Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:38]=[CH:37][C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:22]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[C:39]([C:36]1[CH:37]=[CH:38][C:21]([O:20][CH2:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=2)=[C:22]([CH:35]=1)[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)=[O:24])([OH:41])=[O:40]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCC3CCCCC3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCc2ccc(OCCCC3CCCCC3)cc2)c(C(=O)N2CCC(C(=O)O)CC2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Absolution of 10.4 g of methyl 1-[2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate in a mixture of 160 ml of THF and 160 ml of methanol is mixed with 160 ml of 2 molar sodium hydroxide solution and stirred at a temperature of 60° C. for 1 hour. The organic solvents are then removed as far as possible in a rotary evaporator. 165 ml of 2 molar hydrochloric acid are added to the remaining aqueous solution with stirring. A precipitate separates out. Precipitation is completed by stirring at 0° C. The precipitate is filtered off with suction and washed with water. The crude product is purified by recrystallization from a solvent mixture composed of 250 ml of acetone and 200 ml of water. 8.7 g of a solid are obtained and are again heated to reflux in a mixture of 300 ml of water and 100 ml of acetone for 6 hours. Cooling to 0° C., filtration, washing with water and drying result in 8.6 g of a solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH:8]=[C:7]([C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:6][C:5]=2[S:4][CH:3]=1.[O-]CC.[Na+].[Na].Br[CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:9]2[CH:8]=[C:7]([C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:6]([CH2:24][C:25]([OH:27])=[O:26])[C:5]=2[S:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1csc2[nH]c(C(=O)c3ccccc3)cc12
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1csc2c1cc(C(=O)c1ccccc1)n2CC(=O)O
Reaction time: 0.25 h

Procedure:
The previously obtained 3-methyl-5-benzoyl thieno[2,3-b]pyrrole, suspended in 500 ml of ethanol is added to a sodium ethoxide solution freshly prepared by dissolving 24.6 g of sodium in 500 ml of ethanol, and the whole is agitated for 15 minutes; then 125 g of ethyl bromoacetate are added. The whole is refluxed for 4 hours and then hydrolysed by the addition of 600 ml of sodium hydroxide solution (N). The whole is refluxed for 30 minutes and the ethanol is eliminated by distillation. The cooled solution is then filtered. The filtrate is acidified to a pH of approximately 3, and the precipitate obtained is washed with water and recrystallised in a mixture of benzene and cyclohexane. In this manner 150 g of 3-methyl-5-benzoyl-6-carboxymethylthieno[2,3-b]pyrrole are obtained; m.p.=197° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)c(F)c1)C(=O)OCC
Temperature: 100 °C
Yield: 77.7 %

Procedure:
A mixture of 3-fluoro-4-methoxy-aniline (0.7 g, 4.96 mmol) and diethyl 2-(ethoxymethylene)propanedioate (1.1 g, 4.96 mmol) was heated at 100° C. for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure, and then purified via silica gel column chromatography using 1 to 60% EtOAc in hexanes to yield diethyl 2-((3-fluoro-4-methoxyphenylamino)methylene)malonate (1.2 g, 78%). LC/MS: m/z 312.3 (M+H)+ at 1.69 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:17]=1
Reactant: Ic1cccnc1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccnc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.54 mmol) and 3-iodopyridine (122 mg, 0.60 mmol) according to the general procedure IC to give 27 mg (43% b.r.s.m.) of an orange brown solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.09 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.76-7.75 (m, 1H), 7.54-7.52 (m, 1H), 7.81-7.77 (m, 1H), 7.48-7.45 (m, 2H), 7.29-7.25 (m, 1H), 7.22-7.19 (m, 2H), 3.67 (s, 3H), 3.00-2.95 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 152.2, 148.4, 141.5, 138.3, 131.8, 128.4, 123.0, 120.5, 120.4, 92.5, 85.7, 51.6, 35.3, 30.8; EI-MS calcd for C17H15NO2 (M+): 265. found: 265.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: OCC1CCC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCC1CCC2CN(c3ncccn3)CCN2C1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 4.5 g (26 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874), 3.0 g (26 mmol) of 2-chloropyrimidine, and 6.7 g (63 mmol) of sodium carbonate in 100 mL of water is heated at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with methylene chloride (3×), the combined organic layers were washed with water and brine, dried, filtered and evaporated to give 4.68 g (72%) of the title compound which was used without purification in subsequent reactions.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:17][C:18]([CH:20]1[C:25](=O)[CH:24](Br)[CH2:23][CH2:22][CH2:21]1)=[O:19]>O.[Cl-].[Zn+2].[Cl-]>[CH2:8]([N:7]1[C:22]2[CH2:23][CH2:24][CH2:25][CH:20]([C:18]([OH:19])=[O:17])[C:21]=2[C:2]2[C:1]1=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=C(O)C1CCCc2c1c1ccccc1n2Cc1ccccc1

Procedure:
A mixture of 53 g. of phenylbenzylamine and 30 g. of ethyl 6-bromocyclohexanone-2-carboxylate was maintained in a nitrogen atmosphere at 35° C. for several days. Fused powdered zinc chloride (48 g.) was added and the mixture was heated at 125°-130°C. for 11/2 hours. The cooled mixture was slurried in water and extracted with ether. The ether extract was washed with 5% hydrochloric acid and water, dried, and evaporated to dryness to give 38.5 g. crude ethyl ester of the title compound which was treated with a solution of 48 g. potassium hydroxide in 200 ml. water and 200 ml. ethyl alcohol at reflux temperature for three hours. The solution was evaporated to dryness under reduced pressure, the resulting residue was dissolved in water and the aqueous solution was extracted with ether and acidified with 10% hydrochloric acid. The resulting solids were collected and dried to give 27.4 g. of the title compound; m.p. 212°-215°C. (tetrahydrofuran-pentane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]2)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1CCN(CC2CCCCN2)CC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(piperidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(Cl)cc3)c2c1
Yield: 65.8 %

Procedure:
N-{3-[(E)-2-(4-Chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 631 mg of trans-2-(4-chlorophenyl)vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 48 mg of tetrakis(triphenylphosphine)-palladium[0]. 556 mg of N-{3-[(E)-2-(4-chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 247° C. (analysis C22H18ClN3O4S2 % calculated C, 54.15; H, 3.72; Cl, 7.27; N, 8.61; O, 13.11; S, 13.14. % found C, 54.32; H, 4.40; Cl, 5.65; N, 7.83; S, 11.93).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:16])[CH3:15]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC(C)(CO)NC(=O)c1ccc(Cl)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 26, using 5-chloro-2-pyridinecarboxylic acid obtained in Example 40-2) and 2-amino-2-methyl-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:28])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([F:27])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:13]([F:28])[F:12])=[N:15][CH:16]=1)[CH2:23][C:24]1([F:27])[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.89. [α]D20=+21.70 (c=3.00 mg/mL,CHCl3)
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](O)=[O:19])[CH:14]=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:5]1=2)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C([O-])([O-])=O.[K+].[K+].[N:42]1[CH:47]=[CH:46]C=NN=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]3[O:19][CH:46]=[CH:47][N:42]=3)[CH:14]=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:5]1=2)(=[O:3])[CH3:2]
Reactant: c1cnnnc1
Reactant: CC(=O)N1Cc2cc(-c3ccccc3C(=O)O)ccc2C=Cc2cc(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(-c3ccccc3-c3ncco3)ccc2C=Cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a mixture of Example 222 (20 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added one drop of DMF. The solution was cooled to 0° C., oxalyl chloride (3 μl, 0.055 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated to a yellow solid, taken up in sulfolane and treated with K2CO3 (14 mg, 0.1 mmol) and 1,2,3-triazine (3 μl, 0.05 mmol). The mixture was heated at 140° C. for 5 hours, then water was added. The resulting mixture was filtered, and the solid was purified by preparative reversed-phase HPLC to give the title compound (3.3 mg, 15%). HPLC Rt=2.36 (b) min. m/z=427 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].FC(F)(F)C1C=CC(C2C=C(C(O)=[O:33])SC=2)=CC=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:17]([OH:33])=[O:18]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O

Procedure:
The title compound was prepared using 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 74) by a method analogous to the preparation of 4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid (intermediate 38).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17](OCC)=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Li+]>CO>[O:1]([CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN1CC(COc2ccccc2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OC(COc2ccccc2)CN1CCCO
Yield: 100.4 %

Procedure:
A procedure similar to that described in Preparation 5(a) was repeated, except that 1.64 g of ethyl 3-(5-phenoxymethyl-2-oxooxazolidin-3-yl)propionate (prepared as described in Preparation 113), 15 ml of anhydrous tetrahydrofuran, 244 mg of lithium borohydride and 179 mg of anhydrous methanol were used, to give 1.41 g of the title compound having an Rf value of 0.28 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][O:17][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26]1)=[O:31])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Yield: 80.2 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.23 g, 30.1 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and cooled to 0° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.23 g, 10.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.03 g, 12.3 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. A sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give 3-(4-phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.35 g, 80%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[N:41]=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Clc1cccnn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of the compound (556 mg, 1.0 mmol) obtained in Example 16-5), 3-chloropyridazine (172 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (292 mg, 58%) as a light yellow oily substance.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]1([S:10]([CH2:13]P(=O)(OCC)OCC)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([C:37](=O)[C:38]([F:41])([F:40])[F:39])[CH:33]=[C:34]([Cl:36])[CH:35]=1>C(OCC)(=O)C.O.C(#N)C>[C:4]1([S:10]([CH:13]=[C:37]([C:32]2[CH:33]=[C:34]([Cl:36])[CH:35]=[C:30]([Cl:29])[CH:31]=2)[C:38]([F:41])([F:40])[F:39])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Magnesium chloride (dry, 3.16 g, 33.2 mmol) was put in a flask under a nitrogen atmosphere and acetonitrile (100 mL) was added. The mixture was stirred for five minutes at room temperature. Diethyl [(phenylsulfonyl)methyl]phosphonate (10.0 g, 89% purity, 30.4 mmol) was added. After 5 minutes stirring the magnesium chloride was nearly dissolved. Triethylamine (5.01 mL, 35.9 mmol) was added and after 10 minutes at room temperature a yellow solution was obtained. Then 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (6.89 mg, 98% purity, 27.7 mmol) was added. After stirring for one hour additional magnesium chloride (0.1 eq.) and triethylamine (0.1 eq.) were added and the mixture was stirred for additional 30 minutes. Then, additional triethylamine (0.1 eq.) was added. Water (100 mL) and ethyl acetate (200 mL) were added and the phases were separated. After extracting the aqueous phase twice with ethyl acetate (100 mL) the combined organic phases were washed three times with water (100 mL), three times with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and the solvents evaporated. The yellow oil was recrystallized from n-heptane. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfone was obtained (10.5 g, 97% purity, 98% yield, E/Z (not assigned)=64/36).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:19]([O:21]CC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[K+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:19]([OH:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CCCCCOCOCCOC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCCCCOCOCCOC)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 1.029 g of diethyl 2-[5-(2-methoxyethoxy)methoxypentyl]malonate (prepared as described in Preparation 41) dissolved in ethanol (1.5 ml) was added an aqueous solution (1.5 ml) containing potassium hydroxide (0.203 g) whilst ice-cooling. The reaction mixture was stirred at room temperature for 5 hours, after which it was washed with diethyl ether. The aqueous layer was adjusted to a pH value of 2 by adding 10% aqueous hydrochloric acid, and it was then extracted four times with methylene chloride. The combined extracts were dried and concentrated by evaporation under reduced pressure. The oily residue (0.94 g) was subjected to column chromatography through silica gel (20 g) and the title compound (0.764 g) Was obtained, as a colorless oil, from the fractions eluted with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:1 by volume.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+].[CH2:19]([O:21][C:22](=[O:28])[CH2:23][C:24]([CH2:26]Br)=O)[CH3:20]>C(O)C>[CH:11]([O:10][C:8]([C:3]1[CH:2]([CH3:1])[CH2:6][N:5]2[C:24](=[CH:23][C:22]([O:21][CH2:19][CH3:20])=[O:28])[CH2:26][S:7][C:4]=12)=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)C1C(=S)NCC1C
Reactant: CCOC(=O)CC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.5 %

Procedure:
4.9 g of isopropyl 4-methyl-2-thioxopyrrolidine-3-carboxylate was dissolved in 50 ml of ethanol and 3.0 g of anhydrous sodium acetate and 7.7 g of 4-bromoacetoacetic acid ethyl ester were added thereto. The obtained mixture was stirred at room temperature for 3.5 hours. The crystals thus precipitated were collected by filtration, washed with water and dried. After recrystallization from a mixture of chloroform and ethanol, 3.3 g of the title compound was obtained.