Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[C:12]([O:16][C:17](=[O:28])[NH:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)[CH3:20])([CH3:15])([CH3:14])[CH3:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(#N)C>[C:12]([O:16][C:17](=[O:28])[NH:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:25][CH:26]=1)[CH3:20])([CH3:13])([CH3:14])[CH3:15]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 65 °C

Procedure:
24.6 g (168 mmol) 1-ethoxy-4-ethynyl-benzene, 52.8 g (176 mmol) [1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (50.2) and 42.6 mL (307 mmol) TEA are added to 400 mL ACN. The mixture is warmed to 65° C. 8.84 g (7.65 mmol) Pd(PPh3)4 and 2.91 g (15.3 mmol) CuI are added and the reaction mixture is stirred at reflux for 2 h. The mixture is cooled to r.t. and the solvent is removed in vacuo. The crude product is purified by column chromatography (hexane/EtOAC 9:1→3:1).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(C=O)c2)cc1
Yield: 45.6 %

Procedure:
The title compound (130 mg, 46%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (265 mg, 0.788 mmol, prepared in example 1), 3-formylbenzeneboronic acid (160 mg, 0.964 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane (5.25 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]([Br:1])=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OCc1ccccc1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 141.6 %

Procedure:
Dibromoisocyanuric acid (15.9 g) was added at room temperature to a DMF (150 mL) solution of methyl 3-(benzyloxy)-2′,4′-difluorobiphenyl-4-carboxylate (28.0 g), and the mixture was stirred overnight at the same temperature as above. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (34.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=[O:13].S(C)C.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C(O)CCc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: OCCCc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
3-(2,4,5-Trifluorophenyl)propionic acid (3.25 g, 16.0 mmol; from Step 1) was dissolved in THF (15 mL) and cooled to 0° C. To this solution was added Me2S.BH3 (3.2 mL, ˜32 mmol) dropwise under 30 min and the resulting mixture was then heated at 70° C. for 30 min. After cooling to 0° C., 6 M aqueous HCl (20 mL) was added dropwise. The mixture was heated at 70° C. for 1 h. After cooling to room temperature the mixture was extracted with ether (2×20 mL) and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation and drying in vacuum gave the title compound as a colorless liquid (3.17 g, 97% pure by HPLC) that was used directly in the next step. *Previously reported in EP 369812.
Reaction SMILES: [C:1]1(=O)[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[N+:16]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])#[C-:17]>>[C:18]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:17][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]3[CH:1]=[CH:2][CH2:3][C@H:4]3[C:13]=12
Reactant: O=C1Nc2ccccc2N2C(=O)CC[C@@H]12
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CC=CN1c1ccccc1-2

Procedure:
Following the general procedure of EXAMPLE 30 and making non-critical variations but starting with (S)-3,3a-dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione (intermediate formed in EXAMPLE 282, 0.638 g) and tert-butyl isocyanoacetate (0.621 g), the title compound is obtained, mp 202°-207° (decomp); MS (m/z) at 325; IR (mineral oil) 1719, 1363, 1700, 1507, 1161, 1293 cm-1 ; NMR (CDCl3) 1.64, 2.25-2.40, 2.55-2.81, 3.31-3.41, 5.26, 7.23-7.29, 7.33, 7.52, 8.06, 8.34 δ; [α]D =-248° (0.96, methanol).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[C:26](C)=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].[C:33]1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[C:29]([CH3:33])[CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2cccc(C)c2)n1C
Yield: 16.76 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-04) (35.0 mg, 16.76%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (14-11) (260.0 mg, 0.571 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]COCC.Cl>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1noc2ccccc12

Procedure:
A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G. Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated with dry HCl (150 ml) and methanol (200 ml) was stirred for 2 h at room temperature. Removal of the volatiles in vacuo gave methyl 1,2-benzisoxazole-3-acetate (17 g) as an oil. The oil was dissolved in tetrahydrofuran (100 ml) and added dropwise to a suspension of lithium aluminium hydride (6 g) in tetrahydrofuran (200 ml) at 0°-10° C. followed by stirring for 30 min at 15° C. Usual work-up gave 2-(1,2-benzisoxazol-3-yl)ethanol (13 g) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[N:2]1.Cl.[CH3:17][O:18][NH2:19].O>CN(C)C=O>[CH3:17][O:18]/[N:19]=[C:7](\[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CON
Reactant: O=C(C1=NOCCO1)c1ccccc1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C1=NOCCO1)c1ccccc1O
Yield: 31.2 %

Procedure:
4.4 g (0.021 mol) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone (III-1) and 1.87 g (0.022 mol) of O-methylhydroxylamine hydrochloride in 22 ml of dimethylformamide are heated to 100° C. for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 5.7 g of crude (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) comprising 17.5% of the E isomer and 38% of the Z isomer by HPLC are obtained. This crude product is chromatographed over silica gel using a mixture of petroleum ether/tert-butyl methyl ether (1:1). 1.55 g of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 91.5% (HPLC)=28.27% of theory) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8]Cl)=[O:7])[CH3:2].[CH3:11][CH2:12][O-:13].[Na+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][O:13][CH2:12][CH3:11])=[O:7])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)CCl
Agent: [Na+]
Solvent: CC#N
Product: CCOCC(=O)CC(=O)OCC
Yield: 90.4 %

Procedure:
Using the method described in Example 1, 108.6 g of 4-chloroacetoacetic acid ethyl ester in 143 g of acetonitrile was reacted with 103.6 g of sodium ethylate. 4-ethoxyacetoacetic acid ethyl ester was obtained in a yield of 90.4 percent, related to the amount of 4-chloroacetoacetic acid ethyl ester used. The purity of the product was 98.5 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1.[Sn](Cl)Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc(N)cc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
Benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-vinyl ester (675 mg, 1.26 mmoles) is dissolved in tetrahydrofuran (30 mL). Tin dichloride (SnCl2*2H2O, 2.84 g, 12.6 mmoles) is added and the resulting mixture is stirred at room temperature for 24 hours and at 40° C. for 3 hours. The mixture is diluted with water and a saturated NaHCO3 solution and extracted with DCM; the combined organic layers are dried over sodium sulphate and evaporated to dryness. The crude (468 mg) is purified by preparative HPLC to yield 80 mg of pure product.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:26]=[C:25](Cl)[N:24]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:22]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C1COCC1>[Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:22]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:24]=[C:25]([N:37]4[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]4)[N:26]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O[Si](C)(C)C(C)(C)C)cccc43)n2)CC1

Procedure:
Reaction of 4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole with 2.2 equivalents of tert-butyl 1-piperazinecarboxylate in THF at room temperature gave a quantitative yield of tert-butyl 4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate as an oil: 1H NMR (CDCl3) 7.91 (d, J=8.2 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 3.85 (m, 8H), 3.77 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H); MS (APCI+) 648.7 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)=[O:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:42]([C:41]4[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:32]5[CH:31]=[CH:30][C:29]([N:26]6[CH2:25][CH2:24][O:23][CH2:28][CH2:27]6)=[CH:34][CH:33]=5)=[O:37])=[CH:45][CH:44]=4)[NH:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: N#Cc1ccc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)cc1

Procedure:
Compound 641 was prepared according to the procedure similar to that described in Scheme III from 1-(4-cyanobenzyloxy)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C32H27N5O3: 530.21; found: 530.10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[C@H:23]1[O:25][CH2:24]1>CC(C)=O>[CH2:22]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15])[C@@H:23]1[O:25][CH2:24]1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OCc2ccccc2)cc1C[C@H]1CO1

Procedure:
A mixture of 4-benzyloxyphenol (2.0 g, 10 mMol) and potassium carbonate (4.14 g, 30 mMol) in acetone (50 ml) was heated under reflux for 15 mins. (S)-Glycidyl-3-nitrobenzenesulphonate (2.23 g, 10 mMol) was added and the reaction mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[N:32]=[CH:31][C:30]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CNC(=O)c1ccc(-c2ccc(F)nc2)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CNC(=O)c1ccc(-c2ccc(N3CCc4ccc(-c5cc(N6CCN(C)CC6)nc(N)n5)cc4C3)nc2)cc1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 4-(6-fluoropyridin-3-yl)-N-methylbenzamide using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=535.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid (Compound E19, 150.0 mg, 0.484 mmol), ethyl 4-hydroxybenzoate (88.5 mg, 0.530 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120.6 mg, 0.630 mmol), and 4-N,N-dimethylaminopyridine (77.0 mg, 0.630 mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure and column chromatography (10-15% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].Br[CH2:11][CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9]
Reactant: OCCCBr
Reactant: Cc1occc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1occc(=O)c1OCCCO
Reaction time: 72 h
Yield: 7.3 %

Procedure:
A suspension of 3-hydroxy-2-methyl-4-pyrone (25 g, 200 mmol), 3-bromo-1-propanol (70 g, 500 mmol) and K2CO3 (111 g 800 mmol) in 600 ml acetone was stirred for three days. The solvent was evaporated and the residue partitioned between 300 ml methylene chloride and 500 ml 2.5% NaOH. The aqueous layer was separated and extracted with 2×300 ml methylene chloride. The organic phases were combined, dried over Na2SO4 and evaporated at 50° C. Eight grams of the residue (24 g) was chromatographed on silica gel with methanol/methylene chloride (5:95) as eluent which afforded 2.7 g (22%) of the desired product as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)=[NH:9].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[C:27]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([NH:7][CH2:6][C:5]2[C:4]([O:3][CH3:2])=[CH:24][CH:23]=[CH:22][C:21]=2[O:25][CH3:26])=[NH:9])[S:12][CH:13]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2C(C)=O)cs1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mg (0.25 mmol) N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine hydrochloride, Example 147, 0.021 ml acetyl chloride and 0.04 ml pyridine in 10 ml THF were stirred for 1 hour at 5° C. and then 4 hours at room temperature. Chromatography of the crude product on RP-silica gel (Chromabond column, acetonitrile/water+0.1% glacial acetic acid; 0-100%) yielded 33 mg of the desired product; ESI-MS [M+H+]=404.15.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 80 °C
Yield: 73 %

Procedure:
In an autoclave were charged 5.303 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (20 mmol, optical purity: 100% e.e.), and 42.53 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80° C. whereby an internal pressure of 8 barr was observed. After allowing the reaction for 20 hrs, the reaction mixture was cooled to room temperature, followed by addition of 4.00 g of a 30% by weight aqueous sodium hydroxide solution (1.5 equivalent), and then ammonia was removed by distillation under reduced pressure. The residue was extracted with 30 mL of ethyl acetate three times, and the organic layers were combined. After washing with 3 mL of a saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave 3.6146 g of a dark red oily material (reaction yield: 73%, optical purity: 92.4% e.e.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2cccc(Cl)c2Cl)c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4cccc(Cl)c4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,3-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.102 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,3-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.159 g, 80%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:27](Br)[CH3:28]>CN(C)C=O>[C:1]1([N:7]2[C:11]([S:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:27][CH3:28])[C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCBr
Reactant: O=C(NCCCSc1nnnn1-c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCSc1nnnn1-c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
1-Phenyl-5-[3-(N-benzoylamino)propylthio]-1,2,3,4-tetrazole (1.7 g) is dissolved in dimethylformamide (30 ml). To the mixture is added with stirring 50% oily sodium hydride (0.3 g) at room temperature. After foaming is finished, the mixture is stirred at 60°-70° C. for one hour. After cooling until room temperature, ethyl bromide (0.8 g) is added dropwise to the resulting mixture, and thereafter, the mixture is stirred at 60°-70° C. for 8 hours. After dimethylformamide is distilled off, the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-phenyl-5[3-(N-ethyl-N-benzoylamino)propylthio]-1,2,3,4-tetrazole (1.2 g), as a colorless liquid, nD24 =1.5898.