Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([OH:28])=[CH:25]2)=[CH:20][CH:19]=1.Br[C:30]1[C:31]([NH2:36])=[N:32][CH:33]=[CH:34][CH:35]=1>[Cu]I.O.CS(C)=O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([O:28][C:30]3[C:31]([NH2:36])=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25]2)=[CH:20][CH:19]=1
Reactant: Nc1ncccc1Br
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccn1
Solvent: CS(C)=O
Product: COc1ccc2ccc(Oc3cccnc3N)cc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
A mixture of picoline acid (0.427 g), tripotassium phosphate (11.04 g), copper (I) iodide (0.660 g), 7-methoxynaphthalen-2-ol (6.04 g), 3-bromopyridin-2-amine (3 g) and DMSO (50 mL) was stirred under a nitrogen atmosphere at 140° C. overnight. Water was added, and the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.667 g) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C1(C)C=CC=CC=1>[C:10]([C:3]1[C:4]([S:7][CH2:8][CH3:9])=[N:5][S:6][C:2]=1[NH:1][C:13](=[O:14])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCSc1nsc(N)c1C#N
Solvent: Cc1ccccc1
Product: CCSc1nsc(NC(=O)Oc2ccccc2)c1C#N

Procedure:
Under a nitrogen atmosphere, a mixture of 45.0 g of 5-amino-4-cyano-3-(ethylthio)isothiazole and 47.0 g of phenyl chloroformate in 175 ml of dried toluene was heated under reflux for 16 hours; thin-layer chromatography indicated the reaction to be complete. The reaction mixture was cooled to 10°, and the solid collected by filtration to obtain 66.2 of phenyl (4-cyano-3-(ethylthio)-5-isothiazolyl)carbamate, m.p. 223°-225° after recrystallization from acetic acid. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C1C2CCC3C=CC=CC=3N(C(Cl)=O)C=2C=CC=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][C:50]=1[O:51][CH3:52])[N:47]=[CH:46][CH:45]=[C:44]2[O:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][C:55]=1F.C1(C)C=CC=CC=1>C(O)C>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][C:37]([NH:58][C:57]3[CH:59]=[CH:60][C:54]([O:53][C:44]4[C:43]5[C:48](=[CH:49][C:50]([O:51][CH3:52])=[C:41]([O:40][CH3:39])[CH:42]=5)[N:47]=[CH:46][CH:45]=4)=[CH:55][CH:56]=3)=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)N1c2ccccc2CCc2ccccc21
Agent: O=C(N=C=S)N1c2ccccc2CCc2ccccc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4c5ccccc5CCc5ccccc54)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was prepared using commercially available 10,11-dihydro-5H-dibenzo(b,f)azepine-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 65%).
Reaction SMILES: [Se]=[O:2].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1>O1CCOCC1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([CH:3]=[O:2])=[CH:5][CH:6]=[N:7]2)=[CH:12][CH:11]=1
Reactant: COc1ccc2c(C)ccnc2c1
Reactant: O=[Se]
Solvent: C1COCCO1
Product: COc1ccc2c(C=O)ccnc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
A mixture of 1.9 g of selenium oxide dissolved in 35 ml of dioxane is added dropwise to a solution of 2.7 g of 4-methyl-7-methoxyquinoline in 35 ml of dioxane preheated to 65° C. At the end of the addition, the brown suspension is heated to a temperature in the region of 80° C. for 5 hours. The reaction medium is stirred for 16 hours at a temperature in the region of 20° C. The greenish suspension is suction-filtered and then washed with EtOAc. The filtrate is concentrated under reduced pressure. The suspension obtained is crystallized from isopropyl ether to give 1.54 g of 7-methoxyquinoline-4-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16].[OH-].[K+].Cl>O>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc(Cl)c(N)c(OC)c1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C(=O)O)cc(Cl)c(N)c1OC
Yield: 84.7 %

Procedure:
A mixture of intermediate (2-d) (0.27 mol) and potassium hydroxide (2.7 mol) in water (1000 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled and acidified with hydrochloric acid (36%), and the resulting precipitate was filtered off, washed with water and dried, yielding 53 g (84.8%) of 4-amino-5-chloro-2,3-di-methoxybenzoic acid (intern. 2-e).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.Cl>O1CCCC1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:46]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:47])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2)N1CCOCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.4 %

Procedure:
To the solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.009 mL, 0.064 mmol). The mixture was cooled to 0° C. and 4-morpholinecarbonyl chloride (0.004 mL, 0.035 mmol) was added. The reaction mixture was warmed to 23° C. and stirred for 15 hours. 1 N hydrochloric acid (0.065 mL, 0.064 mmol) was added and the mixture was then concentrated under reduced pressure. The product was washed with diethyl ether and water to give the title compound (7.5 mg, 40%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (500 MHz, DMSO-d6) δ 3.57 (t, 4 H) 4.38 (d, J=4.88 Hz, 2 H) 5.60 (bs, 2 H) 7.11 (m, 2 H) 7.27 (m, 6 H) 7.38 (m, J=7.32, 3.05 Hz, 1 H) 7.49 (m, J=7.32 Hz, 1 H) 7.73 (bs, 1 H) 8.21 (d, J=7.32 Hz, 1 H).
Reaction SMILES: FC(C1NC(=O)C2N=CC=CC=2N=1)(F)F.O=P(Cl)(Cl)[Cl:18].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[CH:25][C:26]2[N:27]=[CH:28][NH:29][C:30](=O)[C:31]=2[N:32]=1>>[Cl:18][C:30]1[C:31]2[N:32]=[C:23]([C:22]([F:35])([F:34])[F:21])[CH:24]=[CH:25][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=c1[nH]c(C(F)(F)F)nc2cccnc12
Product: FC(F)(F)c1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
The title compound was prepared from trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one using the procedure described in Example 599, Step 2. A POCl3 (9.3 ml) suspension of 6-Trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one (1.0 g, 4.7 mmol) was heated at reflux for 4 hours, over which time the amber suspension became a clear, deep blue solution. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue concentrated from dichloromethane 3× to remove residual POCl3. The residue was partitioned between 1:1 EtOAc and saturated sodium bicarbonate (28 ml). The mixture was stirred until visible gas evolution ceased. The suspension was filtered through a plug of celite. The layers of the filtrate were separated, and the organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried with magnesium sulfate and concentrated under reduced pressure to yield the semi-pure product as a purple solid. No further purification was carried out. The crude product was greater than 90% pure (as determined by analytical HPLC). MS: ES+ 234.11 (M+H, 100%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6].C=O.Cl.[CH:19](Cl)(Cl)[Cl:20]>[Cl-].[Zn+2].[Cl-]>[Cl:20][CH2:19][C:15]1[CH:14]=[CH:13][C:4]([C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)CCC(=O)c1cccc(O)c1
Agent: C=O
Agent: Cl
Agent: [Cl-]
Product: COC(=O)CCC(=O)c1ccc(CCl)c(O)c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(3-hydroxybenzoyl)propionate in chloroform at -5° to 0° was added paraformaldehyde and zinc chloride. Dry hydrogen chloride was passed through the well-stirred solution until the saturation point was reached and the stirring was continued for a further hour at room temperature. The reaction mixture was then poured into ice-water, the product extracted into dichloromethane and the organic layer washed with water and dried over magnesium sulphate. Evaporation of the dichloromethane gave an oily residue from which methyl 3-(4-chloromethyl-3-hydroxybenzoyl)-propionate was obtained by crystallisation from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 44.2 %

Procedure:
Using 1-(tert-butoxycarbonyl)-3-hydroxypiperidine (201 mg, 1.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (258 mg, 1.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 187 mg (44%) of the desired compound as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][N:4]([CH2:22][O:23][CH3:24])[N:3]=1.[BH4-].[Na+].O>CO>[I:1][C:2]1[C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:5][N:4]([CH2:22][O:23][CH3:24])[N:3]=1
Reactant: COCn1cc(C=NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCn1cc(CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Reaction time: 3 h
Yield: 19.3 %

Procedure:
N-((3-Iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methylene)-4-(trifluoromethyl)benzenesulfonamide (41) (7.41 g, 15.66 mmol) was suspended in MeOH (20 mL). NaBH4 was added portionwise and the reaction was stirred for 3 hr until TLC monitoring revealed the disappearance of starting material. Water (20 mL) was added and MeOH was removed in vacuo. The residue was taken up in EtOAc (100 mL) and washed with sat. aq. NaHCO3 (100 mL) and dried over Na2SO4. The reaction was concentrated in vacuo. The resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield N-((3-iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (42) (1.44 g, 37% over two steps) as a clear oil that solidified upon standing.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:50][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2cnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Temperature: 100 °C
Yield: 67 %

Procedure:
A suspension of protected oxazolidine-amide 6 (180 mg, 1.0 equivalent) and Lawesson's Reagent (390 mg, 3.0 equivalents) in toluene (5 mL) was sealed and heated at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) as a thick colourless oil in 67% yield (120 mg). TLC (1:2 EtOAc:Hex), Rf=0.8; MS (ESI, M+H+)=571.11; 1H NMR (400 MHz, CDCl3) δ 7.73 (br s, 1H), 7.70 (s, 1H), 7.61 (d, 1H, J=6.8 Hz), 7.01 (d, 1H, J=6.8 Hz), 3.96-4.28 (m, 4H), 1.21-1.99 (m, 30H), 0.89 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([O:16]CC)=O)[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([NH:20][NH2:21])=[O:16])[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: NN
Reactant: CCCN1CCc2cc(C(=O)OCC)sc2CC1
Solvent: O
Solvent: CCO
Product: CCCN1CCc2cc(C(=O)NN)sc2CC1

Procedure:
13.0 gm (0.0486 mol) of ethyl 5,6,7,8-tetrahydro-6-propyl-4H-thieno[2,3-d]azepine-2-carboxylate were dissolved in 15 ml of absolute ethyl alcohol, and the solution was refluxed for 3 hours with 14 ml (0.23 mol) of 80% hydrazine hydrate. After cooling, the mixture was concentrated by evaporation in vacuo, and the residue was recrystallized from isopropyl alcohol.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([NH2:25])[CH:3]=1.[OH-].[Na+].Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N:25]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cn2c(CF)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cn2c(CF)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 110 °C
Yield: 33.9 %

Procedure:
Into a 100 ml round bottomed flask with 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.3 g, 5.53 mmol), tetrabutylammonium iodide (0.102 g, 0.276 mmol) was added 6N sodium hydroxide (13.82 ml, 83 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.378 ml, 11.05 mmol). Reaction was heated to 110° C. for 2 h then cooled to room temperature and the mixture was extracted with EtOAc, washed with Brine and concentrated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 50% over 10 column volumes. The appropriate fractions were collected and evaporated to yield 4-(4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (911 mg, 1.873 mmol, 33.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 3.04-3.11 (m, 4H) 3.77-3.85 (m, 4H) 5.40 (s, 2H) 5.42-5.60 (m, 2H) 6.45 (d, J=2.02 Hz, 1H) 6.53 (d, 1H) 7.12 (t, J=7.83 Hz, 1H) 7.21 (d, J=2.02 Hz, 1H) 7.56 (d, J=7.83 Hz, 1H); LC/MS: MS (ES+) m/e 487 [M+H]+.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C(Cl)Cl>[CH2:12]([NH:14][C:15]([N:9]1[CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1)=[O:16])[CH3:13]
Reactant: C#CCCCN1CCNCC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: C#CCCCN1CCN(C(=O)NCC)CC1

Procedure:
A solution of 1-(pent-4-ynyl)piperazine (1.08) in DCM (5 mL) was treated with ethyl isocyanate (0.56 mL) at rt for 2 h, and evaporated to yield N-ethyl-4-(pent-4-ynyl)piperazine-1-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=O)[C:13]([CH3:15])=[CH2:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[OH-].N>CCO>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[C:12]([C:13]([CH3:15])=[CH2:14])[NH:9][C:7]2=[O:8]
Reactant: C=C(C)C(=O)Nc1ccc(Cl)cc1C(N)=O
Agent: N
Agent: [OH-]
Solvent: CCO
Product: C=C(C)c1nc2ccc(Cl)cc2c(=O)[nH]1

Procedure:
5-Chloro-2-(2-methyl-acryloylamino)-benzamide (1.5 mmoL) in EtOH (10 mL) was treated with ammonia hydroxide (˜3.0 mmoL) at 80° C. for 4 h. The reaction was then cooled down and the solvent was removed. The reaction mixture was then partitioned between DCM and water. The organic layer was washed with sat. NH4Cl, brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:7]=1[CH:6]=[CH:5]2
Reactant: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)cc3c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)c(Cl)c3c21
Temperature: 50 °C
Reaction time: 5 h
Yield: 22.2 %

Procedure:
To a solution of N-{2-[(8S)-2-methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl]ethyl}acetamide (80 mg, 0.311 mmol) in acetonitrile (3.1 mL) was added N-chlorosuccinimide (45.7 mg, 0.342 mmol), and the mixture was stirred at 50° C. for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90), preparative HPLC (acetonitrile/water=10/90→90/10) and recrystallization (ethyl acetate/hexane) to give the title compound (20.1 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6](=[O:13])[CH2:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6](=[O:13])[CH2:5]2
Reactant: COc1ccc(CN)cc1
Reactant: O=C1Cc2cc(Br)ccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)Cc3cc(Br)ccc3C2=O)cc1
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-isochroman-1,3-dione (0.6 g) (product of step ii)) and 4-methoxybenzylamine (0.313 g) in toluene:acetic acid (4:1, 20 mL) was heated at reflux for 17 hours. The reaction mixture was evaporated and the residue was dissolved in dichloromethane before washing with 2N hydrochloric acid. The organic phase was dried, filtered and evaporated then triturated with diethyl ether to yield the sub-title compound (680 mg).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:28][C@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:28])[CH2:34]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CCN1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.18 mmol) was used in general procedure 3 with (S)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (S)—N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 468.3 (M)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([N+:29]([O-])=O)=[C:27](O)[C:22]=4[O:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[CH:40]([OH:43])[CH2:41][CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>Cl.[Fe].C1COCC1>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[CH:40]([O:43][C:27]1[C:22]2[O:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[C:23]=2[CH:24]=[N:25][C:26]=1[NH2:29])[CH2:41][CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3coc4c(O)c([N+](=O)[O-])ncc34)cn2)CC1
Reactant: CCC(O)c1c(Cl)cccc1Cl
Agent: [Fe]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1c(Cl)cccc1Cl
Temperature: 50 °C

Procedure:
General procedure AA: To a mixture of 4-[4-(7-hydroxy-6-nitrofuro[3,2-c]pyridine-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.047 mmol), 1-(2,6-dichlorophenyl)propan-1-ol (28.6 mg, 0.14 mmol), triphenylphosphine (24.4 mg, 0.093 mmol) and THF (2 mL) at rt was added diisopropyl azodicarboxylate (37.7 mg, 0.186 mmol) dropwise, and the solution was flushed with nitrogen and heated to 50° C. for 4 h. The solvents were removed in vacuo, and the material was redissolved in EtOH (3 mL). Iron powder (30 mg, 0.5 mmol) and 5 drops of conc. HCl were added, and the solution was refluxed for 30 min. The solution was directly passed through a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The crude product was concentrated in vacuo, redissolved MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.06 (t, J=7.5 Hz, 3H), 1.93-2.05 (m, 2H), 2.09-2.17 (m, 2H), 2.33 (dt, J=13.7, 7.5 Hz, 1H), 2.48 (dd, J=14.3, 6.9 Hz, 1H), 2.78 (td, J=12.7, 2.7 Hz, 2H), 3.16-3.24 (m, 2H), 4.35 (tt, J=11.7, 4.1 Hz, 1H), 6.43 (t, J=7.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.80 (s, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 8.13 (s, 1H). MS (ES+): m/z 498.06/500.05 (100/72) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min).