Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[CH:38][C:39]2[O:43][CH:42]=[CH:41][C:40]=2[CH:44]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].CC#N>O1CCOCC1.O.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[O:43]1[C:39]2[CH:38]=[CH:37][C:36]([C:17]3[CH:16]=[C:15]4[C:11]([CH:12]=[N:13][NH:14]4)=[C:10]([NH:9][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH:18]=3)=[CH:44][C:40]=2[CH:41]=[CH:42]1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: Brc1ccc2occc2c1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3ccc4occc4c3)cc3[nH]ncc23)cs1
Reaction time: 1 h
Yield: 10.7 %

Procedure:
2-methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (53 mg, 0.11 mmol) was dissolved in 1,4-Dioxane (0.4 mL) and added to 5-bromo-1-benzofuran (20 mg, 0.1 mmol, available from ABCR) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.51) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by Mass Directed AutoPrep (Method C) to afford the title compound (4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1.[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:3]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:4]=2)[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)#[N:17]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 95 %

Procedure:
A solution of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (119 mg, 0.332 mmol, as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (123 mg, 0.398 mmol, as prepared in Example 1, step (d)) in CH2Cl2 (10 mL) was treated with PyBroP (217 mg, 0.465 mmol) and DIEA (231 μL, 1.33 mmol) at room temperature for 45 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with satd aq NaHCO3 (1×30 mL). The aqueous layer was extracted with CH2Cl2 (1×30 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column (FlashMaster system) with 10-25% EtOAc-hexane afforded the title compound (193 mg, 95%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C31H41N5O4SSi, 608.3 (M+H). found 608.3.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([O:31][C:32](=O)[C:27]=12)=[O:30])(=[O:24])[CH3:23].C(N(CC)CC)C.O>CN(C=O)C>[CH:17]1([O:16][C:10]2[CH:9]=[C:8]([CH:3]([N:2]3[C:32](=[O:31])[C:27]4[C:28](=[CH:34][CH:35]=[CH:36][C:26]=4[NH:25][C:22](=[O:24])[CH3:23])[C:29]3=[O:30])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(C(N)CC(C)O)cc1OC1CCCC1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Temperature: 85 °C

Procedure:
A stirred mixture of 4-amino-4-(3-cyclopentyloxy-4-methoxyphenyl)butan-2-ol hydrochloride(1.20 g, 3.80 mmol), 3-acetamidophthalic anhydride (0.78 g, 3.80 mmol) and triethylamine (0.38 g, 3.80 mmol) in DMF (15 mL) was heated at 80-90° C. for 7 hours. The mixture was allowed to cool to room temperature and poured into water (80 mL). The resulting mixture was extracted with EtOAC (3×30 mL). The combined ethyl acetate extracts were washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:EtOAC 8:2) to give N-{2-1-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.3 g, 73%) as a white solid: 1H NMR (CDCl3) δ 9.53 (s, 1H), 8.71 (d, J=8.4 Hz, 1 H), 7.63 (t, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.08-7.03 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 5.57-5.51 (dd, J=4.2, 11.6 Hz, 1H), 4.78 (m, 1H), 3.81 (s, 3H), 3.77-3.74 (m, 1H), 2.91-2.81 (m, 1H), 2.25 (s, 3H), 2.13-1.60 (m, 10H), 1.29 (d, J=6.1 Hz, 3H); 13C NMR (CDCl3) δ 170.38, 169.21, 168.06, 149.70, 147.50, 137.33, 135.84, 131.54, 131.20, 124.71, 120.28, 117.93, 115.31. 115.07, 111.55, 80.45, 64.89, 55.97, 51.35, 39.92, 32.73, 24.91, 24.04, 23.76, 21.02.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NS(N)(=O)=O
Reactant: BrCCCOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)NCCCOCc1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To a solution of sulfamide (1.0 g, 10.4 mmol) in dry DMF (50 mL) is added NaH (416 mg 60% dispersion in mineral oil, 10.4 mmol) in portions. After the evolution of gas has stopped, (3-bromo-propoxymethyl)-benzene (2.38 g, 10.4 mmol) is added and the reaction mixture is stirred at 50° C. for 18 h. The suspension is cooled to rt, neutralized with 1N aq. HCl (5 mL) and concentrated. The solid residue is suspended in acetone and filtered. The filtrate is evaporated and the residue is purified by column chromatography on silica gel eluting with hexane/EA to afford 3-benzyloxypropylsulfamide (651 mg) as a colourless oil. LC-MS: tR=0.73 min, [M+H]+=245.18; 1H NMR (CDCl3): δ 7.39-7.27 (m, 5H), 4.94 (t br, J=4.6 Hz, 1H), 4.53 (s br, 2H), 4.50 (s, 2H), 3.60 (t, J=5.9 Hz, 2H), 3.26 (q, J=5.9 Hz, 2H), 1.89 (p, J=5.9 Hz, 2H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium borohydride (0.18 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.34 g) in methanol (25 ml) at room temperature. The mixture was stirred for 30 minutes, treated with acetic acid (1 ml), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, and dried over magnesium sulfate. The ethyl acetate layer was evaporated to dryness and the residue was recrystallized from a mixture of ethanol and water to give pale yellow prisms of 2'-(2,4-difluorophenoxy)-4'-(1-hydroxyethyl)methanesulfonanilide (0.97 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(OCOCC)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:27]([N:30]=[C:31]=[O:32])[CH:28]=[CH2:29].C[Si](Cl)(C)C>C(OC)(C)(C)C.C1COCC1>[CH2:27]([NH:30][C:31](=[O:32])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=[CH2:29]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCN=C=O
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CCOCOCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C=CCNC(=O)C#C[Si](C)(C)C
Temperature: 0 °C

Procedure:
The reaction is carried out by dissolving trimethylsilylacetylene in an solvent. Preferred solvents include ethereals such as THF, diethoxymethane and t-butylmethyl ether. At about 0° C., a strong base is added dropwise over a period of about 15 minutes. Examples of strong bases are n-butyl lithium and lithium diisopropyl amide. While still maintaining the temperature near 0° C., a solution of allyl isocyanate in solvent is added dropwise over about 15 minutes. This is followed by the dropwise addition of trimethylsilyl chloride. After holding the reaction mixture at about 0 to about 10° C. for about 3 hours, the reaction is quenched with aqueous ammonium chloride and extracted with dichloromethane. The solvent is evaporated to yield the product, N-allyl-3-trimethylsilylpropiolic amide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-(phenylthio)aniline gave the title compound as a tan solid, mp 88-94° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N1CCCN2CCCN=C12)C1C=CC=CC=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: c1ccc(CN2CCCN3CCCN=C32)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(Cc3ccc(C#N)cc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 30.4 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.100 g, 0.275 mmol), 4-(bromomethyl)benzonitrile (0.054 g, 0.275 mmol), 1-benzyl-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine on polystyrene (0.055 g, 0.413 mmol) in DMF (2 ml) was heated in a microwave reactor at 150° C. for 7 mins. The reaction mixture was filtered, evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (0.040 g, 30%); 1H NMR (500 MHz CDCl3): δ 7.59 (d, 2H), 7.52-7.49 (m, 2H), 7.48-7.42 (m, 3H), 7.37 (d, 2H), 5.21 (d, 1H), 3.41 (s, 2H), 3.01-2.90 (m, 1H), 2.65-2.56 (m, 2H), 1.74 (s, 9H), 1.69-1.60 (m, 4H), 1.44-1.34 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 144.5, 134.2, 132.3, 131.9, 129.9, 129.4, 128.9, 125.4, 119.1, 111.1, 106.9, 62.3, 61.8, 51.9, 50.1, 32.5, 27.8; Mass Spectrum M+H+ 479.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH2:8][CH2:9][C:10]([CH3:12])=[O:11].[Mg].[CH:16](Br)=[CH2:17]>O1CCCC1>[CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH2:8][CH2:9][C:10]([OH:11])([CH:16]=[CH2:17])[CH3:12]
Reactant: C=CBr
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)CC/C=C(\C)CCC=C(C)C

Procedure:
According to the method reported by A. Ofner et al in Helv. Chim. Acta., 42, 2577-2584 (1959), cis- or trans-nerolidol was prepared respectively from cis- or trans-geranylacetone. That is, in 420 ml. of tetrahydrofuran were placed 12.5 g. of freshly-prepared metallic magnesium turnings and 60 g. of vinyl bromide were added dropwise thereto under water cooling to form a Grignard reagent. 50 g. cis- or trans-geranylacetone were added dropwise thereto at 25° C. The reaction mixture was neutralized with ammonium chloride and extracted with ether. The extract was dried over sodium sulfate and distilled off under reduced pressure. The residue was subjected to vacuum distillation (1.0 mmHg) in a rectifying column having about 40 theoretical plates (about 30 practical plates) with a reflux ratio of 10 ~ 20 and a bottom temperature of approximately 190° C., to give cis-nerolidol from cis-geranylacetone in a yield of 82 percent. The product was identified by the standard product obtained in Example 12. The trans-isomer was obtained in the same manner.
Reaction SMILES: N1CCC(CNC(C2C3OCCOC=3C=CC=2)=O)CC1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31](S(CCCCl)(=O)=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Agent: O=C(NCC1CCNCC1)c1cccc2c1OCCO2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 193.6 %

Procedure:
A mixture of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(piperidin-4-ylmethyl)amide (28.6 g, 104 mmol), 4-(3-chloropropane-1-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester (33.9 g, 104 mmol), sodium iodide (7.8 g, 52 mmol), and triethylamine (29 mL, 209 mmol) in N,N-dimethylformamide (70 mL) was stirred at 90° C. for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water (three times) and brine, dried (Na2SO4) and the solvents evaporated in vacuo. The crude product was purified by silica gel chromatography (5% methanol-dichloromethane) and crystallization from ethyl acetate-hexane to give 4-[3-(4-{[2,3-dihydrobenzo[1,4]dioxin-5-carbonyl)amino]-methyl}piperidin-1-yl)propane-1-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (37.5 g, 64%); m.p. 130-132° C. Analysis for C27H43N4O7 S: Calcd.: C, 57.12; H, 7.63; N, 9.87. Found: C, 57.01; H, 7.40; N, 9.94.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[C:17]1([S:23]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 84 %

Procedure:
A solution of 1-[3-(trifluoromethyl)-2-pyridyl]piperazine (60 mg, 0.26 mmol), and Benzene sulfonyl chloride (0.043 mL, 0.31 mmol) in DCM (4 mL) and saturated sodium bicarbonate (2 mL) was stirred at room temperature for 12 hours. The mixture was diluted with DCM (5 mL) and water (5 mL). The organic layer was collected and washed two times with water, dried with magnesium sulfate, and concentrated. The product was purified using column chromatography (20% Ethyl Acetate in Hexanes) to produce 1-(phenylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine (81.1 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[CH:23][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:26]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:21])=[CH:16][CH:15]=1)=[CH:7]3
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCN(C)CC4)cc3)cc12

Procedure:
8-Methyl-2-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 1-methylpiperazine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.84 (s, 1H), 8.80 (s, 1H), 8.41 (d, 1H), 7.52 (s, 1H), 7.42-7.46 (m, 3H), 7.36-7.38 (m, 2H), 3.53 (m, 1H), 3.18 (m, 2H), 3.12 (m, 2H), 2.92 (s, 2H), 2.66 (s, 2H), 2.56 (s, 2H), 2.16 (s, 3H), 1.99 (m, 2H), 1.69 (d, 3H), 1.30 (s, 3H). LRMS [M+H]=440.2
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:6]12)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].C(OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[OH:10][C:8]1[C:7]2[C:6](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:11](=[O:12])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O

Procedure:
Reagents: Comp 19 (1.36 mmols, 0.3 g); Sodium hydride (5.75 mmols, 0.138 g); Diethyl malonate (6.84 mmols, 1.1 g). Yield: 0.15 g (38%), yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.CN(C)C1C=C(C=CC=1OCOC)C=O.[Cl:28][C:29]1[CH:47]=[CH:46][C:32]([CH:33]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:31][CH:30]=1.[Na].C(=O)([O-])O.[Na+]>CO.O.C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:33]([N:40]2[CH2:41][CH2:42][N:43]([CH2:6][C:5]3[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=3)[CH2:44][CH2:45]2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:46][CH:47]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CN(C)c1cc(C=O)ccc1O
Agent: COCOc1ccc(C=O)cc1N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)c1cc(CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 3-dimethylamino-4-hydroxybenzaldehyde (see Synthesis of Compound A) (600 mg, 3.63 mmol) in methanol (10 ml) was added 1-(4-chlorobenzhydryl)piperazine (1.25 g, 4.36 mmol) while stirring at room temperature. Thereto was added sodium cianoborohydride (95% content) (700 mg, 10.6 mmol) by portions. After stirring for 1 hour, acetic acid (0.2 ml) was added thereto, and the mixture was further stirred for 3 hours. The reaction mixture was poured into water, and the pH of the solution was made basic by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate. The extract was then extracted with 1N hydrochloric acid, and the aqueous layer was neutralized and extracted with ethyl acetate. Then thus obtained extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the object Compound 7. Yield 569 mg (36%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.CS(C)=O>[O:17]1[CH2:4][CH:8]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCc1ccccc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: c1ccc(CCC2CO2)cc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulphoxide (100 ml) was added over 5 minutes to sodium hydride (6.76 g of a 55% oil dispersion, 0.155 mol) under a nitrogen atmosphere. The mixture was stirred vigorously for 10 minutes, then diluted with anhydrous tetrahydrofuran (80 ml). The mixture was cooled to 5° C. and a solution of trimethylsulphonium iodide (31.63 g, 0.155 mol) in dimethyl sulphoxide (80 ml) was added slowly keeping the temperature of the reaction mixture at 5° C. After addition the reaction mixture was stirred at 5° C. for 2 minutes then a solution of hydrocinnamaldehyde (20.0 g, 0.149 mol) in anhydrous tetrahydrofuran (20 ml) was added over 1 minute. After 15 minutes at 5° C. the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (200 ml), then extracted with ethyl acetate (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (200 ml), dried (potassium carbonate) then evaporated to give an orange oil which was purified by distillation under vacuum. (±)-(3,4-Epoxybutyl)-benzene was obtained as a colourless oil (5.2 g, 23%), bp 80°-85° C. (4 mbar).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[CH:21]1[CH2:26][CH2:25][CH2:24][C:23](=O)[CH2:22]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[CH:21]1[CH2:26][CH2:25][CH2:24][C:23](=[CH2:1])[CH2:22]1
Reactant: CC(C)(C)[O-]
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Potassium tert-butoxide (50 mg) was added to a suspension of methyltriphenylphosphonium bromide in tetrahydrofuran (4 ml) at 0° C. After 0.5 hr, a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (100 mg) in tetrahydrofuran (1 ml) was added, and the mixture was allowed to warm to ambient temperature. After 16 hr, the reaction mixture was partitioned between ammonium chloride (30 ml of a saturated aqueous solution) and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2×30 ml), and the combined organic extracts were washed with brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as pale yellow oil (80 mg, 81%). δH (CDCl3) 1.50 (2H, m), 1.90 (2H, m), 2.05 (1H, m), 2.16 (1H, m), 2.35 (1H, m), 2.44 (1H, m), 2.97 (1H, m), 3.44 (3H, s), 3.48 (3H, s), 4.64 (1H, s), 4.69 (1H, s), 5.13 (2H, s), 5.17 (2H, s), 6.68 (1H, m), 6.77 (1H, m), 7.12 (1H, d).