Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.Cl>CCCCCC>[CH:6]([C:8]1([C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14])=[CH:8][CH2:9][CH3:10]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CCC=CC1(C(=O)OCC)CCCCC1=O
Temperature: 25 °C
Yield: 186.4 %

Procedure:
Sodium hydride, 60% in mineral oil (8.3 g, 200 mmol) was washed with 2 portions of hexane and then dried under an N2 flow. This was suspended in dimethylformamide and ethyl 2-cyclohexanonecarboxylate (34.1 g, 200 mmol) was added slowly under N2 (note the foaming and exotherm), with cooling with a 25° C. water bath. After complete addition, the mixture was stirred at 25° C. for ~1 hour and the treagents added. The stirring mixture was heated to 50° C. for 18 hours (overnight). The reaction was then cooled to room temperature. The entire mixture was poured into water, neutralized with dilute HCl and extracted with two portions of 1:1 ether-hexane The combined organics were then washed with two portions of water followed by saturated brine, then dried over MgSO4, filtered and stripped giving 41.8 g of an impure mixture of products. Purification of the product by chromatography (silica gel,: 5% methyl t-butyl ether/90% hexane) gave 28.4 g of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36](B5OC(C)(C)C(C)(C)O5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>>[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36]([C:2]5[N:3]=[CH:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(B3OC(C)(C)C(C)(C)O3)ccc1-2
Reactant: Brc1cn(CCOC2CCCCO2)cn1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn(CCO)cn3)ccc1-2

Procedure:
Following the procedure for 258, 4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole was reacted with 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene to give 486. MS(ESI+) 423.1. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.11 (s, 1H), 7.73 (d, J=1.0, 1H), 7.68 (d, J=0.9, 1H), 7.58 (dd, J=8.3, 1.7, 1H), 7.44 (d, J=1.7, 1H), 5.95-5.74 (m, 1H), 5.00 (t, J=5.2, 1H), 4.39 (t, J=5.0, 2H), 4.03 (t, J=5.4, 2H), 3.70 (q, J=5.3, 2H), 3.44 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.C([O-])=O.[NH4+]>C(O)(C)C.O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Temperature: 75 °C
Yield: 77.7 %

Procedure:
84.3 g (0.26 mol) of 6-chloro-1-(ethoxycarbonylmethyl)-7-nitroquinoxaline-2,3(1H,4H)-dione were suspended in 1.5 l of isopropanol and successively 194.2 g (3.1 mol) of ammonium formate dissolved in 500 ml of water, and 8.5 g of palladium/carbon (10%) were added. The mixture was then heated at 75° C. for 4 h and, after cooling, filtered, and the filter cake was extracted three times with 800 ml of dimethylformamide. The combined dimethylformamide phases were concentrated under reduced pressure, and the residue was washed with water. 53.2 g (79%) of the product were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1.[OH2:32]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16]([O:32][CH2:4][CH2:3][O:2][CH3:1])[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: O
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(N2CCCCC2)c2nc(OCCOC)nc(N3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
2-Methoxyethanol (0.38 g, 5 mmol) was dissolved in dry THF (5 ml) and added to sodium hydride (0.12 g, 5 mmol) and stirred for 8 hours at room temperature. 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) in dry THF (10 ml) was added to this and the mixture heated under reflux for 32 hours. After cooling to room temperature, water (30 ml) was added and the product extracted into ethyl acetate (4×20 ml), the organic layers combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as a white solid (0.076 g, 34%), m.p. 127-128° C. Found C, 59.31; H, 7.60; N, 18.80. C22H34N6O4 requires C, 59.17; H, 7.67; N, 18.82%.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[C:29](=O)(O)[O-].[Na+]>C(O)=O.O>[CH3:29][N:8]1[CH:7]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc(C2c3ccccc3Oc3ccccc3N2C)cc1
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Title compound 4 (0.508 g, 1.48 mmol) was dissolved in formic acid (5.0 mL) and the mixture was cooled at 4° C. Sodium borohydride (0.502 g) was added and the reaction mixture was stirred at room temperature for 90 min. The mixture was diluted in water (50 mL) and solid sodium bicarbonate was added until alkaline (pH=8-9). This mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 7 (408 mg, 77%) as a colorless oil. LRMS (ESI): (calc) 359.15. (found) 360.3 (MH)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)nc1C
Yield: 59.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and by the reaction and treatment in the same manner as in Example 1, the title compound (234 mg) was obtained.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[S:12]([O:22][CH2:23][CH:24]1[CH:28]([CH2:29][O:30][S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:27][O:26][CH2:25]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([N:48]1[CH2:23][CH:24]2[CH2:25][O:26][CH2:27][CH:28]2[CH2:29]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[S:12]([O:22][CH2:23][C@H:24]1[C@@H:28]([CH2:29][O:30][S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=2)(=[O:33])=[O:32])[CH2:27][O:26][CH2:25]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COCC2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COC[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Product: c1ccc(CN2CC3COCC3C2)cc1

Procedure:
Using another route as shown in the accompanying schematic, one mole of the mixture of the cis-trans 3,4-bis (hydroxymethyl)tetrahydrofuran (III) can be reacted with p-toluenesulfonyl chloride according to the process of Example 9 to form a cis-trans mixture of 3,4-bis(tosyloxymethyl)tetrahydrofuran (XIX). This product, (XIX), can in turn be reacted with benzylamine according to the process of Example 10 to form 5-benzyl hexahydro-1H-furo(3,4-c)pyrrole (IX) from the cis 3,4-bis(tosyloxymethyl)tetrahydrofuran. 5-Benzyl hexahydro-1H-furo( 3,4-c)pyrrole (IX) is separated from the reaction product mixture by distillation at about 95° to 105°C. at 0.15 mm Hg. This product in turn can be debenzylated according to the method of Example 11 to form hexahydro-1H-furo(3,4-c)pyrrole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:23]([OH:25])=[O:24])[C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
To a solution of sodium (0.95 g) in ethanol (80 ml) are added diethyl malonate (7.2 g) and 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate (13.7 g). The mixture is refluxed for 2 hours with stirring. After the further addition of a mixture of sodium (0.25 g), ethanol (25 ml) and diethyl malonate (1.8 g), the reflux is continued for further 2 hours. After evaporation of ethanol, the residue is diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract is dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oil. To a mixture of this ester and ethanol (30 ml) is added dropwise a solution of sodium hydroxide (6 g) in water (50 ml). After the addition is complete, the mixture is diluted with water (150 ml) and extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml). The organic extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oil. This acid is heated for 1 hour at 160°-165° C. with stirring. The resulting oil is purified by silica gel column chromatography using hexane-ethyl acetate (3:1-1:1) as an eluent to yield 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:17]1[CH2:19][CH2:18]1)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].C(N(C(C)C)CC)(C)C.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[F:42][C:43]1[CH:44]=[C:45]([C:49]2([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=3)[CH:53]3[CH2:54][NH:55][CH2:56][CH2:57][N:52]3[C:51](=[O:58])[O:50]2)[CH:46]=[CH:47][CH:48]=1>O1CCCC1.C(OCC)(=O)C>[F:42][C:43]1[CH:44]=[C:45]([C:49]2([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=3)[CH:53]3[CH2:54][N:55]([C:30]([NH:1][CH2:2][CH2:3][N:4]([CH:17]4[CH2:19][CH2:18]4)[S:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])=[O:31])[CH2:56][CH2:57][N:52]3[C:51](=[O:58])[O:50]2)[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1OC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCCN12
Reactant: NCCN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCN2C(=O)OC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of N-(2-aminoethyl)-N-cyclopropyl-2-nitrobenzenesulfonamide (0.51 g, 1.8 mmol) and diisopropylethylamine (0.80 mL, 4.5 mmol) in tetrahydrofuran (20 mL) was added 4-nitrophenyl chloroformate (0.36 g, 1.8 mmol) with ice cooling, and the mixture was stirred at room temperature for 1 hour. 1,1-Bis(3-fluorophenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.50 g, 1.5 mmol) was added thereto, and the mixture was stirred at room temperature overnight. To the reaction solution was added ethyl acetate, and the resulting mixture was sequentially washed with 1 N hydrochloric acid and a 1 N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=49:1 to ethyl acetate), and then crystallized from ethyl acetate-diethyl ether to obtain the title compound (0.24 g, yield 25%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:36](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOC(C)=O>[CH2:27]([C@H:26]1[C@@H:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[CH:36]2)[CH2:23][C@@H:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: COC(OC)OC
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 65 °C
Yield: 79.7 %

Procedure:
A mixture of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.160 g, 0.309 mmol), trimethyl orthoformate (3.42 mL, 30.9 mmol) and toluene-4-sulfonic acid hydrate (0.006 g, 0.031 mmol) in MeOH (3.1 mL) was heated at about 65° C. for about 1 h then heated at about 60° C. for about 14 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide as a yellow solid (0.130 g, 76%): LC/MS (Table 1, Method n) Rt=0.76 min; MS m/z 528 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1.C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: OCCc1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Brc1ccc(CCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added to a solution of 2-(4-bromophenyl)-ethanol (1.0 g, 4.97 mmol) and triethylamine (0.84 mL, 5.96 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then at ambient temperature for 2 h. The reaction mixture was partitioned between water and DCM and the organic phase was dried over sodium sulfate, filtered and evaporated to give a colourless oil. The resultant residue was dissolved in acetonitrile (10 mL), piperidine (0.491 mL, 4.97 mmol) and potassium carbonate (0.823 g, 5.96 mmol) were added and the reaction mixture was heated at 70° C. for 2.5 h. The reaction mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and evaporated and the resultant residue dissolved in methanol and loaded onto a 10 g SCX-2 cartridge. The column was washed with methanol then eluted with 2N ammonia in methanol and the basic fractions were evaporated to afford the title compound (1.27 g, 95%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): 7.41-7.36 (m, 2H), 7.10-7.04 (m, 2H), 2.79-2.71 (m, 2H), 2.54-2.40 (m, 6H), 1.66-1.56 (m, 4H), 1.50-1.40 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[O:2][CH3:1])=[O:21])[N:19]=2)[CH:16]=1
Reactant: COc1ccccc1N
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: COc1ccccc1NC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2-methoxyaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][CH2:21][O:22]C(/N=N/C(OCC)=O)=O.[S:32]1C=CC=C1CC(O)=O.[CH2:41]([O:48][C:49]([N:51]1[CH2:54][CH:53](O)[CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:21]([S:32][CH:53]1[CH2:54][N:51]([C:49]([O:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:50])[CH2:52]1)(=[O:22])[CH3:20]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 20 h

Procedure:
To triphenylphosphine (4.40 g, 16.8 mmol) in tetrahydrofuran (25 mL, THF) at -78 ° C. was added diethylazodicarboxylate (2.60 mL, 16.5 mmol) in THF (15 mL). After 7 min thiolacetic acid (1.25 mL, 17.5 mmol) in THF (15 mL) was added followed by, after 7 min, the resultant compound from Example 112 (2.789 g, 13.46 mmol). The mixture was stirred at -78 ° C. for 1 h and at room temperature for 20 h, and was then evaporated and chromatographed on silica gel with 20% ethyl acetate in hexane affording 3.250 g (91%) of a white solid, m.p. 94.5°-95.5 ° C. TLC (20% ethyl acetate/80% hexane) Rf =0.17; 1H NMR (CDCl3) 7.28-7.41 (m, 5H), 5.09 (s, 2H), 4.48 (d, 1H), 4.44 (d, 1H), 4.15-4.26 (m, 1H), 3.92 (d, 1H), 3.89 (d, 1H) 2.34 (s, 3H).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([CH2:43][CH2:44][CH2:45][N:46]6[CH2:51][CH2:50][O:49][CH2:48][CH2:47]6)[CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: ClCCCN1CCOCC1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCN(CCCN5CCOCC5)CC4)sc23)c(F)c1)NC1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a stirred solution of compound 271 (150 mg, 0.302 mmol) and DIPEA (227 μl, 1.302 mmol) in DMF (10 mL) was added 4-(3-chloropropyl)morpholine (53.3 mg, 0.325 mmol). The reaction mixture was stirred at 50° C. for 2 h. More 4-(3-chloropropyl)morpholine (212 mg, 1.3 mmol) was added in 4 h and the reaction mixture was heated at 50° C. for an additional 19 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) to produce a material that upon trituration with AcOEt afforded title compound 276 (40 mg, 0.07 mmol, 22% yield) as beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 7.71 (dd, J=2.4 and 13.6 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J=9.2 Hz, 1H), 7.22-7.18 (m, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.55 (d, J=5.2 Hz, 1H), 6.37 (s, 1H), 3.56 (q, J=4.8 Hz, 4H), 3.12 (bs, 2H), 2.70-2.62 (m, 2H), 2.62-2.58 (m, 2H), 2.58-2.50 (m, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.40-2.32 (m, 2H), 2.30 (t, J=7.2 Hz, 2H), 1.64 (quint, J=6.8 Hz, 2H), 0.66-0.62 (m, 2H), 0.44-0.41 (m, 2H). MS (m/z): 552.4. (M+H).
Reaction SMILES: CO/N=C(/C1OCCON=1)\C1C=CC=CC=1O[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:13]=1[F:26].[Cl:33]C1C(F)=C(Cl)N=CN=1.ClC1C=CC=CC=1O>>[Cl:33][C:12]1[C:13]([F:26])=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[N:15]=[CH:16][N:17]=1
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Reactant: Fc1c(Cl)ncnc1Cl
Agent: Oc1ccccc1Cl
Product: Fc1c(Cl)ncnc1Oc1ccccc1Cl

Procedure:
As further shown in Scheme 5, fluoxastrobin may be prepared by sequentially reacting 4,6-dichloro-5-fluoropyrimidine (5) with 2-chlorophenol that gives 4-chloro-6-(2-chlorophenoxy)-5-fluoropyrimidine (17) which on further reaction with (Z)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (15) gives (Z)-fluoxastrobin, which under appropriate conditions may undergo isomerization to fluoxastrobin.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1C=O.CC(C)=[O:22]>>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:22])[CH2:3][CH:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CC(C)=O
Product: O=C1CC(c2ccccc2)Oc2ccccc21

Procedure:
Analogously, (-)-4H-2-carboxamido-4-phenyl-thieno[3,2-c][1]benzopyran, [α]43625 =-110° (c=0.5, acetone) is prepared starting from the pure enantiomeric 4-chloro-3-formyl-flav-3-ene which is obtained by chloroformylation of (-)-flavanone [(-) at 436 nm].
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:40][NH:41][C:42](=[O:66])[C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:65]=[CH:64][C:53]3[N:54]=[C:55]([NH:57][C@H:58]4[CH2:63][CH2:62][CH2:61][NH:60][CH2:59]4)[S:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CC(N(C)C)=O>[C:1]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:58]([NH:57][C:55]2[S:56][C:52]3[CH:51]=[C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([C:42]([NH:41][CH3:40])=[O:66])[CH:48]=4)[CH:65]=[CH:64][C:53]=3[N:54]=2)[CH2:59]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)C(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To the reaction solution of isobutyric acid (4 μl, 40 μmol), HATU (15 mg, 40 μmol) and DIEA (14 μL, 80 μmol) in 400 μl of DMA was added (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (6 μL, 30 μmol). The reaction solution was stirred at room temperature for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-isobutyrylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (6.8 mg, 15 μmol) as white powder. ES/MS m/z 454.2 (MH+).