Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]OC(OC)N(C)C.Cl.CO>C(#N)C=C.CO>[ClH:1].[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Agent: Cl
Solvent: CO
Solvent: C=CC#N
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1

Procedure:
To a suspension of 10.0 g. (39.0 m. mol) of 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in acrylonitrile (CH3CN) (50 ml.) is added 9.3 g. (78.0 m mol) of dimethylformamide dimethylacetal (DMF-DMA) and the resulting solution, in a bomb, is heated to 100°-105° C. for one hour. After cooling the reaction mixture is placed in a round bottom flask and concentrated under reduced pressure. The residue is partitioned between H2O and CHCl3 and the layers separated. The aqueous layer is extracted with CHCl3 (1×50 ml). The combined CHCl3 extracts are washed with H2O (1×50 ml) dried (MgSO4) and concentrated under reduced pressure. A small amount of the residue is triturated in hexane to give a white solid, having melting point 224. NMR and IR show the product to be identical with that of Example 3. The remainder of the residue is dissolved in MeOH and acidified with HCl/MeOH. The MeOH is removed under vacuum and the residue crystallized from CH3CN to give 6.8 g. (65%) of 1-(2',60'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one hydrochloride, melting point 234°-8° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH2:47][CH2:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1CCC=C2

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>ClCCl.C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (20 g, 128 mmol) in dichloromethane (600 mL) and acetic acid (200 mL) was slowly added bromine (13 mL, 256 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 16 hours. The mixture was concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was washed with sodium bisulphite solution and concentrated and the residue recrystallized from hexane/dichloromethane to provide the title compound (22.7 g, 76%). MS (DCI/NH3) m/z 236 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1>[F:37][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2ncccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol) in THF (1.1M, 3.7 mL) at −78° C. was added LiHMDS (1M in THF) (5.24 ml, 5.24 mmol). The reaction was stirred at −78° C. for ˜15 minutes, then to it was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44 mmol) in THF (1.0M, 4.5 mL). The reaction was allowed to warm to −10° C. over 2 h. The reaction was filtered through a plug of Celite, washed with EtOAc and the filtrate was then concentrated in vacuo. The concentrated material was rediluted with EtOAc and washed with saturated NH4Cl solution. The aqueous layer was then extracted with EtOAc, and the organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl 2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellow oil. To synthesize the corresponding acid, methyl 2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similar to that of 2-(quinolin-6-yl)propanoic acid.
Reaction SMILES: C1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]N1.[H-].[Na+].[CH3:15]I.[CH3:17][N:18](C)[CH:19]=[O:20]>>[CH3:17][N:18]1[N:11]=[C:4]([O:3][CH3:15])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:19]1=[O:20]
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: COc1nn(C)c(=O)c2ccccc12
Yield: 78 %

Procedure:
2,3-Dihydrophthalazine-1,4-dione (0.02 mol) was added to a suspension of sodium hydride (0.04 mol; 50% solution in mineral oil) in anhydrous dimethylformamide (100 ml). To this was slowly added an excess amount of methyl iodide (0.05 mol). The mixture was stirred under reflux for 24 hours. The solvent was evaporated and the product purified by recrystallization from benzene. The purified product was obtained in a yield of 78 percent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C1([O:22][C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCC2CCNCC2)cc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(COc2ccc(Br)cc2)CC1

Procedure:
The procedure described in Example 4.3. is repeated. Starting from 1.6 g (5.9 mmol) of 4-{[(4-bromophenyl)oxy]methyl}piperidine, prepared in Step 5.2., and from 1.32 g (5.9 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1., gives the product in oil form.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[ClH:1].[ClH:1].[CH3:27][N:26]1[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:29])[N:18]=[C:17]1[S:16][CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:9](=[O:10])[C:8]2[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCN(C)CC5)cc4)cc3)n(C)c(=O)c12
Product: Cl

Procedure:
A solution of 2-[4-[4-(2-chloroethoxy]benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (173 mg) and 1-methylpiperazine (0.12 ml) in DMF (5 ml) was stirred at 100° C. for 15 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (122 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[CH2:3][CH2:2]1.[NH2:17][NH2:18]>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([NH:17][NH2:18])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(N2CCOCC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 52 %

Procedure:
Methyl 3-morpholinobenzoate (100 mg, 0.452 mmol) was added to hydrazine (14.48 mg, 0.452 mmol) in methanol (10 mL) and refluxed for 12 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum and the compound was purified by column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (52 mg). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 7.35 (s, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 4.45 (bs, 2H), 3.74 (m, 4H), 3.14 (m, 4H). ESI-MS: 222.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1(F)F.C1(CBr)CC1.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:5]1([CH2:4][N:26]2[CH2:27][CH2:28][N:24]([C:16]3[S:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH3:13])[N:15]=3)[C:25]2=[O:29])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC1(F)CC1CBr
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Yield: 96 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace bromomethyl-2,2-difluorocyclopropane with cyclopropylmethyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 96% yield: 1H NMR (300 MHz, CDCl3) δ 4.23 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 3.67 (t, J=7.8 Hz, 2H), 3.16 (d, J=6.9 Hz, 2H), 2.58 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 0.97-0.88 (m, 1H), 0.59-0.42 (m, 2H), 0.25-0.12 (m, 2H); MS (ES+) m/z 310.3 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.BrC(C(F)(F)F)=C.BrC1C=CC([C:25](N(OC)C)=[O:26])=CC=1C.C[CH:35]([N:37](C(C)C)[C:38]([C:50]([F:53])([F:52])[F:51])=[CH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[C:44]([CH3:49])[CH:43]=1)=[O:41])C>O1CCCC1.O>[Br:48][C:45]1[CH:46]=[CH:47][C:42]([C:40](=[O:41])[CH:39]=[C:38]([NH:37][CH2:35][O:26][CH3:25])[C:50]([F:53])([F:52])[F:51])=[CH:43][C:44]=1[CH3:49]
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Reactant: Cc1cc(C(=O)C=C(N(C(C)C)C(C)C)C(F)(F)F)ccc1Br
Agent: C=C(Br)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCNC(=CC(=O)c1ccc(Br)c(C)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a stirred solution of diisopropylamine (11.1 mL, 83.3 mmol) in tetrahydrofuran (100 mL) at −78° C. was added 2.5 M n-BuLi in hexanes (33.31 mL, 83.3 mmol). The reaction mixture was allowed to warm to 0° C., stirred for 20 minutes, and then cooled to −78° C. 2-Bromo-3,3,3-trifluoropropene (6.78 g, 38.7 mmol) was added to the reaction mixture, which was stirred for 30 minutes. Then a solution of 4-bromo—N-methoxy-N,3-dimethylbenzamide (i.e. the title product of Step A) (5.0 g, 19.4 mmol) in tetrahydrofuran (20 mL) was added to the reaction mixture at −78° C., which was then warmed to 0° C. Water (25 mL) was added to the mixture, which was then stirred for 1 hour at 0° C. The reaction mixture was extracted with ether and concentrated under reduced pressure, and the oily residue was purified by chromatography on silica gel to afford a mixture of 3-[bis(1-methylethyl)amino]-1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-2-buten-1-one and 1-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-3-(methoxymethylamino)-2-buten-1-one (2.5:1 ratio by LCMS) (6.55 g, approx. 92% yield) as a bright orange oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH2:8]([N:15]1[CH2:21][CH:20]2[C:22](=O)[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C=[O:28])C>CCOC(C)=O.O>[CH2:7]([O:6][C:5](=[O:28])[CH:4]=[C:22]1[CH:17]2[CH2:18][CH2:19][CH:20]1[CH2:21][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16]2)[CH3:3]
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: CN(C)C=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
60% sodium hydride (109 mg) was added to a mixture of triethyl phosphonoacetate (1.02 g) and THF (12 mL) at 0° C. in a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. 3-Benzyl-3-azabicyclo[3.2.1]octan-8-one (978 mg) and DMF (5 mL) were added to the mixture, and the mixture was stirred at room temperature overnight. After water was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=97:3 to 80:20), whereby ethyl(3-benzyl-3-azabicyclo[3.2.1]oct-8-ylidene)acetate (362 mg) was obtained as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(O)C2CC(C)(C)OC=2C=1[F:45])=O.N1(C(C2C=CC(Br)=CC=2)=O)CCC1>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:26][CH2:27][CH2:28]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]=1[F:45])=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: COC(=O)c1cc(O)c2c(c1F)OC(C)(C)C2
Agent: O=C(c1ccc(Br)cc1)N1CCC1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1F)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a) and azetidin-1-yl-(4-bromo-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.61-7.65 (m, 2 H) 7.05 (d, J=4.55 Hz, 1 H) 6.94 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 4.27-4.37 (m, 2 H) 4.23 (s, 2 H) 3.90 (s, 3 H) 2.91 (s, 2 H) 2.32-2.40 (m, 2 H) 1.52 (s, 6 H); LCMS for C22H22FNO5 m/z 400.20 (M+H)+.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(OCC)C>[N:31]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc2nc(N3CCC[C@@H](N4CCC4)C3)sc2c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
One equivalent of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10, 0.078 g, 0.2 mmol) and two equivalents of potassium carbonate (55.3 mg, 0.40 mmol) were weighed into a 2.5 mL Biotage microwave vial equipped with a magnetic stirbar. Acetonitrile (1 mL) was added, then 6 equivalents of azetidine (68.5 mg, 1.2 mmol) was weighed into the reaction mixture. The vial was sealed with a septum cap and the reaction mixture was stirred at 80° C. for 72 hours. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4g, 100% dichloromethane to 98:2 dichloromethane/2 M NH3 in methanol). Fractions containing product were combined and concentrated under reduced pressure to give an oil that was dissolved in diethyl ether and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give a semi-solid that was triturated with diethyl ether/hexane to give (R)-2-(3-(azetidin-1-yl)piperidin-1-yl)-6-bromobenzo[d]thiazole as a solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.23-1.38 (m, 1H), 1.53-1.69 (m, 1H), 1.80-1.96 (m, 2H), 2.11 (pentet, J=7 Hz, 2H), 2.32-2.43 (m, 1H), 2.93-3.02 (m, 1H), 3.22-3.38 (m, 5H), 3.79 (dt, J=4, 13 Hz, 1H), 3.96 (dd, J=4, 13 Hz, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37][CH2:36]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:41][CH:38]1[CH2:37][CH2:36][N:35]([C:3]2[C:2]([Cl:1])=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH:25]4[CH2:27][CH2:26]4)[C:12]4=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]4[N:10]=3)[CH:6]=[C:5]([C:33]#[N:34])[CH:4]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
To a round bottom flask charged with tert-butyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I12C) (0.517 g, 0.773 mmol) in dichloromethane (5.15 ml) was added anisole (1.688 ml, 15.45 mmol), followed by the slow addition of trifluoroacetic acid (2.381 ml, 30.9 mmol). The reaction mixture was stirred at rt 2 d. The reaction mixture was warmed to 45° C. for 1 h. The reaction mixture was cooled to rt and concentrated in vacuo. After cooling to rt, 25 mL 2 N ammonia/methanol was added and a white solid crashed out of solution. The slurry was stirred for 30 min and the solid was isolated by vacuum filtration washing with cold methanol. 2-((3-(4-Aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.1563 g) was isolated as a white solid. Material used as is in subsequent transformations.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)([CH3:24])[CH3:23]
Reactant: c1ccc(-c2cc(OCC3CO3)c3ccccc3n2)cc1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, m. p. 109-111° C., MS: m/e=337.2 (M+H+), was prepared from (RS)-4-oxiranylmethoxy-2-phenyl-quinoline and isopropylamine.
Reaction SMILES: Br[C:2]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:7]([C:4]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: Cc1cc(C#N)ccc1-n1c(Br)ccc1C=O
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C=O)n2-c2ccc(C#N)cc2C)cc1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A mixture of compound 50C (24 mg, 0.083 mmol), compound 4-methoxyphenylboronic acid (15.2 mg, 0.1 mmol) and sodium carbonate (17.6 mg, 0.166 mmol) in a mixture of DME (5 mL) and water (1 mL) was degassed, and [11′-bis(diphenlphospino)-ferrocene]dichloropalladium(II) (96 mg, 0.008 mmol) was added. The reaction mixture was heated at 90° C. for 10 hours, poured into water, and extracted with ethyl acetate (10 mL×3). The combine organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure, and purified by preparative TLC to afford the compound 50D (15 mg, 57%).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.[NH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16].[N+:19]([O-:22])([OH:21])=[O:20].N([O-])=O.[Na+]>O>[N+:19]([O-:22])([O-:21])=[O:20].[S:15]([CH2:14][CH2:13][N+:12]#[N:4])([OH:18])(=[O:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: NCCS(=O)(=O)O
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]CCS(=O)(=O)O
Product: O=[N+]([O-])[O-]

Procedure:
This example shows another method for the preparation of a carbon black product of the present invention. A fluffy carbon black with a surface area of 230 m2/g and a DBPA of 70 ml/100 g was used. Twenty grams of this black were added to a solution of 4.9 g of 2-aminoethanesulfonic acid in 180 g of water. Concentrated nitric acid (4.32 g) was added. A solution of 3.33 g of sodium nitrite in 15 g of water was added slowly with stirring, forming 2-sulfoethanediazonium nitrate in situ, which reacted with the fluffy carbon black. A large quantity of bubbles evolved. The product was dried in an oven at 135° C., leaving a carbon black product. The resulting carbon black product contained 1.68% sulfur after Soxhlet extraction with ethanol overnight, compared to 0.4% for the untreated fluffy carbon black. This corresponds to attaching 20% of the C2H4SO3 -- groups to the carbon black product. Therefore, the carbon black product had 0.40 mmol/g of attached C2H4SO3 -- groups.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([NH2:16])=O)[CH:7]=[CH:6]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]#[N:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(N)=O)ccc2c1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1ccc2cc(C(C)C#N)ccc2c1

Procedure:
In 50 ml of dry THF, were suspended 3.0 g of oa (6-methoxy-2-naphthyl)-propanamide, followed by adding thereto 8.3 g of trifluoroacetic anhydride and then stirring at room temperature for 12 hours. The resulting reaction mixture was poured into 200 ml of iced water, and then precipitated white solid was filtered off. After purifying with silica gel column, the product was recrystallized twice with ethanol to obtain 2.1 g of oa (6-methoxy-2-naphthyl)propanonitrile (Compound No. 1-1) of this invention.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:13]([OH:16])[C:14]#[CH:15]>C(O)(C)(C)C.O.O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][N:1]2[CH:15]=[C:14]([CH2:13][OH:16])[N:3]=[N:2]2)=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2cc(CO)nn2)cc1
Reaction time: 48 h
Yield: 59.1 %

Procedure:
93 mmol 1-(azidomethyl)-4-methoxybenzene, 110 mmol propargyl alcohol were mixed in 230 ml tert-butyl alcohol/H2O (1:1) solution. 1 mmol CuSO4.5H2O and 10 mmol Ascorbic acid sodium salts dissolved in 2 ml water were added into the solution. The mixture was stirred for 2 days. After evaporation, the mixture was purified by flash column to give 55 mmol (1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-yl) methanol. 1H NMR (CDCl3): 7.42 (1H, s), 7.22 (2H, d, JH-H=8.70), 6.88 (2H, d, JH-H=8.70), 5.43 (2H, s), 4.73 (2H, s), 3.79 (3H, s).