Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[Si]([N:29]=[N+:30]=[N-:31])(C)(C)C>C1(C)C=CC=CC=1>[NH:29]1[C:20]([C:19]2[CH:22]=[CH:23][C:16]([C:7]3[C:6](=[O:24])[C:5]4[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=4)[O:9][C:8]=3[C:12]([F:15])([F:13])[F:14])=[CH:17][CH:18]=2)=[N:21][N:31]=[N:30]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C(F)(F)F)oc2cc(O)ccc12

Procedure:
To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzonitrile (50 mg, 0.15 mmol) in toluene (2 ml), was added TMSN3 (296 mg, 2.72 mmol) and Bu2SnO (10 mg, 0.045 mmol) at room temperature. The mixture was refluxed overnight. The volatiles were removed under reduced pressure. The residue was purified by prep-HPLC to afford desired product in Example 1 as a yellow powder (19.4 mg, 34.6%).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.Br[CH2:29][C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=O>C(O)C>[Br:27][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]([NH:12][C:10]2[S:11][CH:29]=[C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[N:9]=2)=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (3.00 g, 8.77 mmol; prepared according to Example 179, Step D), TEA (2.08 mL, 14.9 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (3.49 g, 11.4 mmol) were refluxed in ethanol (75 mL) for 2 hours. The reaction was cooled to room temperature and filtered to afford the title compound (3.6 g, 74.7% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12](OC)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:19])=O.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:19][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][N:13]=1
Reactant: COc1ccc(CCCn2ccnc2)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CCCn2ccnc2)cn1
Temperature: 100 °C
Reaction time: 10 h
Yield: 59.7 %

Procedure:
A mixture of 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine(2.10 g), phosphorus oxychloride (7.44 g) and N,N-dimethylformamide (14.6 g) was stirred at 100° C. for 10 hours. To the reaction mixture was added saturated aqueous sodium acetate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel chloromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.28 g, 60%) was obtained. Oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][C:21]([O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:26]2[CH2:25][CH2:24][CH:23]([O:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:31])[F:32])=[CH:30][CH:29]=3)[CH2:28][CH2:27]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-[4-(trifluoromethyl)phenoxy]piperidine (16.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C23H21F3N2O3: 430.1504, found 430.1510.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].C([O-])(O)=O.[Na+]>CC#N>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([S:25][CH3:24])[CH:27]=2)[N:11]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Reactant: CSc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(SC)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
A mixture of methyl 2,6-dichloro-4-cyanonicotinate (340.8 mg, 1.475 mmol), DIPEA (0.3 mL, 1.718 mmol) and 3-(methylthio)aniline (234.8 mg, 1.687 mmol) in CH3CN (5 mL) was stirred at 60° C. for 2 days. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE and filtered to give the title compound as a yellow solid (157.8 mg). The filtrate was purified by column chromatography (SiO2, hexanes/EtOAc=8/1) to give another crop (135.5 mg) of the title compound as a yellow oil of (total 293 mg, 60%). 1H-NMR (CDCl3) δ ppm 2.52 (s, 3H), 4.05 (s, 3H), 7.00 (s, 1H), 7.03-7.05 (m, 1H), 7.25-7.32 (m, 2H), 7.66-7.67 (m, 1H), 10.51 (br s, 1H). [M+H] calc'd for C15H13ClN3O2S, 334. found, 334.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])[CH3:4].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1>[CH2:3]([N:5]([CH3:10])[C:6]([N:8]([CH3:9])[C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19])=[O:7])[CH3:4]
Reactant: O=C=Nc1ccccc1
Reactant: CCN(C)C(=O)NC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)C(=O)N(C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
In 300 ml of anhydrous tetrahydrofuran, 2.9 g (0.06 mole) of sodium hydride (50% in oil) was added thereto. The mixture was cooled below 10° C. and 7.0 g (0.06 mole) of 1-ethyl-1,3-dimethylurea was added to the mixture under stirring. The reaction was then continued at a room temperature for 15 hours. Next the reaction mixture was cooled below 0° C. and 7.1 g (0.06 mole) of phenyl isocyanate was added dropwise with stirring. The reaction was continued at about 0° C. for 3 hours, then the solvent was removed by distillation under reduced pressure to obtain a residue. Ice-water was added to the residue and 1 N-hydrochloric acid was added to make the mixture acidic, then extracted with chloroform. The extracted liquor was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain a residue. The residue was recrystallized from ethanol-petroleum ether to obtain 7.2 g (yield, 51%) of 1-ethyl-1,3-dimethyl-5-phenylbiuret having a melting point of 88.5°-90.5° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.Cl.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[NH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C1C=CC=CC=1)CC>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][CH:3]=2)[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: Clc1ccnc2ccnn12
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(Nc2ccnc3ccnn23)cc(C(C)(C)C)c1O
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A suspension of 7-chloropyrazolo[1,5-a]pyrimidine (1.0 g), 3,5-di-t-butyl-4-hydroxyaniline hydrochloride (1.8 g) and diethylaniline (2.3 ml) in toluene (50 ml) is heated at 120° C. for 30 minutes. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; CHCl3) to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)aminopyrazolo[1,5-a]pyrimidine (890 mg) as colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([C:22]2[CH:27]=[C:26]([NH:28][CH3:29])[N:25]=[CH:24][N:23]=2)[N:20]=[C:19]([CH3:30])[CH:18]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:3]([NH:16][C:17]2[N:21]([C:22]3[CH:27]=[C:26]([NH:28][CH3:29])[N:25]=[CH:24][N:23]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)OC(C)(C)C)ccc2C)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(-n2nc(C)cc2Nc2cc(N)ccc2C)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-methyl-3-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenylcarbamate 38 (2.0 g) is dissolved in a mixed solvent of TFA:DCM/1:1 (20 mL). The mixture is stirred at room temperature for 4 hours, then concentrated in vacuo. The residue is dissolved in EtOAc and washed with aqueous NaHCO3. The organic layer is separated, dried with MgSO4, then concentrated in vacuo to provide 6-methyl-N1-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-yl)benzene-1,3-diamine 39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=2[N:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2[nH]c(-c3n[nH]c4ccc(Cl)cc34)nc2c1
Temperature: 100 °C

Procedure:
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and EtOH. The reaction mixture was heated to 100° C. for 18 hours. The solvent was then evaporated, and the residue was purified by reverse phase HPLC yielding a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1(C)[C:11](S(O)(=O)=O)=CC=C[CH:15]=1>COC(OC)(C)C.C1C=CC=CC=1>[OH:2][C:1]1[C:3]2[O:4][C:10]([CH3:11])([CH3:15])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Oc1cccc(O)c1O
Solvent: c1ccccc1
Solvent: COC(C)(C)OC
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
A solution of pyrogallol (63 parts) in 2,2-dimethoxypropane (100 parts) and benzene (100 parts) containing toluenesulphonic acid (0.01 parts) was slowly distilled through a fractionating column during 4 hours, removing liquid (150 parts), boiling point 57°-64° C. A few drops of triethylamine were then added and the mixture thoroughly washed with water, dried and evaporated. Distillation gave 4-hydroxy-2,2-dimethyl-1,3-benzodioxole (36 parts), boiling point 110° C/0.7 mm., which was purified by recrystallisation from carbon tetrachloride. Melting point 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[CH:13]([NH2:15])=O>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:13][NH:15][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cnc(Cl)cc12
Yield: 86 %

Procedure:
A solution of 5-amino-2-chloropyridine-4-carboxylic acid (8.1 g, 4.7 mmol) in formamide (100 mL) is stirred at 140° C. for 12 h. Dilution of the cooled mixture with water gives a precipitate of 6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (7.3 g, 86% yield). 1H NMR (DMSO) 6 12.73 (1H, m), 8.90 (1H, d, J=0.7 Hz), 8.23 (1H, s 7.97 (1H, d, J=0.7 Hz).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to a solution of 136 mg (0.37 mmol) of N-benzyl-4′-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml, of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 117 mg (84.3% of theory) of the title compound are obtained.
Reaction SMILES: [OH2:1].[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1>O>[CH:8]1[CH:9]=[CH:10][C:5]2[N:4]([OH:1])[N:3]=[N:2][C:6]=2[CH:7]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O
Product: On1nnc2ccccc21

Procedure:
H2O: 1H-benzotriazole monohydrate
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1c(CCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-3-yl)pentanoate (1.1 eq., prepared in Synthetic Example 9) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 172 to 173° C./DMF-EtOH. 1H NMR(CDCl3) δ: 2.02-2.11(2H, m), 2.71-2.79 (4H, m), 7.18-7.24 (2H, m), 7.54-7.92(5H, m), 8.19-8.20 (1H, m), 8.34-8.49(4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:34]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]3[C:19](=[O:34])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1-c1ccccc1C2=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 1-(4-fluorophenyl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (368 mg) in THF was added sodium hydride (38 mg) and was stirred at room temperature for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; yield 91%; mp 180-182° C.; ESMS 383 (M++1); IR (KBr) 1707 cm−1 (CO), 2219 (CN); 1H NMR (300 MHz, CDCl3) δ 1.69-1.75 (m, 2H, CH2), 1.80-1.89 (m, 4H, 2CH2), 3.39-3.44 (m, 4H, 2CH2), 6.63 (s, 1H, ArH), 7.16 (t, J=8.6 Hz, 2H, ArH), 7.41 (t, J=7.6 Hz, 1H, ArH), 7.46-7.53 (m, 2H, ArH), 7.56-7.65 (m, 2H, ArH), 8.37 (d, J=7.6 Hz, 1H, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>C(COC)OC>[Cl:12][CH2:13][C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]2[CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: COCCOC
Product: FC(F)(F)c1ccc2nc(CCl)cn2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
A mixture of 2-amino-5-trifluoromethylpyridine (Fluorochem; 3.19 g), 1,3-dichloroacetone (Aldrich; 3.00 g), and dimethoxyethane (Aldrich; 15 mL) is stirred at room temperature for 4 days. The resulting solid is collected and washed with several milliliters of dimethoxyethane. The solid is then taken up in ethanol (30 mL) and the mixture is heated at 80° C. for 2.5 h, at which time diisopropylethylamine (Aldrich; 3.5 mL) is added. After stirring with heating an additional 3.5 h, the mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate and concentrated; the residue is chromatographed on silica gel using methanol/dichloromethane (1/99) to give 3.33 g of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine. 1H NMR (CDCl3) δ 4.78, 7.36, 7.69, 7.73, 8.48.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16].B(Cl)(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:15]([C:4]1[CH:5]=[C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][C:3]=1[OH:2])(=[O:17])[CH3:16]
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(O)c(C(C)=O)c1
Reaction time: 0.17 h

Procedure:
Titanium tetrachloride (82.3 mls) was added dropwise to a stirred solution of methyl 2-(4-methoxyphenyl)propionate (25g) in dry dichloromethane (250 mls), cooled in an ice/salt-bath, at a rate sufficient to maintain the temperature between -10° C and -5° C. The mixture was stirred for 10 minutes and acetyl chloride (10g) was added dropwise at a rate sufficient to maintain the temperature below 0° C. The solution was stirred at -5° C for 11/2 hours when boron trichloride (15 mls) was added. Stirring was continued for one half hour at +3° C before pouring on to crushed ice/concentrated hydrochloric and separating the two phases. The aqueous phase was extracted with ether (3x) and the combined organic extracts were washed with saturated sodium bicarbonate solution, saturated brine solution, and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the crude product as a pale yellow oil. Vacuum distillation furnished a pale yellow oil bp 120°-125° C/ 0.15mm (16.2g; 59%)
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:9]3[CH:19]=[CH:20][S:21][C:8]3=[C:7]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[C:5]=2[CH:6]=1.[Cu][C:32]#[N:33]>>[CH2:29]([CH:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][O:22][C:7]1[C:8]2[S:21][CH:20]=[CH:19][C:9]=2[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]2[S:3][C:2]([C:32]#[N:33])=[CH:6][C:5]=12)[CH3:30]
Reactant: CCCCC(CC)COc1c2cc(Br)sc2c(CC(CC)CCCC)c2ccsc12
Reactant: N#C[Cu]
Product: CCCCC(CC)COc1c2cc(C#N)sc2c(CC(CC)CCCC)c2ccsc12
Yield: 37.5 %

Procedure:
A dry 100-mL three-neck flask, equipped with a condenser, charged with 6-bromo-8-(2-ethylhexoxy)-4-(2-ethylhexyl)thieno[2,3-f]benzothiophene (4.2 g, 8.2 mmol) and flushed with N2. Deoxygenated pyridine (15 mL, 0.5 M) was then added via syringe. Copper (I) cyanide (2.2 g, 25 mmol) was added to the reaction flask and the mixture was evacuated and refilled with nitrogen three times. The reaction flask was heated to reflux for 48 hours. As the reaction was completed, the reaction mixture was poured into 50 mL of water and extracted with MTBE (50 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The product was purified using column chromatography on silica gel with hexanes/ethyl acetate (gradient) to yield oil (1.4 g, 38%).
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:22]([O:24]C)=[O:23])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=O)C.[OH-].[Na+].Cl>C1COCC1.O>[SH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:22]([OH:24])=[O:23])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(-c2ccc(CSC(C)=O)cc2C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccc(CS)cc2C(=O)O)c1
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a solution of 4-acetylthiomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.27 g, 0.75 mmol) in deoxygenated THF was added a degassed solution of sodium hydroxide (0.12 g, 3.0 mmol) in H2O (5 mL) at rt. After 24 h, additional solution of sodium hydroxide (0.09 g) in H2O (2 mL) was added to the reaction mixture and the mixture was stirred for 24 h. The mixture was acidified with 10% HCl and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The crude material was purified by column chromatography with (9:1 dichloromethane/EtOAc with 1% acetic acid) to afford 4-mercaptomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid (0.20 g, 92%) as a white solid: 1H NMR (DMSO-d6) δ 3.10 (t, J=8.03 Hz, 1H), 3.89 (d, J=8.03 Hz, 2H), 7.43 (d, J=7.53 Hz, 1H), 7.58–7.65 (m, 3H), 7.83 (d, J=2.01 Hz, 1H), 7.92 (s, 1H), 7.97–8.00 (m, 1H). Anal. Calcd. for C15H12O4S.0.5AcOH: C, 60.37; H, 4.43; O, 25.13; S, 10.07. Found: C, 60.28; H, 4.45; S, 10.15.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.Cl.O>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:13]2
Reactant: CC(=O)OC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)OC1Cc2ccc(N)cc2C1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A slurry of 8.0 g (0.045 moles) of 2-acetoxy-5-nitroindan in 25 ml of absolute ethanol and 32 ml of concentrated hydrochloric acid was treated over 1 hr with a solution of 24 g (0.11 moles) of stannous chloride in 32 ml of absolute ethanol, with water bath cooling to maintain T=20°C. The mixture was stirred for 1 day at room temperature, diluted with 100 ml of water and extracted twice with ether. The aqueous phase was basified with 10% sodium hydroxide until the hydroxides redissolved, then extracted with chloroform, dried (sodium sulfate) and evaporated to an oil which crystallized to 3.9 g (82%) 5-amino-2-hydroxyindan, the hydrochloride of which had mp 237°-239° after one crystallization from ether-methanol isopropanol.