Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.CN(C)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C
Solvent: ClCCl
Product: OCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
2.6 g of 1-(2-hydroxyethyl)piperazine was dissolved in a mixture of 20 ml of dry methylene chloride and 10 ml of trimethylamine and stirred at room temperature during the slow addition of a solution of 5.6 g of trityl chloride in 20 ml of dry methylene chloride. When the addition was complete, the solution was stirred for a further 18 hours at room temperature and then evaporated to dryness. Basification with 5% aqueous sodium bicarbonate solution and extraction with methylene chloride gave 4.0 g of 1-(2-hydroxyethyl)-4-triphenylmethylpiperazine, m.p. 82°, used directly in the next stage.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[CH3:65][C:66]1[C:78]([CH3:79])=[CH:77][C:69]2[N:70]([CH2:73][C:74](O)=[O:75])[CH:71]=[N:72][C:68]=2[CH:67]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:74](=[O:75])[CH2:73][N:70]3[C:69]4[CH:77]=[C:78]([CH3:79])[C:66]([CH3:65])=[CH:67][C:68]=4[N:72]=[CH:71]3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: Cc1cc2ncn(CC(=O)O)c2cc1C
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: Cc1cc2ncn(CC(=O)NC(Cc3cc(F)cc(F)c3)c3cnc(-c4ccc(Cl)cc4)o3)c2cc1C

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 9.06-8.94 (m, 2H), 8.10 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.17 (s, 1H), 6.97 (m, 3H), 5.17-4.95 (m, 3H), 3.24-3.07 (m, 1H), 3.04 (dd, J=13.7, 9.7 Hz, 1H), 2.29 (s, 1H), 2.22 (s, 1H). MS (m/z) 520.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OC)(=[O:16])[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)CC(=O)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In dimethylformamide (22 ml), 1-(2-chlorophenyl)ethanone (3.56 g) and dimethyl oxalate (3.26 g) were dissolved, and 60% sodium hydride suspension in oil (1.1 g) was added thereto while stirring at 5° C. The mixture was heated at a room temperature for one hour and then at 50° C. for 30 minutes. After being allowed to cool, the mixture was acidified with 2-N hydrochloric acid, and the precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (3.83 g, 69%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[F:10][C:11]([F:26])([F:25])[C:12]([N:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13].Cl>ClC(Cl)C>[Cl:1][CH2:2][C:3]([C:23]1[CH:22]=[CH:21][C:18]2[CH2:19][CH2:20][N:14]([C:12](=[O:13])[C:11]([F:25])([F:10])[F:26])[CH2:15][CH2:16][C:17]=2[CH:24]=1)=[O:4]
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of chloroacetyl chloride (7.0 g) in dichloroethane (50 ml) was added aluminum chloride (8.2 g) at room temperature, and then a solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g) in dichloroethane (50 ml) was added. The obtained mixture was stirred at room temperature for 3 hr, and poured into ice-cooled 1N is hydrochloric acid (80 ml). Dichloroethane was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (3.5 g) as a colorless powder.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a suspension of 4-(pyrazol-1-yl)benzoic acid (1.56 g) in dichloromethane (25 ml) was added oxalyl chloride (1.04 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours to yield a clear solution. The volatile material was removed under reduced pressure to afford 4-(pyrazol-1-yl)benzoyl chloride as a pale yellow solid (1.58 g), which was utilized without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[N:33]=[C:32]([O:34][C@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:31]([C:40]#[N:41])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl>C1COCC1.O>[C:40]([C:31]1[C:32]([O:34][C@H:35]2[CH2:39][CH2:38][O:37][CH2:36]2)=[N:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:41]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1ncc(C#N)c(O[C@H]2CCOC2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)nc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37Q, 76 mg, 0.13 mmol) was dissolved in THF (2 ml) and water (1 ml), treated with conc. HCl (0.5 ml) and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with DCM (3×). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, 4EP column) to give the title compound as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:47]([O:49][C:50](=[O:68])[CH2:51][CH2:52][C:53]1[O:54][C:55]2[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=2[C:57]=1[CH2:58][CH:59]1[CH2:63][CH2:62][CH2:61][NH:60]1)[CH3:48]>CN1C(=O)CCC1.C(OCC)C>[CH2:47]([O:49][C:50](=[O:68])[CH2:51][CH2:52][C:53]1[O:54][C:55]2[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=2[C:57]=1[CH2:58][CH:59]1[CH2:63][CH2:62][CH2:61][N:60]1[C:13](=[O:15])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[CH3:48]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
A solution containing Boc-L-valine (352 mg, 1.6 mmol) in NMP (3 mL) was treated with HATU (543 mg, 1.4 mmol) followed by NMM (0.2 mL, 1.8 mmol) at ambient temperature. After 10 min, amine 48 (0.4 g, 1.3 mmol) in NMP (5 mL) was added in a dropwise fashion. After 16 h, the reaction mixture was diluted with diethyl ether and washed successively with NaHCO3, 1 M HCl, water, and brine. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated to afford 630 mg (96%) of 49 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.82-7.79 (m, 1H), 7.38-7.35 (m, 1H), 7.28-7.21 (m, 2H), 5.37 (d, J=9.3 Hz, 1H), 4.50-4.44 (m, 1H), 4.31 (dd, J=6.0, 9.0 Hz, 1H), 4.14 (q, J=6.9 Hz, 2H), 3.72-3.60 (m, 3H), 3.38 (t, J=7.2 Hz, 1H), 3.29 (dd, J=3.0, 13.5 Hz, 1H), 3.12 (app t, J=7.5 Hz, 2H), 2.80-2.74 (m, 4H), 2.46-2.35 (m, 2H), 2.11-1.92 (m, 2H), 1.81-1.73 (m, 1H), 1.69-1.65 (m, 1H), 1.44 (s, 9H), 1.25 (t, J=6.0 Hz, 3H), 1.03 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H) ppm. Mass spectrum: m/z 501 [M+H]+; and, 523 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]([C:7]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)OC
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCCCCl)c1cc([N+](=O)[O-])ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of methyl 2-ethoxycarbonylamino-4-nitrobenzoate (4.00 g) in dry dimethylformamide (40 ml) was added sodium hydride (715 mg, 60% oil suspension) in several portions on an ice-bath. After stirring for 1 hour, 1-bromo-4-chlorobutane (2.81 g) was added thereto, and the resulted mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (180 g). Elution with a mixed solvent of hexane and ethyl acetate (3:1 V/V) gave methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4-nitrobenzoate (2.30 g) as an oil.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[N:16]([CH2:19][CH3:20])[CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.O>[CH2:19]([N:16]1[C:12]2[C:13]3[CH2:14][CH2:15][NH:6][CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[CH:18]=[CH:17]1)[CH3:20]
Reactant: CCOC(=O)N1CCc2sc3ccn(CC)c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ccc2sc3c(c21)CCNCC3
Temperature: 100 °C

Procedure:
To a stirred solution of the product from step (a) (0.060 g, 0.21 mmol) in EtOH (2 ml) was added 40% aqueous KOH (2 ml). The reaction mixture was heated to 100° C. until LCMS indicated that the reaction was complete (usually 16-32 hours). The reaction mixture was cooled to RT, diluted with water (30 ml), and extracted with DCM (3×). The combined DCM extracts were dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by preparative HPLC gave the title compound as a tan solid. 1H NMR (CD3)2CO™ 6.82 (d, J=2.7 Hz, 1H), 6.14 (d, J=2.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.01-2.92 (m, 6H), 2.86-2.78 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); MS: ESI (positive): 221 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=4)[C:4](=[O:29])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][O:26][N:25]=1
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.257 mmol) and THF (2.5 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (42.4 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and a yellow precipitate formed. The precipitate was filtered then washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 25% yield (0.034 g, 0.0634 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BrH:11].BrBr.C(OCC)C>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: CC(=O)c1cccnc1C
Agent: Br
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ncccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
150 mg (1.11 mmol) of 1-(2-methylpyrid-3-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 365 μl (2.22 mmol) of hydrobromic acid and 63 μl (1.22 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 1 hour. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 280 mg of product obtained have the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([Br:34])[CH:36]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(Br)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85.5 %

Procedure:
Using 0.6 g (1.32 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 1-bromo-3-bromomethyl-benzene (0.33 g, 1.32 mmol) and following the procedure of Example 42(b) afforded 0.7 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.2 (2H, s), 6.76 (1H, d), 7.0 (1H, s), 7.12 (2H, d), 7.2 (1H, s), 7.44 (3H, m), 7.56 (1H, d), 7.68 (1H, s), 7.84 (2H, d), 8.3 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[Sb](F)(F)[F:14].ClCl>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:10])([Cl:9])[F:14])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: F[Sb](F)F
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: ClCl
Product: FC(Cl)(Cl)c1cc(Cl)nc(Cl)c1

Procedure:
A mixture containing 138.5 grams (0.522 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine and 34 grams (0.187 mole) of Antimony trifluoride was heated to 80°-84° C. and maintained under agitation for 23 minutes. During this step, a slow stream of chlorine gas was passed over the surface of the reaction mixture. The reaction mixture was steam distilled and the crude 2,6- dichloro-4-(dichlorofluoromethyl)pyridine product was purified by fractionation. The product had a boiling point of 74°-76° C. at 1.0 millimeter of mercury.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole (1.1 g, 3.4 mmol) and KI (566 mg, 3.4 mmol) in DMF (7 mL) was added sodium azide (443 mg, 6.8 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 960 mg (89%) of the title compound as pale yellow amorphous: MS (ESI) m/z 318 [M+H]+, 1H-NMR (CDCl3)δ1.26 (2H, t, J=7.5 Hz), 2.72 (3H, q, J=7.7 Hz), 2.98 (2H, t, J=6.6 Hz), 3.59 (2H, t, J=6.6 Hz), 7.20-7.41 (9H, m), 7.79 (2H, dd, J=7.1, 1.3 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH:6]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccc2sccc2c1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2sccc2c1
Yield: 40.9 %

Procedure:
To a solution of 5-bromobenzo[B]thiophene (9.4 mmol) in 100 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° C. was added 5.9 mL of a 1.6 M hexanes solution of n-butyllithium (9.4 mmol). The 5bromobenzo[B]thiophene was synthesized by procedures well known in the art. See, European Patent Application 355827 (published Feb. 28, 1990). The reaction was warmed to 0° C. and stirred for 30 minutes. Sulfur dioxide gas was bubbled through this mixture for 20 minutes at 0° C., and the reaction concentrated under vacuum. The residue was dissolved in 50 mL of water. Sodium acetate (74 mmol) and hydroxylamine-0-sulphonic acid (24 mmol) were added to this solution and this reaction was stirred at room temperature for 1.5 hours. This mixture was diluted with 50 mL of water and the reaction extracted with ether (3×50 mL). The combined organic layer was extracted with 1 N sodium hydroxide (3×50 mL), the organic layer discarded, and the aqueous layer acidified with about 150 mL of 1 N hydrochloric acid. The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography with 30% acetone in hexanes with 1% acetic acid on silica gel to obtain 340 mg of 5benzo[B]thiophenesulfonamide. The sulfonamide (1.6 mmol) was reacted with 4-chlorophenylisocyanate (1.9 mmol) as described in Method A above to obtain 240 mg of the title product as a solid. 1H NMR (CD3SOCD3): δ9.04 (s, 1 H), 8.16 (s, 1 H), 8.08 (d, J =6 Hz, 1 H), 8.04 (d, J =6 Hz, 1 H), 7.52 (d, J =6 Hz, H), 7.46 (m, 2 H), 7.42 (d, J =9 Hz, 2 H), 7.30 (d, J =Hz, 2 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:14][F:15])=[N:8][N:9]([CH3:13])[C:10]=1[CH2:11][F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:13][N:9]1[C:10]([CH2:11][F:12])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH2:14][F:15])=[N:8]1
Reactant: CCOC(=O)c1c(CF)nn(C)c1CF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(CF)c(C(=O)O)c1CF
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.5 g, 2.0 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (0.8 ml) and stirred at room temperature for 2 h. The solvent was removed by rotary evaporation; the residue was taken up in water (10 ml) and extracted with diethyl ether (10 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×10 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Methyl-3,5-difluoromethyl-4 pyrazolecarboxylic acid (0.44 g, 1.95 mmol, 97%) was isolated as a colourless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:5][N:4]=1.CCCCCCC.N.Cl>C(OCC)(=O)C.O=[Pt]=O.CO.ClCCl>[ClH:13].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:5][N:4]=1
Reactant: NC1=NCC(c2ccccc2[N+](=O)[O-])c2cc(Cl)ccc21
Agent: O=[Pt]=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCCC
Product: NC1=NCC(c2ccccc2N)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
was obtained in analogy to the method indicated in Example 1 g) from 1-amino-6-chloro-4-(2-nitrophenyl)-3,4-dihydroisoquinoline hydrochloride by hydrogenation with PtO2 and MPLC and an elution mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. The product was dissolved in a little ethyl acetate, acidified with ethereal HCl, stirred at room temperature and filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].FC1C(F)=C(C=CC=1)C=O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[N:13]([CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: CCNCC
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=Cc1cccc(F)c1F
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(C=O)cc1F
Reaction time: 6 h
Yield: 93 %

Procedure:
In a 250 mL round bottom flask equipped with stirbar, condenser and nitrogen inlet was placed 3,4-difluorobenzaldehyde (25.0 g, 176 mmol), dimethylsulfoxide (50 mL) and diethylamine (38.6 g, 528 mmol). The resulting solution was boiled gently for 6 hr at which time thin layer chromatography indicated all the difluorobenzaldehyde was consumed. The solution was cooled and transferred to a separatory funnel with ethyl acetate and water. The phases were separated, the organic phase washed well with water, dried (MgSO4) and filtered through a short pad of silica gel. Silica gel (50 g) was added to the filtrate and the mixture concentrated to dryness. This material was placed at the top of a column of silica gel and eluded with a gradient of ethylacetate in hexane (0→4%). Concentration of the pure fractions by rotary evaporation afforded a light brown oil (31.97 g, 92%) of sufficient purity for subsequent transformations: IR (CCl4)1695 cm-1 ; 1H NMR (CDCl3)δ9.70 (s, 1H), 7.41-7.50 (m, 2H), 6.78 (t, J= 8Hz, 1H), 3.39 (q, J=7 Hz, 4H), 1.20 (t, J=7 Hz, 6H); 13C NMR (CDCl3) ppm 189.048, 151.901 (d, J=244 Hz), 142.844 (d, J=8 Hz), 127.880. 126.244 (d, 6 Hz), 116.433 (d, J=23Hz), 115.316 (d, 5 Hz), 45.845 (d, J=6Hz), 12.858 d,J=1 Hz).