Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C1C(=O)N([I:34])C(=O)C1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8]([I:34])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(I)cnc23)cc1

Procedure:
To 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (940 mg, 2.57 mmol) from Example X, step (1a) in chloroform (10 mL) at room temperature was added NIS in one portion and the resulting mixture was refluxed for 5 h. Concentration and purification by flash chromatography provided 6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine as a foamy, yellow solid (960 mg, 76%). LCMS [M+H]+ 490.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:39](OCC)(=[O:41])C.O>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=2[CH2:39][OH:41])=[CH:16][CH:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 13 g of N-[4-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 250 ml of tetrahydrofuran is added dropwise with stirring under argon 59.14 ml of 1 molar lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature for 0.5 hours and refluxed for 5 hours. Ethyl acetate is added dropwise followed by water. The mixture is filtered and the cake washed with ether. The filtrate is evaporated to a residue which is purified by chromatography on silica gel with 2:1 chloroform:hexane to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC1CCNCC1
Solvent: CN(C)C=O
Product: Cc1csc2c(N3CCC(C)CC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 10 ml of DMF was dissolved 1.0 g (4.6 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 1.06 g (10.7 mmol) of 4-methylpiperidine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume to room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 1.20 g (yield: 93.3%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH2:17][CH2:18]Br>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:17][CH3:18]
Reactant: CCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1C#N

Procedure:
75 g (630 mmol) of 2-hydroxybenzonitrile, 174 g (1.26 mol) of potassium carbonate and 232.3 g (1.89 mol) of n-propyl bromide in 11 of acetone are refluxed overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:13]([F:14])=[C:12]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][C:9]=1[OH:18].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][O:18][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[C:13]([F:14])[C:8]=1[F:7])[CH3:24]
Reactant: OCCc1ccc(O)c(F)c1F
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(CCO)c(F)c1F)OCC
Temperature: 90 °C

Procedure:
Cesium carbonate (0.99 g) was added to a solution of 2,3-difluoro-4-(2-hydroxyethyl)phenol (example 77, step b) (0.44 g) and 2-bromo-1,1-diethoxyethane (0.4 mL) in DMF (10 mL). The resulting suspension was heated at 90° C. for 18 h. The reaction was allowed to cool and poured into water (100 mL). The aqueous mixture was extracted with diethylether (3×100 mL). The combined organic solutions were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography eluting with isohexane to 1:1 ethyl acetate:isohexane gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 0.49 g.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][CH:23]3[CH:28]4[CH:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27]4)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1CCOCC1.[ClH:44]>C(Cl)Cl>[ClH:44].[CH:24]12[CH:23]([NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]3[CH:16]=[N:17][C:13]([C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=4)=[N:14]3)[CH:28]1[CH2:27][NH:26][CH2:25]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NC1C2CNCC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
(Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.05 g, 1.0 eq.) was dissolved in DCM (3 mL) and cooled to 0° C. where dioxane:HCl (0.2 mL) was added dropwise and stirred for 30 min. The reaction was allowed to warm to room temperature and stirred for 30 min, concentrated under reduced pressure. The crude product was triturated with ether to afford (Z)—N-(3-azabicyclo[3.1.0]hexan-6-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide hydrochloride (0.015 g, 37.5% yield). 1H NMR (400 MHz, DMSO) δ, 9.61 (s, 1H), 8.75 (s, 2H), 8.60 (s, 2H), 8.30 (s, 1H), 7.38-7.40 (d, J=10.4 Hz, 1H), 5.87-5.89 (d, J=10.4 Hz, 1H), 2.91 (s, 1H), 2.14 (s, 2H), 1.23 (s, 3H); LCMS for Chemical Formula: C18H16F6N5O [M+H]+ 432.34 found 432.19 at retention time 2.302 min.
Reaction SMILES: CS(C1C=CC([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].N1CCCC1>>[CH3:33][CH:32]([S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:31])=[O:30])[CH3:34]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CC(C)S(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 72 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(propane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 72% yield. MS (m/e): 296.2 (MH−, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[C:12]1([C:18]2([NH2:21])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(C#N)(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:21][C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: NC1(c2ccccc2)CC1
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NC1(c2ccccc2)CC1
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a suspension of 4,6-dichloronicotinamide (191 mg, 1 mmol) in AcCN (2 mL) was added 1-phenylcyclopropanamine (160 mg, 1.2 mmol) and DIPEA (0.213 mL, 1.2 mmol). The mixture was heated at 60° C. for 2 days. The mixture was concentrated and purified by column chromatography to give 6-chloro-4-(1-phenylcyclopropylamino)nicotinamide (105 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][C:28]1([CH3:36])[O:32][CH:31]([CH2:33][CH2:34]O)[CH2:30][O:29]1>C1COCC1.C(#N)C>[I:25][CH2:34][CH2:33][CH:31]1[CH2:30][O:29][C:28]([CH3:36])([CH3:27])[O:32]1
Reactant: II
Reactant: CC1(C)OCC(CCO)O1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C)OCC(CCI)O1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triphenylphosphine (172 mmol, 45 g) and imidazole (172 mmol, 12 g) were dissolved in THF/acetonitrile (3:1, 300 ml). The mixture was cooled under an ice bath, and iodine (172 mmol, 44 g) was added in four portions with vigorous stirring over 20 minutes. The resulting slurry was warmed to 20° C. and then cooled to 0° C. (±)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (156 mmol, 25 g) was added dropwise to the reaction mixture over 15 minutes. The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with 5% sodium bicarbonate solution and extracted with hexane. The combined organic layer was dried with MgSO4 and concentrated. Silica gel chromatography gave 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 4.18-4.12 (m, 1H), 4.06 (dd, 1H, J=8.0 Hz, J2=6.1 Hz), 3.55 (dd, 1H, J1=8.0 Hz, J2=6.5 Hz), 3.28-3.17 (m, 2 H), 2.11-1.98 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[O:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:35]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)=[CH:36]1
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1CCN(c2ncnc3c2c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D6 (450 mg), 2-(3-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mg, 1.245 mmol, commercially available from e.g. Maybridge, Sigma-Aldrich or Apollo), potassium phosphate trihydrate (660 mg, 2.5 mmol), palladium tetrakis (30 mg, 0.026 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml) and stirred under nitrogen at 90° C. overnight. Cooled to room temperature, solvent removed in vacuo, water (150 ml) was added extracted with EtOAc (3×150 ml). The combined extracts were washed with brine and dried over MgSO4, concentrated to give crude product which was purified by silica gel column eluting with pet eth/EtOAc 1:1 to give 60 mg of desired product D28. LCMS [MH+] 528.2@1.88 min (5 min run)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cnc2ccccc2n1
Yield: 41 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.27 g), 2-quinoxalinylcarbonyl chloride (0.29 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and evaporated. The residue was triturated under ethyl acetate. There was thus obtained the title compound as a solid (0.175 g); NMR Spectrum: (DMSOd6) 2.31 (s, 3H), 2.95 (s, 6H), 3.31 (s, 3H), 6.91 (d, 1H) 7.27 (m, 4H), 7.59 (d, 1H), 8.01 (m, 2H), 8.24 (m, 3H), 9.56 (s, 1H), 10.15 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+426.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)(=[O:11])=[O:10])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)cc(F)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of 3,5-difluoro-benzenesulfonyl chloride (252 mg, 1.19 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (300 mg, 1.19 mmol) in CH2Cl2 (7 mL) was added anhydrous pyridine (144 μL, 1.77 mmol, 1.50 equiv.) and the vial capped and shaken for 72 h. The reaction solution was transferred to a separatory funnel with CH2Cl2 (100 mL), washed with 1M citric acid solution (100 mL), water (50 mL×4), brine (100 mL), dried (MgSO4), filtered and evaporated to give a white solid (300 mg, 59%). Mass Spectrum (−ESI): 427.8 [M−H]−
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:15]1([CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[OH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:15]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: ClCCCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 10 g of 2-(6-chlorohexyloxy)tetrahydropyrane, 25 g of hydroquinone, 31 g of potassiumcarbonate, 0.752 g of potassiumiodide and 250 ml of dimethylsulfoxide was allowed to react for 4 days at 80° C. Subsequently, the reaction mixture was cooled to room temperature and after addition of water extracted with ether. The organic phase was then dried over sodium sulphate, filtered and concentrated to dryness. Chromatography on silica with 10% ethylacetate in toluene gave 11 g of product as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and ethanesulfonyl chloride (45 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give ethanesulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 379.20.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])(=[O:9])=[O:8])[N:3]=1.[C:19](OCC)(OCC)([O:21][CH2:22][CH3:23])[CH3:20]>C(#N)C.C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][S:7]([C:4]1[N:3]=[C:2]([N:1]=[C:19]([O:21][CH2:22][CH3:23])[CH3:20])[NH:6][N:5]=1)(=[O:9])=[O:8]
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(C)=Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1

Procedure:
6.16 g (20.0 mmol) 5-amino-N-(2,6-dichlorophenyl)-1H-1,2,4-triazole-3-sulphonamide was heated in 50 ml acetonitrile with 4.2 ml (23.0 mmol) triethyl orthoacetate and 3 drops glacial acetic acid for 5 hours under reflux. The mixture was cooled and evaporated to dryness. The residue was recrystallized from ethyl acetate.
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+]>O1CCCC1.CCOCC>[ClH:18].[N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH2:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1N1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of 17.18 g (0.078 mole) of 2(1-indolinyl)benzonitrile of Example 1a in 150 ml dry tetrahydrofuran (THF) was added dropwise to a rapidly stirred ice cold solution of BH3 in THF (236 ml of 1 M solution; 0.236 mole) under nitrogen. At the end of the addition the resultant solution was permitted to warm to room temperature and stir for 3 hours and then heated at reflux for 50 minutes. The product was then cooled to 0° C., treated dropwise with 6 N HCl (100 ml), and permitted to stand overnight (about 16 hours) at room temperature. The reaction mixture was cooled to 0° C. and made basic using solid NaOH. The resulting aqueous layer was extracted with ether (200 ml) and the combined organic portions were washed twice with brine (200 ml portions), dried over K2CO3, and concentrated to afford 21.1 g of crude free base. The free amine was dissolved in dry ether (300 ml), cooled to 0° C., and treated with gaseous HCl. The resulting salt was filtered, washed with dry ether (300 ml), and dried under vacuum at 40° C. thus affording 19.25 g (94.4%) of crude salt, m.p. 226°-228° C. Recrystallization of 15.59 g of the crude salt from methanol-ether afforded 10.49 g (67.3% recovery) of 2-(1-indolinyl) benzenemethanamine hydrochloride, m.p. 231°-232° C.
Reaction SMILES: [Br:1]Br.Cl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14])(=[O:6])[CH3:5].N>C(O)(=O)C>[C:4]([C:7]1[CH:8]=[C:9]([Br:1])[C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:14])[CH3:15])(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(N)c(CN(C)C)c1
Reactant: BrBr
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(CN(C)C)c1

Procedure:
9.0 gm of bromine were added dropwise to a solution of 12.8 gm of 5-acetyl-2-amino-N,N-dimethyl-benzylamine hydrochloride in 100 ml of 80% acetic acid. Subsequently, the reaction mixture was made alkaline with 2 N ammonia, extracted twice with chloroform, and the organic extract was evaporated. By recrystallization of the residue from ethanol/water, 5-acetyl-2-amino-3-bromo-N,N-dimethyl-benzylamine, m.p. 92°-95°C, was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH:10][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: Nc1cccc2sccc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a stirred solution of benzo[b]thiophen-4-amine (1 g, 6.70 mmol) and pyridine (1.355 mL, 16.75 mmol) in CH2Cl2 (15 mL) was added dropwise methanesulfonyl chloride (0.574 mL, 7.37 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature while stirring overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, water, brine and dried over sodium sulfate. Evaporation of the solvent furnished a crude residue, which was subjected to BIOTAGE® (100% methylene chloride) to give the title compound as a white solid (1.2 g, 79%). LC/MS: Example 105A @ 2.88 min (RT) (Condition H). MS (ES): m/z=226.0, [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 7.77 (1 hr, d, J=7.81 Hz), 7.59 (2 hr, d, J=1.26 Hz), 7.25-7.42 (2 hr, m), 2.94 (3 hr, s).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH3:12]>C(Cl)(Cl)(Cl)Cl.[W]>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][Br:1]
Reactant: Cc1c(F)ccc(F)c1Cl
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(F)c(CBr)c1Cl
Temperature: 0 °C
Yield: 81.9 %

Procedure:
A solution of bromine (24.4 g) in carbon tetrachloride (50 ml) was added slowly over a period of 2 hours 45 minutes to a vigorously stirred solution of 2-chloro-3,6-difluorotoluene (24.4 g) in carbon tetrachloride (150 ml) irradicated by a 200 watt tungsten lamp maintained at 0° C. The solvent was removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-3,6-difluorobenzyl bromide (29.7 g) b.p 96°-101°/0.7 cm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH2:15])=[O:14].C(N)CN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([NH:15][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Fc1c(I)ccnc1Cl
Reactant: NC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A mixture of 2-chloro-3-fluoro-4-iodopyridine (4.78 g, 18.6 mmol), 2-chloro-6-nitrobenzamide (3.91 g, 19.5 mmol), ethane-1,2-diamine (0.2 mL, 2.97 mmol), copper(I) iodide (0.57 g, 2.97 mmol) and K3PO4 (7.90 g, 37.2 mmol) in dioxane (80 mL), was degassed with a stream of argon and the reaction mixture was then heated under reflux for 4 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with dioxane. The filtrate was concentrated to dryness under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in petroleum ether (40-60° C.), to afford the title compound as a pale yellow solid (1.87 g, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.42-11.37 (br s, 1H), 8.35-8.24 (m, 3H), 8.08 (dd, J=1.1, 8.1 Hz, 1H), 7.81 (t, J=8.2 Hz, 1H).