Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3.[O:19]1[CH2:21][CH:20]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:21][CH:20]([OH:19])[CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: c1ccc(NCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1cc(Br)ccc1n2CC(O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
NaH (0.0023 g of 60% suspension (in oil), 0.093 mmol) was added to a solution of 3-bromo-6-methoxy-9H-carbazole (0.014 g, 0.052 mmol) in anhydrous THF (0.1 mL) at 0° C. and stirred for 30 min. A solution of N-(oxiran-2-ylmethyl)aniline (0.0093 g, 0.062 mmol) in anhydrous THF (0.1 mL) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred for 48 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organics were concentrated and purified by chromatography (SiO2, 0-30% EtOAc/Hexane) to afford the title compound (0.007 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[C:20]([NH2:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:20]1[C:9]([C:4]2[C:3]([Cl:22])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([S:17][CH3:18])=[N:13][C:12]=2[N:19]=1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
To a solution of 6-(3-amino-2,6-dichloro-phenyl)-2-methylsulfanyl-pyrido[2,3-d]-pyrimidin-7-ylamine (0.5 g, 1.42 mmol) in CH2Cl2 (40 mL) is added 3-(trifluoromethyl)benzoyl chloride (1.07 mL, 7.1 mmol). After the mixture is stirred for 24 hours at room temperature, the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by a flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(95/5%), to give the title intermediate as a solid (0.591 g, 79.4 %).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](I)[C:12]([NH2:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:20]=[CH2:21])[C:12]([NH2:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc(N)c(I)cc1CNC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1N
Yield: 42.7 %

Procedure:
To a solution of (4-amino-5-iodo-2-methoxy-benzyl)-carbamic acid tert-butyl ester (700 mg, 1.85 mmol) and tributylvinyltin (783 mg, 2.68 mmol) in toluene was added Pd(PPh3)4 (214 mg, 0.19 mmol) under argon. The resulting mixture was heated with reflux for 8 hrs, filtered through celite, and then concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=2/1 to 1/1) to yield (4-amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 89.5 %

Procedure:
2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 h. cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1–2%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89%) of 2-bromomethyl-benzoic acid methyl ester as a solid.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH2:22](/[C:24](=[CH:30]/O)/[C:25](OCC)=[O:26])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:24]([CH2:22][CH3:23])[C:25](=[O:26])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Reactant: CCOC(=O)/C(=C\O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Temperature: 110 °C
Yield: 30.4 %

Procedure:
A mixture of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (130 mg, 0.427 mmol), ethyl (2Z)-2-ethyl-3-hydroxy-2-propenoate (123 mg, 0.853 mmol) and K2CO3 (118 mg, 0.853 mmol) in DMF (3 mL) was heated with a microwave condition at 110° C. for 1.5 h. After cooling, the mixture was filtered, and purified via MDAP to afford the title compound (50 mg, 30.5% yield) as white solid. LCMS: rt=3.80 min, [M+H+]=385
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.I[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:15]2>>[C:15]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[C:14][CH2:13][CH2:12][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: Ic1ccc2[nH]ccc2c1
Product: CCCCCCC#Cc1ccc2[nH]ccc2c1
Yield: 36 %

Procedure:
When 5-iodo-1H-indole was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the identical process afforded the title compound in 36% yield. 1H-NMR (CDCl3) 0.9 (tr, 3H, J=6.9 Hz); 1.31 (m, 6H); 1.46 (m, 2H); 1.6 (m, 2H); 2.41 (tr, 2H, J=7.1 Hz); 6.49 (m, 1H); 7.14-7.31 (m, 3H); 7.71 (s, 1H); 8.13 (broad s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=1[C:5]1([C:3]([OH:4])=[O:2])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C#N)cc2Cl)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.6 g, 2.0 mmol) is dissolved in THF/water 3:2 (20 mL) and to it, is added LiOH (0.17 g, 4.0 mmol). The mixture is stirred at room temperature for 2 h before being neutralized to pH 6 with 1M HCl. The solution is evaporated to dryness to give acid, 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid as a solid. MS (ESI) m/z 288.2, 290.2 (M+H); 1H NMR (400 MHz, MeOD) (ammonium salt) δ ppm 2.64-2.74 (m, 1H), 2.77-2.86 (m, 1H), 2.94-3.02 (m, 1H), 3.74 (ddd, J=13.1, 9.1, 8.0 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.85 (s, 1H), 7.59 (dd, J=8.1, 1.5 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.91 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 480 (M+H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[S:31][C:30]([NH2:32])=[N:29][CH:28]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C1COCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[S:31][C:30]([NH:32][C:40](=[O:42])[CH3:41])=[N:29][CH:28]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)s4)nc(N4CCOCC4)c3s2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of 5-[6-(4-methanesulphonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-thiazol-2-ylamine (12 mg, 0.024 mmol) in THF (1 ml) at RT triethylamine (8 ul, 0.053 mmol, 2 eq) and acetyl chloride (2 ul, 0.026 mmol, 1.1 eq) was added and the reaction allowed to stir at RT overnight. The solution was extracted into ethyl acetate (10 ml) washing with water (2×10 ml), and dried over MgSO4. The crude material was triturated with diethyl ether to give 401 as a yellow solid (7 mg, 54% yield). NMR (CDCl3, 400 MHz), 2.34 (3H, s), 2.69 (4H, t, J=4.8), 2.83 (3H, s), 3.22 (4H, t, J=4.8), 3.89-3.91 (6H, m), 4.03 (4H, t, J=4.8), 7.33 (1H, s), 8.23 (1H, s), 9.44 (1H, br s). MS: (ESI+): MH+=538
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)ccc1F
Reaction time: 1 h

Procedure:
2,5-Difluoroaniline (100 g, 0.775 mol) is added dropwise to a mixture of concentrated sulfuric acid (4 drops) in acetic anhydride (250 mL) while maintaining the reaction mixture temperature below 15° C. After the addition is complete, the reaction mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with diethyl ether and air dried to give the title product as a white solid, mp 124°-125° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[Cl:11][C:12]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=O>O.C(O)C>[ClH:11].[Cl:11][C:12]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: O=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Product: N=C(N)NN=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
Aminoguanidine hydrogen carbonate (1.24 g, 9.1 mmol) was added to a solution of concentrated hydrochloric acid (0.8 cm3, 9.3 mmol) in water (3 cm3). After diluting the resulting solution with ethanol (20 cm3), 2,6-dichloro-3-nitrobenzaldehyde (2.0 g, 9.1 mmol) was added and the mixture heated under reflux for 7 h. The solution was evaporated under reduced pressure and the residual solid suspended in refluxing ethanol, basified (pH 11) by addition of dilute sodium hydroxide solution and cooled to yield a white solid which was collected. This solid was dissolved in hot methanol and the solution acidified (pH 2) with ethanolic hydrogen chloride, diluted with diethyl ether and cooled to yield (2,6-dichloro-3-nitrobenzylideneamino)-guanidine hydrochloride as a white solid, m.p. 186°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([O:10][CH3:11])[CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:14])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1CO
Product: COc1cc(Cl)ccc1CCl
Yield: 95 %

Procedure:
Step A In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.1 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.560 g, 2.12 mmol) was dissolved in THF (15 mL) and then DIPEA (1.85 mL, 10.6 mmol) was added followed by the addition of pyridin-2-ylmethanamine (0.688 g, 6.36 mmol). Then the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove THF and to this residue water (10 mL) added. The aqueous solution was extracted with CH2Cl2 (25×3 mL) and the organic layer was separated, dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to afford 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.250 g, 35.1%). LCMS Condition B-39: retention time 2.10 min, [M+1]=336.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added piperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 DCM: MeOH) to afford compound 5.
Reaction SMILES: Br[C:2](=[CH2:14])[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Mg].II.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.O>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:14])[C:21]([C:20]1[CH:23]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)[C:25]([F:27])=[CH:26][C:19]=1[F:18])=[O:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: O=Cc1cc(-c2cncnc2)c(F)cc1F
Reactant: C=C(Br)CCCO[Si](C)(C)C(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.99 %

Procedure:
A solution of ((4-bromopent-4-en-1-yl)oxy)(tert-butyl)dimethylsilane (prepared following the procedures of Rostami, Organic Letters, 2007), 9(4), 703-706) (3.30 g, 11.81 mmol) in THF (25 mL) was added to a flask filled with magnesium (0.574 g, 23.62 mmol) and iodine (0.092 g, 0.363 mmol), and the resulting dark brown suspension was stirred at rt for 15 min and then heated under reflux for 45 min. The color changed from brown to deep reddish and the color of iodine faded 10 min under reflux. Eventually, the color of the reaction mixture turned to grey. This regent was cooled to rt and then added to a suspension of 2,4-difluoro-5-(pyrimidin-5-yl)benzaldehyde (Preparation 15, 2 g, 9.08 mmol) in THF (14 mL), and the reaction mixture was stirred at rt for 12 h. Water was added and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-35% EtOAc/Hexane to give 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (0.95 g, 2.270 mmol, 24.99% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (s, 1H), 8.93 (d, J=1.4 Hz, 2H), 7.59 (dd, J=8.2, 7.3 Hz, 1H), 7.20-7.03 (m, 1H), 6.04 (s, 1H), 5.78 (d, J=1.8 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.62-2.41 (m, 2H), 1.85-1.70 (m, 2H), 0.93 (m, 9H), 0.09 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[N:8]=2)[CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CN(C=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:10]1[CH:11]=[CH:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][C:9]1=[O:13]
Reactant: O=c1nc(-c2cccnc2)cc[nH]1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccnc2)ccn1CCCCCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of 4-pyridin-3-yl-1H-pyrimidin-2-one (50 mg, 0.29 mmol) in dry DMF (11 ml), 60% NaH (15 mg, 0.37 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (43 μl, 0.37 mmol) was added at room temperature and the mixture was stirred overnight. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to give 40 mg of the title compound as a solid (54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>O1CCCC1.C(=O)=O.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([NH2:24])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: NC(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.52 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. Liquid ammonia (50 ml) was added to the reaction mixture (cooled in dry ice/acetone bath) and the mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.86 g (52%) of title compound, mp. 248°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH:3]=1.CC(O)=[O:27]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[C:3]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:13]=3)[NH:10][C:4]=2[C:5]([C:6]([NH2:7])=[O:27])=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(F)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccc(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 160 °C

Procedure:
4-Fluoro-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (100 mg, 0.246 mmol) was mixed with Pd(OAc)2 (138 mg, 0.615 mmol) in AcOH (7 mL) in a sealed microwave tube. The mixture was heated in microwave at 160° C. for 90 mins. The mixture was filtered and washed with 5 ml AcOH. The filtrate was concentrated and purified using preparative HPLC to give 4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 342.13 (M+H). 1H NMR (DMSO-d6) δ ppm 11.87 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.03 (dd, 1H, J=8.3, 5.0), 7.83(d, 1H, J=8.6), 7.53 (m, 2H), 7.08(m, 1H), 3.64-3.57 (bm, 8H).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]=1[C:30](=[O:40])[N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:17][C:15]1[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:29])([F:27])[F:28])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]([C:30](=[O:40])[N:31]([CH3:39])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[C:11]([CH:16]=1)[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5]
Reactant: Cc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Yield: 16.7 %

Procedure:
4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid tert-butyl ester (410 mg, 0.7 mmol) was stirred in a mixture of trifluoroacetic acid in DCM (1/1, 3 mL) for 2 hrs. Concentration followed by purification by HPLC gave 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid 20-1 (62 mg). MS: 532.6 (M+H)+; tR=5.29 min (method 3). NMR (CDCl3, reported as the major isomer of cis-trans amide rotamers), δ, 8.54 (1H, s), 7.94 (1H, s), 7.34-7.25 (1H, m), 7.18-7.14 (2H, m), 7.14-7.04 (1H, m), 7.02 (1H, s), 6.92 (1H, s), 4.08 (2H, t, J=6.3 Hz), 3.40 (3H, s), 2.62 (2H, t, J=6.3 Hz), 2.30-2.18 (2H, m), 2.57 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccccc1O
Yield: 92 %

Procedure:
A solution of 200 g (1.218 mole) of 2-hydroxycinnamic acid in 2L of anhydrous methanol was treated with 10 drops of concentrated sulfuric acid. This solution was refluxed for 72 hr., using a Soxhlet extractor charged with 200 g of 3A molecular sieves. The methanolic solution was then concentrated under reduced pressure and cooled to afford 200 g (92%) of white crystals, which were used directly in the next step without additional purification.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:10]1[S:11][C:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[S:8][C:7]=2[CH:9]=1
Reactant: c1cc2sc3ccsc3c2s1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1cc2sc3ccsc3c2s1

Procedure:
Compound 2 was synthesized as shown in Scheme 2. Under acid condition, dithieno[3,2-b:2′,3′-d]thiophene (Organic Syntheses, Vol. 83, p. 209 (2006)) was reacted with NBS affording 2-bromodithieno[3,2-b:2′,3′-d]thiophene 7, which underwent Suzuki cross-coupling reaction with boronic acid R1—B(OH)2 (J. Mater. Chem., 2010, 20, 2182-2189) to afford intermediate 8 in 71% yields. Finally 8 was converted to PhN—OFFT-TCN by reacting with n-BuLi and tetracyanoethylene at low temperature in 85% yield.