Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:10]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-tert-butylbenzylbromide (500 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.250 g (58.7%); MS m/z: 426.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.24 (s, 18H); 4.62 (s, 4H); 6.69 (br s, 1H); 6.74 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.17-7.22 (m, 4H); 7.31-7.33 (m, 5H); 7.94 (s, 1H); 11.89 (br s, 1H); HPLC (METHOD [A]): rt 20.49 min (86.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:22]>O1CCOCC1>[NH2:22][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)[CH:20]=[CH:19][N:18]=1
Reactant: N
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: C1COCCO1
Product: Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 200 °C

Procedure:
A suspension of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) in dioxane (150 ml) and ammonia (20 g) is heated in an autoclave at 200° C. for 48 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is evaporated under reduced pressure and the product is purified by chromatography on silicagel.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=O)[NH:7][C:6]1=[S:15])[CH:2]([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[S:25])[NH:7][C:6]1=[S:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=S)[nH]c(=S)c2[nH]cnc21
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
3-Isobutyl-2-thioxanthine (0.20 g, 0.89 mmol) and Lawesson's reagent (1.1 g, 2.7 mmol) were suspended in toluene (8 mL). This mixture was heated at 120° C. for 17 h. The reaction mixture was cooled and the solvent removed under reduced pressure. 10% Sodium hydroxide (20 mL) was added and the mixture stirred for 10 minutes. This solution was filtered to remove insoluble solids and the solid washed with 10% sodium hydroxide solution. The basic filtrate was treated with dilute acetic acid until pH 4 was reached. The resulting precipitate was collected by filtration and washed with water. Drying of the substance afforded the title compound (0.16 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[C:6]([OH:23])[N:5]=[C:4]([CH3:24])[N:3]=1.CC(O)C.[ClH:29]>C1COCC1>[ClH:29].[ClH:29].[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[N:5]=[C:6]([OH:23])[C:7]=1[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)OC(C)(C)C)CC2)c(O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1nc(N)c(CCC2CCNCC2)c(O)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Combine tert-butyl 4-[2-(4-amino-6-hydroxy-2-methyl-pyrimidin-5-yl)ethyl]piperidine-1-carboxylate (3.73 kg, 11.09 mol) and IPA in a 50 L reactor under a nitrogen atmosphere. Add 12 N hydrochloric acid (3.05 L, 36.6 mol) with stiffing over 3 h. Heat the mixture at 50° C. for 16 h, forming a thick slurry. At that time NMR analysis shows no BOC group remaining. Cool the reaction mixture to 20-25° C., diluting with THF (12 L). Collect the solids by filtration. The filtration is slow and may take over 24 h to complete. Wash with IPA (2×10 L). Dry the material in a vacuum oven at 50° C. to provide the title compound (3.117 kg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([CH3:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:6]([Cl:15])=[C:5]([C:7]([F:8])([F:10])[F:9])[N:4]([CH3:11])[N:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cn1nc(N)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
2.0 g (12.1 mmole) 3-Amino-1-methyl-5-trifluoromethylpyrazole in 20 ml acetonitrile was treated with 1.8 g (13.3 mmole) sulfuryl chloride and the mixture stirred for 2 hours at room temperature. It was poured into aqueous saturated sodium hydrogen carbonate, extracted with ethyl acetate, dried over sodium sulfate and concentrated. 2.24 g 3-Amino-4-chloro-1-methyl-5-trifluoromethylpyrazole was obtained, which was treated without further purification as described under 2 (Example 1) to give 4-chloro-3-hydrazino-1-methyl-5-trifluoromethylpyrazole.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5](/[CH:7]=[CH:8]/[C:9]2[CH2:10][CH2:11][N:12]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Cc1ccc(C=Cc2ccncc2)o1
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/C2=CCN(Cc3nc4ccccc4[nH]3)CC2)o1
Yield: 28.9 %

Procedure:
A solution of 4-[2-(5-methylfuran-2-yl)ethenyl]pyridine (1.0 g, 5.41 mmol) in anhydrous dimethylformarnide (20 ml) was treated with 2-chloromethylbenzimidazole (1.0 g, 5.95 mmol). The reaction was stirred at reflux for two hours. The solvent was evaporated and the residue redissolved in absolute ethanol (50 ml). Sodium borehydride (251 mg, 6.76 mmol) was added and the mixture stirred at reflux for 40 mins. The solvent was evaporated and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using 97:3:1 dichloromethane/methanol/ammonia as eluant to afford the title compound (500 mg, 30%) as a pale lemon solid, m.p. 191°-193° C.; (Found: C, 75.33; H, 6.32; N, 13.17. C20H21N3O requires C, 75.21; H, 6.63; N, 13.16); δH (DMSO-d6) 2.25-2.35 (5H, m, CH3 and tetrahydropyridinyl CH2), 2.66 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.14-3.20 (2H, m, tetrahydropyridinyl CH2), 3.82 (2H, s, NCH2Ar), 5.82-5.88 (1H, m, tetrahydropyridinyl CH), 6.06-6.10 (1H, m, furan 4-H), 6.22-6.30 (2H, m, CH=CH and furan 3-H), 6.58 (1H, d, J 16.1 Hz, CH=CH), 7.05-7.20 (2H, m, 5-H and 6-H), 7.38-7.60 (2H, m, 4-H and 7-H), and 12.29 (1H, s, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:35]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:49][CH2:48][C@H:47]([CH2:50][CH2:51][C:52]3[CH:59]=[CH:58][C:55]([CH:56]=O)=[CH:54][CH:53]=3)[CH2:46][CH2:45]2)=[CH:40][CH:39]=1)[CH2:36][CH3:37].O>C1COCC1>[CH2:35]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:45][CH2:46][C@H:47]([CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([CH:56]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([Cl:2])=[CH:28][CH:27]=4)=[CH:58][CH:59]=3)[CH2:48][CH2:49]2)=[CH:40][CH:39]=1)[CH2:36][CH3:37]
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C=O)cc3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C=Cc4ccc(Cl)cc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspension of 11.8 g of 4-chlorobenzyltriphenyl-phosphonium bromide in 100 ml of THF was stirred under nitrogen gas stream, and 2.8 g of potassium-t-butoxide was added to the suspension at room temperature. After stirred at room temperature for 1 hour, a solution of 7 g of the 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzaldehyde in 50 ml of THF was added dropwise. After stirred at room temperature for 2 hours, 300 ml of water was added and extracted with 300 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and then 200 ml of heptane was added. Precipitate thus separated was filtered off, and subjected to a column chromatography over a silica gel by using ethyl acetate/heptane (1/5) as an eluent. Solvent was distilled off under a reduced pressure to obtain 5.6 g 4-(2-(4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)phenyl)ethenyl)chlorobenzene.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22].O>CN(C=O)C>[N:1]([CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C(Cl)SCN1c1cccc(OC(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1SCN(c2cccc(OC(F)(F)F)c2)C1=O
Yield: 70.4 %

Procedure:
Sodium azide (2.78 g) was added to a solution of 5-chloro-3-(3-trifluoromethoxyphenyl)thiazolidin-4-one (7.50 g) in DMF (50 ml). After 2 hours the mixture was poured into water, extracted with ethyl acetate (x3), dried (MgSO4) and concentrated in vacuo to give the sub-title compound (5.40 g), which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccccc1NCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-N,N-dimethylbenzamide (1.15 g, 6,97 mmol), prepared as in Example 22, potassium carbonate (1.44 g, 10.46 mmol) and 1-bromo-3-chloro-propane (0.7 mL, 7 mmol) in 10 mL of DMF was stirred at room temperature for 16 hours and then at 70° C. for an additional 4 hours. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated to give 2-(3-chloropropyl)amino-N,N-dimethylbenzamide as a crude mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[S:13][C:14]([CH2:17]Cl)=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([C:21]1[NH:22][C:23]2[C:24]([N:31]=1)=[N:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[S:13][C:14]([CH2:17][N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CCOCC1
Product: CCOC(=O)C1(c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)s2)CCOCC1

Procedure:
The product of Step 4, above (40), was alkylated as described in Example 1, Step 5, using 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) to obtain the title compound (41).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][N:12]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][NH:30]2)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[N:2]=1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:34]1([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[CH2:28][N:12]([CH2:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2
Yield: 60.5 %

Procedure:
In 1 mL dichloromethane was dissolved 40 mg (0.089 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid isoquinolin-3-ylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amide, to this solution was added 20 mg (0.25 mmol) of cyclobutanone and 53 mg (0.25 mmol) of sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. Fractions containing pure product were evaporated, the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 27 mg of the product as the free base as a pale yellow solid. LC-MSD, m/z for C30H35N3O4 [M+H]+: 502.7. 1H NMR (400 MHz, CDCl3): δ 1.4-2.0 (m, 9 H), 1.7 (s, 6 H), 2.3-2.4 (m, 1 H), 2.8-3.5 (m, 5 H), 3.7 (bs, 3 H), 3.8-4.0 (m, 1 H), 4.9-5.1 (m, 2 H), 6.6 (s, 1 H), 6.7-6.9 (m, 1 H), 7.5 (bs, 1 H), 7.5-7.6 (m, 1 H), 7.6-7.7 (m, 1 H), 7.8-7.9 (m, 1 H), 7.9-8.0 (m, 1 H), 9.2 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CC(C)=O.C(OCC)(=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 4-hydroxy-4′nitrobiphenyl in 5 ml acetone was added potassium carbonate (240 mg, 1.74 mmol) and 1-iodopropane (0.17 ml, 1.74 mmol). The reaction mixture was heated at reflux for 24 h. Additional potassium carbonate (240 mg, 1.74 mmol) and 1-iodopropane (0.17 ml, 1.74 mmol) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature and diluted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml water and 25 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel), eluting with 14:1 hexane/ethyl acetate to yield the title compound (0.267 g, 89% yield) MS: 258.3 (M−1)
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH:27]([S:35](Cl)(=[O:37])=[O:36])=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([CH:28]=[CH:27][S:35]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1ccccc1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (1.39 g, 0.005 mol) was dissolved in DCM (250 ml) and triethylamine (2.1 ml, 0.015 mol) was added. This was cooled to 0° C. and styrene sulphonyl chloride (CAS Number 52147-97-4, 1.11 g, 0.0055 mol) was added. Allowed to reach ambient temperature and stirred overnight. Washed with H2O and separated off the organic phase. Dried over MgSO4, filtered and evaporated to dryness to an oil which was purified by flash column chromatography (Merck 9385 silica), eluting with 80% iso-hexane/ethyl acetate to yield 1-[(-2-phenylvinyl)sulphonyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a yellow solid. Yield 650 mg (25%)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([NH2:31])=[O:30].CC#N>CCOC(C)=O>[C:17]([C:9]1[C:10]([C:13]([F:16])([F:15])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:28][C:29]([NH2:31])=[O:30])[C:4]([CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:12]2)#[N:18]
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2CC(N)=O)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.050 g, 0.17 mmol), Cs2CO3 (0.112 g, 0.34 mmol), 2-bromoacetamide (0.047 g, 0.34 mmol) and CH3CN (4 mL) was stirred at 70° C. for 2 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), brine (1 5 mL), dried over (MgSO4) and concentrated. The residue was stirred in EtOAc (5 mL) for 30 min. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.017 g, 28%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 6.78 (s, 1H), 5.01 (s, 2H), 4.07 (q, 2H); MS m/z 348 (M−H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:8][CH:7]=1.B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:8][CH:7]=1
Reactant: COc1ccc(CCC2CC=C(CCC=C(C)C)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCCC1=CCC(CCc2ccc(O)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of anisole 2F (R=4-Methyl-3-pentenyl) (6 g) in dichloromethane (100 mL) and cooled in an ice bath is added a 1M solution of boron tribromide (3.4 mL). The solution is stirred for one hour, then poured into water. The reaction mixture is extracted with dichloromethane and dried over magnesium sulfate. The solution is concentrated in vacuo. The product is recrystallized from hexane.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[NH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:21]=[C:20]([C:31](N(OC)C)=[O:32])[CH:19]=2)=[CH:14][CH:13]=1)=[O:8]>C1COCC1>[C:31]([C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:7]([NH2:6])=[O:8])=[CH:17][CH:16]=2)[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:21]=1)(=[O:32])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)C(C)C)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.76M solution of isopropylmagnesium bromide in THF (2.0 ml) was added a solution of 5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide (130 mg) in THF (2 ml) dropwise at at 4° C. The mixture was stirred at ambient temperature overnight. Additional 0.76M solution of isopropylmagnesium bromide in THF (2.0 ml) was added and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to ambient temperature and was quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The organic layer was washed with 1M HCl, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHC3 10%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give N-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)urea (30 mg) as amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[S:41](Cl)(=[O:43])=[O:42])[CH:34]=[CH:33][CH:32]=1>>[C:25]1([S:22]([NH:21][C:3]2[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][S:41]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)(=[O:42])=[O:43])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2cccnc12)c1ccccc1

Procedure:
N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 524.2. Calcd: 524.13. 1H NMR δ 9.34 (dd, 1H), 8.79 (dd, 1H), 8.37 (dd, 1H), 8.25 (dd, 1H), 7.92 (dd, 1H), 7.73 (t, 1H), 7.57-7.40 (m, 5H), 7.17 (d, 1H), 6.71 (dd, 1H), 6.14 (d, 1H), 3.23-3.08 (m, 8H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=1>>[CH3:36][N:32]1[CH:33]=[CH:34][N:35]=[C:31]1[C:18]1[CH:19]=[CH:20][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[O:14])=[CH:16][CH:17]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cn1ccnc1Br
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2nccn2C)cc1
Yield: 11 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (439 mg, 1.1 mmol) and 2-Bromo-1-methyl-1H-imidazole (CAS 16681-59-7) (161 mg, 1.0 mmol) to give 39 mg (11% yield). MS (ES+) 353.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=S.CC(C)N=C=NC(C)C>C1COCC1>[C:8]1([NH:7][C:5]([C:4]2[CH:14]=[CH:15][C:16]3[NH:17][C:27]([NH:26][C:20]4[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:25])=[N:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of the product obtained at (1b) (250 mg, 0.99 mmol) in 5.0 mL of THF was combined with 1,3-dichloro-2-isothiocyanato-benzene (222 mg, 1.09 mmol) and stirred for 5 h at ambient temperature under nitrogen. DIC (166 μL, 1.04 mmol) was added and the stirred mixture was heated to 55° C. for 16 h. The mixture was filtrated and concentrated i.vac., the residue purified by HPLC (Symmetry C18, 7 μM, eluent gradient: (H2O+0.15% HCOOH)/acetonitrile=95:5->5:95).