhydrous pyridine (75 mL) was stirred at room temperature. 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (1.869 g, 8.09 mmol) was added, followed by EDCI (2.894 g, 15.1 mmol). The reaction was stirred at room temperature for 14-18 hours under argon. The reaction was partially concentrated, diluted with H2O (20 mL) and transferred to a separatory funnel. The mixture was diluted with brine (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried, filtered and concentrated to afford a dark residue. Column chromatography (0-8% MeOH/CH2Cl2) yielded {(S)-2-[(S)-5-(6-Chloro-4-methyl-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-1-methyl-ethyl}-carbamic acid tert-butyl ester as a light tan solid (2.688 g).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1.CCN(C(C)C)C(C)C.[Cl-].[NH2:26][NH2:27]>CS(C)=O.CO>[N:11]1([C:2]2[C:7]([F:8])=[C:6]([NH:26][NH2:27])[N:5]=[C:4]([CH3:10])[N:3]=2)[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: C1=CCNC1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: NN
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N2CC=CC2)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (181 mg, 1.0 mmol) was dissolved in 4 mL of DMSO and stirred at room temperature. 3-Pyrroline (71 mg, 1.05 mmol) was added, followed by DIPEA (244 μL, 1.4 mmol). The resulting reaction mixture was stirred until displacement of the first chloride was complete, and then hydrazine (350 μL) and MeOH (˜2 mL) were added to the reaction mixture. The contents were then heated to 70° C. for 2 h, until displacement of the second chloride was complete. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 4-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-6-hydrazino-2-methylpyrimidine (142 mg, 68%).
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>C1COCC1>[C:21]([CH2:22][CH2:23][N:9]1[CH2:8][CH2:7][CH:6]([NH2:5])[CH2:11][CH2:10]1)#[N:24]
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: C=CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.9 %

Procedure:
A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine.
Reaction SMILES: CC1C=C[C:5]([C:6](NC2C=C(C(F)(F)F)C=C(N3C=C(C)N=C3)C=2)=[O:7])=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.Cl.Cl.[CH3:42][C:43]1[CH:67]=[CH:66][C:46]([C:47]([NH:49][C:50]2[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[C:52]([N:60]3[CH:64]=[C:63]([CH3:65])[N:62]=[CH:61]3)[CH:51]=2)=[O:48])=[CH:45][C:44]=1[NH:68][C:69]1[N:74]=[C:73]([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH:72]=[CH:71][N:70]=1.[OH2:81].[CH3:82][OH:83]>>[CH2:6]([O:7][CH2:47][OH:48])[CH2:5][O:81][CH2:82][OH:83].[CH3:42][C:43]1[CH:67]=[CH:66][C:46]([C:47]([NH:49][C:50]2[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=[C:52]([N:60]3[CH:64]=[C:63]([CH3:65])[N:62]=[CH:61]3)[CH:51]=2)=[O:48])=[CH:45][C:44]=1[NH:68][C:69]1[N:74]=[C:73]([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH:72]=[CH:71][N:70]=1
Reactant: O
Reactant: CO
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Agent: Cl
Product: OCOCCOCO
Temperature: 42 °C
Reaction time: 0.25 h

Procedure:
4.0 g 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base is dissolved in 60 mL methanol at 50° C. 1.05 equivalent (688.7 μL) of hydrochloric acid is added as a solution in 2 mL of methanol. The solution is let stand for 60 minutes at 50° C. The solution is cooled down to 42° C. and kept at this temperature for 15 minutes. A suspension of 4 mg of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide hydrochloride in methanol (40mg)/water (0.4 mg) homogenized for 10 seconds in an ultrasonic bath is added. The suspension is let stand for 2.5 hours at 42° C., then cooled down in 7 hours at 20° C. The suspension remains at 20° C. for 56 hours. The suspension is not filtrated before analysis. The dimethanol solvate form SB of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:6]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:6]
Reactant: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COC(=O)CN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
In acetic acid (100 ml) was dissolved N-(4-nitro-benzyl)sarcosine methyl ester (5.96 g), and to the mixture was added little by little reduced iron (7 g). The mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added ethyl acetate. The precipitates were filtered off, and the filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give N-(4-aminobenzyl)sarcosine methyl ester (3.0 g) as red oil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCC[O:16]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)C[CH2:37][O:36]4)[C:22]1=[O:41]>>[NH2:8][C:6]1[S:7][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:30]4=[CH:40][C:39]5[O:16][CH2:37][O:36][C:35]=5[CH:34]=[C:31]4[O:32][CH2:33]3)[C:22]2=[O:41])=[C:4]([C:9]([F:12])([F:11])[F:10])[N:5]=1
Reactant: Nc1nc(C(F)(F)F)c(CCl)s1
Reactant: BrCC1CCCCO1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Nc1nc(C(F)(F)F)c(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(chloromethyl)-4-(trifluoromethyl)thiazol-2-amine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2″(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (4.0%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ7.39 (br, 2H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.7 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.12 (s, 1H), 5.91 (s, 2H), 5.02 (ABq, 2H), 4.70 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 167.9, 155.9, 148.9, 142.2, 141.8, 134.7 (q, 1JCF=135 Hz), 132.1, 129.5, 124.5, 123.9, 123.8 (m), 119.9, 109.2, 103.2, 101.9, 93.9, 80.2, 57.8, 40.9; MS (ES+) m/z 462.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30]1>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:34]([C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[CH:30]=3)(=[O:36])=[O:35])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1ccc(S(=O)(=O)Cl)c1
Reactant: NCCOc1ccc2c(c1)C(Cc1cccc(F)c1)C(N1CCCC1)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2cccc(F)c2)C(N2CCCC2)CC3)c1
Temperature: 25 °C

Procedure:
2-(8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine (50 mg, 0.136 mmol) was dissolved in dichloromethane (2 mL). N,N-Dimethyl-4-aminopyridine (49.7 mg, 0.407 mmol) and 1-methyl-1H-pyrrole-3-sulfonyl chloride (24.4 mg, 0.136 mmol) were added successively. The reaction mixture was stirred at room temperature over night. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 31 mg (0.061 mmol, 45%).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[CH3:14][CH2:15][O:16][CH2:17][CH3:18]>ClCCl>[C:11]([O:10][CH2:7]/[CH:8]=[CH:14]\[CH2:15][O:16][CH2:17][C:18]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Solvent: ClCCl
Product: CC(=O)OC/C=C\COCc1ccccc1

Procedure:
A stirred solution of compound A (7.13 g, 40 mmol), pyridine (7.5 mL) in dichloromethane (30 mL) was treated with acetic anhydride (5 g, 49 mmol). After 24 hours the mixture was diluted with ether (150 mL) and washed with water (50 mL), saturated copper sulfate solution (25 mL,3x), dried (magnesium sulfate), filtered and concentrated. The residue was coevaporated with toluene (10 mL, 3x) to obtain the title compound (5.93 g) as a colorless oil.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1

Procedure:
Prepared similarly to Intermediate 10 from phenylmethyl 3-(4-hydroxybutyl)-1-piperidinecarboxylate (for example, as prepared for Intermediate 23).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:23]([CH3:22])([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 1 g (3.5 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 1.15 g (5.3 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride, 2 ml of triethylamine in 10 ml of pyridine is refluxed for 3 hours.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.CCO.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: CC(C)c1cc(Cl)nnc1NN
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)c1cc(Cl)nn2c(N)nnc12
Reaction time: 8 h

Procedure:
(6-Chloro-4-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.009; 258 mg) was initially charged in ethanol/water (6/1 ml) at RT while stirring. Thereafter, cyanogen bromide (182 mg, dissolved in a mixture of 1.5 ml of EtOH and 0.5 ml of water) was cautiously added dropwise. After stirring for 5 hours, the mixture was left to stand overnight, another 1 eq. of the cyanogen bromide solution was added and the mixture was stirred all day. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 180 mg of the title compound were obtained in sufficient purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([Li])(C)(C)C.CN([CH:38]=[O:39])C.Cl>C(OCC)C.C1COCC1.C(OCC)(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:5]2[CH:6]=[C:2]([CH:38]=[O:39])[CH:3]=[C:4]2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(S(=O)(=O)n2cc(Br)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
To a stirred solution of 4bromo-1-p-methoxyphenylsulfonyl-2-(3,4,5-trimethoxyphenyl)-pyrrole (0.30 g, 0.62 mmol, Example 94b) in ethyl ether/THF (5 ml, 1:1 v/v) tert-butyl-lithium (1.5 equiv., 1.7 M in pentane) is added at −78° C. The reaction mixture is stirred for 20 min at −78° C., and DMF (255 mg, 5 equiv.) is added drop wise. The reaction mixture is kept for 1 h at −78° C., allowed to come to 4° C., and poured onto ice, 1 M aqueous HCl and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated, and the residue chromatographed on SiO2 with ethyl acetate/hexane to yield the title compound (0.196 g, 73%) as a light yellow solid. 1H-NMR (300 MHz, DMSO-d6): 9.86 (s, CHO); 8.44 (d, J=1.9, 1H); 7.38 (d, J=9.0, 2H); 7.01 (d, J=9.0, 2H); 6.56 (d, J=1.9, 1H); 6.36 (s, 2H); 3.82 (s, MeO); 3.72 (s, MeO); 3.67 (s, 2MeO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[F:21])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:21])=[CH:14][C:15]([Cl:20])=[C:16]([O:18][CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (1.2 g, 3.5 mmol) was slurried with 4 ml of con. sulfuric acid and was slowly added to a stirred 4 ml mixture of con. sulfuric acid-con. nitric acid (9:1) at −15° C. Solution was allowed to stir at ambient temperature for 2 hr and then added to ice water. Extraction with ethyl acetate and removal of the solvent afforded a crude product which was chromatographed on silica gel. Elution of the column with hexane-methylene chloride (4:6) furnished the title compound (0.72 g).
Reaction SMILES: [C:1]1([CH:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26](Br)=[O:27].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH2:36]>>[C:1]1([CH:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][N:11]2[CH2:25][C:26]([NH:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:27])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Br)CBr
Reactant: CCC(c1ccccc1)C1NCCc2cc(OC)c(OC)cc21
Reactant: NCc1ccccn1
Product: CCC(c1ccccc1)C1c2cc(OC)c(OC)cc2CCN1CC(=O)NCc1ccccn1

Procedure:
prepared by reaction of 1-(1-Phenyl-propyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1>>[CH2:18]([O:17][CH2:16][CH2:15][N:14]1[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=[C:10]1[CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:19]
Reactant: CCOCCn1c(CCl)nc2ccccc21
Reactant: C1CNCCNC1
Product: CCOCCn1c(CN2CCCNCC2)nc2ccccc21
Yield: 65.8 %

Procedure:
In the same manner as described in Example 1, homopiperazine (8.0 g) and 2-chloromethyl-1-(2-ethoxyethyl)benzimidazole (2.4 g) obtained in the same manner as described in Reference Example 3 are reacted to give 1-(2-ethoxyethyl)-2-(1-homopiperazinyl)methylbenzimidazole (2.0 g) as a pale yellow liquid. This liquid is treated with fumaric acid (1.15 g,), and the crude crystal thus obtained is recrystallized from a mixed solvent of ethyl acetate-ethanol to give 1-(2-ethoxyethyl)-2-(1-homopiperazinyl)methylbenzimidazole 3/2 fumarate (1.75 g) as colorless prisms, m.p. 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Product: CCCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1.2 g, 5.2 mmol) and N-butylamine (2 mL) was heated at 170° C. (microwave) for 30 min. The resulting mixture was cooled to room temperature and purified by preparative HPLC (neutral) to afford 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (887 mg, 63% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.69 (d, J=9.9 Hz, 1H), 3.38 (t, J=7.1 Hz, 2H), 1.59-1.73 (m, 2H), 1.41-1.53 (m, 2H), 1.01 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 269.1 [(M+H)+, calcd for C10H14BrN4 269.0].
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:6]=12.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26].Cl.[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.C1COCC1.[Fe].CO>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:45])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:15])[S:13][C:6]=12
Reactant: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CC(C)CNCC(C)C
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)CN(CC(C)C)C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 40 (150 mg, 0.385 mmol) and TEA (107 μl, 0.771 mmol) in anhydrous CH2Cl2 under an atmosphere of nitrogen was added diisobutylamine (67 μL, 0.385 mmol). After stirring for 1 hour, methanol (2 mL) was added followed by iron powder (150 mg) and HCl (conc., 0.4 mL). The reaction mixture was stirred for additional 2 hours and then partitioned between ethyl acetate (20 mL) and a mixture of H2O (20 mL) and NH4OH (2 mL). Organic phase was collected, washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was treated with 2-phenylacetyl isothiocyanate (102 mg, 0.58 mmol) in THF (2 mL), the resultant mixture was allowed to stand for 2 hours at ambient temperature, quenched with methanol (5.0 mL), loaded onto 5 ml of silica gel and purified by flash chromatography using hexane—AcOEt (70:30) as an eluent, to afford title compound 81 (41 mg, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.54 (d, J=5.6 Hz, 1H), 8.08 (dd, J=2.0 and 12.0 Hz, 1H), 7.69 (s, 1H), 7.38-7.49 (m, 2H), 7.28 - 7.35 (m, 5H), 6.77 (dd, J=1.2 and 5.6 Hz, 1H), 3.77 (s, 2H), 3.46 (bs, 4H), 2.18 (bs, 1H), 2.02 (bs, 1H), 1.02 (bs, 6H), 0.87 (bs, 6H). LRMS (M+1):592.7 (calcd), 593.3 (found).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:19])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 25 °C

Procedure:
3-Bromo-4-methylbenzoic acid (5 g, 23.25 mmol) was suspended in CH2Cl2 (100 mL) and stirred under argon at room temperature. Oxalyl chloride (5.9 g, 46.5 mmol) was added followed by DMF (20 μL). Gas evolution began, and the mixture was stirred for 2 days during which time complete solution occurred. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (20 mL). This was stirred for thirty min. The phases were separated and the organic washed 1× with brine dried over anhydrous Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc/hexane and dried under vacuum to afford the title compound as a white crystalline solid. LC-MS m/z 213.8 (M+H)+, 1.41 min (ret time); mp 178-179° C.