Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>CN(C)C=O>[CH2:24]([O:23][C:6]1[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=[C:4]([N:3]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[N:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(OCc3ccccc3)c3c(n2)c(Br)cn3COCc2ccccc2)cc1

Procedure:
Sodium hydride (0.6 g, 50% dispersion) was added to a stirred solution of 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.2 g) in N,N-dimethylformamide (25 mL) followed by 4-methoxybenzyl chloride (1.1 mL). After 1 h the reaction was quenched carefully with water, chloroform was added and the solution was washed (×2) with water. Normal processing followed by chromatography afforded 4-benzyloxy-5-N-benzyloxymethyl-7-bromo-2-{N,N-bis-(4-methoxybenzyl)amino}pyrrolo[3,2-d]pyrimidine (1.7 g) as a white solid. 13C-NMR (CDCl3) δ 159.0, 158.5, 156.5, 151.5, 137.4, 137.0, 131.8, 131.6, 129.7, 128.9, 128.8, 128.4, 128.3, 128.0, 114.1, 110.5, 91.1, 77.8, 70.6, 68.0, 55.7, 49.4. Anal. calc. for C37H35BrN4O4: C, 65.39; H, 5.19; Br, 11.76; N, 8.24. Found: C, 65.47; H, 5.17; Br, 11.55; N, 8.42.
Reaction SMILES: CO.[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[N:15]=[CH:16][C:17]1[N:22]=[C:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH2:33][NH:34][C:35]2[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=2[CH3:43])[CH:20]=[CH:19][CH:18]=1)([CH3:5])[CH3:4].[BH3-]C#N.[Na+].[BH4-]>C(O)=O.C1(C)C=CC=CC=1>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[NH:15][CH2:16][C:17]1[N:22]=[C:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH2:33][NH:34][C:35]2[C:36]([CH3:43])=[CH:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:20]=[CH:19][CH:18]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(CNc3c(C(C)C)cccc3C(C)C)n2)c(C)c1

Procedure:
Methanol (30 mL), toluene (10 mL), and compound 6b (2.11 g, 3.91 mmol) were heated to reflux under nitrogen. Formic acid (95%) (5 drops) was added followed by portions of NaBH3CN (0.983 g, 15.6 mmoL). The borohydride was added in four portions over an hour. After 3 hours at reflux the yellow color of the imine had faded completely and the volatiles were removed by evaporation on a rotary evaporator. Water (20 mL) and Et2O (30 mL) were added, and the organics were separated and dried over brine. The ether solution was then dried over MgSO4, filtered, and evaporated to give the diamine 7o as a pale pink solid. Yield: 2.1 g, 99%. 1H NMR (500 MHz, CD2-Cl2): 7.90 (t, 2H), 7.82 (t, 1H), 7.56 (d, 1H), 7.38-7.52 (m, 4H), 7.29 (d, 1H), 7.07 (d, 2H), 7.03 (m, 1H), 6.74 (s, 2H), 4.28 (m, 2H), 4.08 (br t, 1H), 3.96 (br, 2H), 3.45 (m, 1H), 3.33 sept, 2H), 2.19 (s, 3H), 2.05 (s, 6H), 1.15 (d, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]2[C:10]3[N:11]([CH:23]=[CH:24][N:25]=3)[N:12]=[C:13]([CH2:15][N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)[CH:14]=2)=[CH:5][CH:4]=1.C1COCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.[OH-].[Na+]>[CH2:39]([NH:46][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:13]2[CH:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:10]3[N:11]([CH:23]=[CH:24][N:25]=3)[N:12]=2)[CH2:21][CH2:20]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(=O)CC3)nn3ccnc23)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(NCc4ccccc4)CC3)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
In a 2 dram vial was added 1-((8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)methyl)piperidin-4-one (0.048 g, 0.109 mmol) from (1d), THF (0.362 mL) and benzylamine (0.013 mL, 0.120 mmol). The reaction was allowed to stir at room temperature for 1 hr. Sodium triacetoxyborohydride (0.092 g, 0.435 mmol) was then added and the reaction stirred for 48 hours at ambient temperature. The mixture was diluted with ethyl acetate and 1N NaOH solution and the layers separated. The organics were washed with water and the resulting aqueous solution was back-extracted with ethyl acetate (2×). The combined organics were collected, dried over Na2SO4, filtered and concentrated to provide 6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.05 g, 86% yield) which was subsequently used without further purification m/z=(532, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([CH2:13][CH2:14][CH3:15])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].[CH2:33]([Si](C)(C)C)[CH:34]=[CH2:35]>O1CCCC1.ClCCCl.[I-].[Zn+2].[I-].O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:35][CH:34]=[CH2:33])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([CH2:13][CH2:14][CH3:15])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[Si](C)(C)C
Reactant: CCCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: C=CCC1c2ccc(OC)cc2SCC1(CCC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A solution of 7-methoxy-3-(4-methoxyphenyl)-3-propylthiochroman-4-one (1.7 g, 4.96 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to −78° C. Lithium aluminum hydride (94.2 mg, 2.48 mmol) was added to this solution, followed by stirring for 12 hours at room temperature. Saturated aqueous ammonium chloride (100 ml) was added to the reaction mixture, which was then extracted twice with ethyl acetate (100 ml). The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, zinc iodide (1.9 g, 5.95 mmol) and allyltrimethylsilane (1.57 ml, 5.95 mmol) were added dropwise to a solution of the residue in 1,2-dichloroethane (50 ml) at 0° C., followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/90) to give (3RS,4RS)-7-methoxy-3-(4-methoxyphenyl)-4-(2-propenyl)-3-propylthiochroman (1.32 g, Yield 72%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:2]1[CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH:1]1[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: OCCCCO
Reactant: COC(=O)c1cc(C=O)cnc1C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2OCCCCO2)cnc1C(=O)OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 5-formyl-2,3-pyridinedicarboxylic acid, dimethyl ester, 5-dimethyl acetal (1.3 g, 0.0048 mol), a catalytic amount of p-toluenesulfonic acid, 1,4-butanediol and toluene is heated at reflux temperature for 2 hours and 30 minutes. The reaction mixture is cooled to room temperature, made basic with sodium bicarbonate and concentrated in vacuo to give a liquid. The liquid is partitioned between methylene chloride and 5% sodium bicarbonate solution. The layers are separated and the aqueous layer is extracted with methylene chloride, the combined methylene chloride extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (2:1 to 1:1) as eluant to give the title compound as a clear oil (0.88 g, 62%), identified by IR and NMR spectral analyses.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)=[CH:7][CH:6]=1.N[C:21](N)=[S:22]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:21](=[S:22])[NH:19][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Cc2ccc(N)c(N)c2)cc1
Agent: Cl
Product: COc1ccc(Cc2ccc3[nH]c(=S)[nH]c3c2)cc1
Reaction time: 2 h

Procedure:
A mixture of 0.35 g (1.16 mmoles) of 4-[(4-methoxyphenyl)-methyl]-o-phenylene-diamine dihydrochloride and 0.286 g (3.76 mmoles) of thiourea are melted in an oil-bath at a temperature of 150°-160° C. and kept at the same temperature for 2 hours.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6][C@@H:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[C:4]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CO.O>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C@H:5]1[C:4]([C:25]([O:27][CH3:28])=[O:26])=[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6]1
Reactant: C1CCNCC1
Reactant: COC(=O)C1=C(CBr)NC(c2ncc(F)cc2F)=N[C@H]1c1ccc(F)cc1Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(CN2CCCCC2)NC(c2ncc(F)cc2F)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of freshly prepared methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate from Example XIII in 0.5 ml of methanol is mixed with 5 equivalents of piperidine and stirred at room temperature for 30 minutes. The solution is diluted with water and extracted with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N:44]1([CH2:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:37][CH:38]=2)[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Reactant: CC1(C)OB(c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccc(CCN4CCOCC4)cc3)c2)c1)NOC1CCCCO1
Yield: 85.8 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (7.60 g) and 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholin (8.00 g) are dissolved in DME (300 mL). (Ph3P)3PdCl2 (2.40 g) and a 2M Na2CO3-solution (25 mL) are added and the mixture is heated 5 h to reflux temperature under an inert gas atmosphere. The reaction mixture is filtered and evaporated. After addition of a NaHCO3-solution and ethyl acetate, the organic phase is dried and evaporated. The crude product is purified by silica gel flash chromatography. 8.1 g of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]([CH3:14])C)[C:5]=2[S:4][CH:3]=1.[N:15]1([CH2:20]CCN)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:14][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:5]=2[S:4][CH:3]=1
Reactant: CC(C)Nc1ncnc2c(Br)csc12
Reactant: NCCCN1CCCC1
Product: Brc1csc2c(NCCCN3CCCC3)ncnc12

Procedure:
Compound 78A was prepared in a similar manner to the synthesis of compound 69A by substituting propan-2-amine with 3-(pyrrolidin-1-yl)propan-1-amine: APCI (+)LC/MS: 342 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][C:12]3[CH:17]=[CH:18][C:19]([Br:21])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Br:21][C:19]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:3][CH2:4]3)[C:11]=2[N:20]=1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(Br)nc54)CC3)nc2N1
Yield: 64 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Intermediate 79), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 64% yield.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5].O.[CH2:11](O)[CH3:12]>>[CH2:11]([O:5][C:4](=[O:6])[C:3]([CH3:9])([CH3:2])[CH2:7][CH3:8])[CH3:12]
Reactant: CCO
Reactant: CCC(C)(C)C(=O)O
Agent: Cl
Solvent: O
Product: CCOC(=O)C(C)(C)CC
Temperature: 25 °C

Procedure:
Add 0.2 mL of concentrated hydrochloric acid to 2,2-dimethyl-butanoic acid (5.0 g, 43.0 mmol) in ethanol (43 mL) and heat to reflux for 5 hours. Cool to room temperature. Pour the reaction into water and extract with diethyl ether. Wash the combined organics with saturated aqueous sodium bicarbonate and water, dry over magnesium sulfate, filter, and concentrate under reduced pressure to afford the title compound which was used without further purification (4.0 g, 64.4%): 1H NMR (CDCl3) δ 0.82 (t, 3H, 1.14 (s, 3H), 1.23 (t, 3H), 1.55 (q, 2H), 4.1 (q, 2H).
Reaction SMILES: [CH2:1]=[C:2]([Mg]Br)[CH3:3].[Cl:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:10]=[O:11]>C1COCC1>[Cl:6][C:7]1[C:8]([F:16])=[C:9]([CH:10]([OH:11])[C:2]([CH3:3])=[CH2:1])[C:12]([F:15])=[CH:13][CH:14]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=Cc1c(F)ccc(Cl)c1F
Solvent: C1CCOC1
Product: C=C(C)C(O)c1c(F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of prop-1-en-2-ylmagnesium bromide (0.5M in THF) (2 mL, 1.000 mmol) was added 3-chloro-2,6-difluorobenzaldehyde (136 mg, 0.769 mmol) in THF (1 mL) dropwise at 0° C. under Ar and stirred at 0° C. for 15 mins. The reaction mixture was quenched with sat. aq.NH4Cl and extracted with ether. The organic phase was washed with sat. aq.NH4Cl and brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography to yield 73A as colorless oil (87 mg, 52%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.36-7.28 (m, 1H), 6.91-6.83 (m, 1H), 5.48 (d, J=9.2 Hz, 1H), 5.12-5.06 (m, 1H), 5.04-4.99 (m, 1H), 2.56 (dt, J=9.2, 2.2 Hz, 1H), 1.75 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]=2[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[C:16]([CH3:22])[CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>CC(C)=O>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]=2[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[C:16]([CH3:22])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: Cc1cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)c2c(-c3ccc(OCCN(C)C)cc3)oc3ccccc23)cc(C)c1C

Procedure:
2-p-Hydroxyphenyl-3-(3',4',5'-trimethylbenzoyl)benzofuran (5.4 g., 15.3 mmol.) was dissolved in 200 ml. of dry acetone and 10.5 g. (0.076 mol.) of potassium carbonate and 2.10 g. (15.3 mmol.) of 2-dimethylaminoethyl chloride were added. The reaction mixture was refluxed for three hours, then it was cooled and filtered. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:11]([NH:61][C:60]1[CH:59]=[CH:58][C:57]([O:56][C:49]2[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:48]=2[CH3:47])=[CH:63][CH:62]=1)=[O:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(C)c(Oc2ccc(N)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (89 mg, 0.471 mmol) in dry N,N-dimethylformamide (5 mL), DIPEA (0.103 mL, 0.589 mmol) then HATU (179 mg, 0.471 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 4-{[2-methyl-5-(methyloxy)phenyl]oxy}aniline (Intermediate 14, 90 mg) was added and the reaction mixture was stirred at 60° C. under argon for 1 hour 30 min. The reaction mixture was evaporated. The residues obtained was purified by silica gel chromatography (Companion instrument, 40 g silica cartridge) eluting with a gradient cHex/EtOAc 100/0 to 75/25 during 15 min and then 75/25 during 30 min to afford the title compound (155 mg).
Reaction SMILES: C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[CH2:18])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1>[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[C:24]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH2:18])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 6.6 %

Procedure:
A solution of 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.18 mmol, 1.2 equiv) in 4 M HCl in dioxane (4 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product redissolved in anhydrous DMF (1 mL). To this solution was added 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.1 mg (7%) of the title compound. MS (ISP): 410.7 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[C:4]([S:8](=[O:11])(=[O:10])[NH2:9])[O:5][C:6]=1[CH3:7].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[C:12](=[O:14])[NH:9][S:8](=[O:11])(=[O:10])[C:4]=2[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(S(N)(=O)=O)c(C(=O)O)c1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc2c(c1C)C(=O)NS2(=O)=O
Yield: 73.5 %

Procedure:
A mixture of 1.0 gm (4.6 millimols) of 4.5-dimethyl-2-sulfamoyl-furan-3-carboxylic acid and 0.96 gm (4.6 millimols) of phosphorus pentachloride in toluene was reacted analogous to Example 1, yielding 0.68 gm (73% of theory) of 4,5-dimethylfuro[3,2-d]isothiazole-3-(2H)-one-1,1-dioxide. Rf -value: 0.21 (silica gel 60 F254 plates, thickness 0.25 mm, eluant ethylene chloride; ethyl acetate; glacial acetic acid 100:30:5).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:12]([CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:8]2)[CH3:13])=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CNC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)C1CCN(C2CCCCC2)C1
Reaction time: 2 h

Procedure:
4-Nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was prepared from 15 g. (0.085 mole) of 1-cyclohexyl-3-methylaminopyrrolidine and 15 g. (0.08 mole) p-nitrobenzoyl chloride. The 4-nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was converted to the fumarate salt (8.4 g., 24%) by precipitation with fumaric acid from isopropanol-isopropyl ether. The fumarate salt was dissolved in 95% ethanol and hydrogenated at three atmospheres of hydrogen over Raney Nickel for about two hours. The mixture was filtered, the filtrate concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried and concentrated and the residue treated with hexamic acid in isopropanol-isopropyl ether. Recrystallization from the same solvent gave 5.2 g. (13.5% overall) of the salt melting 196°-199° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[OH:11][CH:12]([C@@H:17]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]1)[C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:23][C@H:20]2[CH2:21][CH2:22][C@@H:17]([CH:12]([OH:11])[C:13]([F:14])([F:15])[F:16])[CH2:18][CH2:19]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: N[C@H]1CC[C@@H](C(O)C(F)(F)F)CC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(O)C(F)(F)F)CC2)c1Cl

Procedure:
1.3 g of 4,5-dichloro-6-ethylpyrimidine, 2.0 g of cis-4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexylamine and 1.5 g of potassium carbonate in 20 ml of dimethylformamide were stirred at 90° C. for 3 hours. For work-up, the mixture was concentrated, the residue was taken up in dichloromethane and water and the organic phase was dried and concentrated. Purification was carried out by silica gel chromatography (petroleum ether/ethyl acetate 1:1) to give the title product as a colourless solid.