Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C@@H:14]([O:19][C:20]([C@H:22]2[C@@H:24]([CH:25]=[C:26]([Cl:31])[C:27]([F:30])([F:29])[F:28])[C:23]2([CH3:33])[CH3:32])=[O:21])[C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1N=C([C@H](OC([C@@H]2[C@H](C=C(Cl)C(F)(F)F)C2(C)C)=O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>>[O:1]([C:8]1[N:13]=[C:12]([CH:14]([O:19][C:20]([C@H:22]2[C@@H:24]([CH:25]=[C:26]([Cl:31])[C:27]([F:28])([F:29])[F:30])[C:23]2([CH3:33])[CH3:32])=[O:21])[C:15]([F:16])([F:17])[F:18])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@H](c1cccc(Oc2ccccc2)n1)C(F)(F)F
Agent: CC1(C)[C@H](C(=O)O[C@@H](c2cccc(Oc3ccccc3)n2)C(F)(F)F)[C@@H]1C=C(Cl)C(F)(F)F
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F

Procedure:
[1-(6-Phenoxy-2-pyridinyl)-(R)-2,2,2-trifluoroethyl]-(1S)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate plus [1-[6-phenoxy-2-pyridinyl]-(S)-2,2,2-trifluoroethyl]-(1R)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH2:21][CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]4=[O:20])[C:3]=3[CH2:21][CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one (40.0 mg, 0.120 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)-amino)-3-ethyl-5,7-difluoro-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.96 (1H, d, J=11.9 Hz), 7.60 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.0 Hz), 6.90-7.07 (1H, m), 6.71 (1H, br. s.), 4.38 (1H, br. s.), 3.85-4.03 (4H, m), 3.71-3.84 (4H, m), 3.58 (1H, d, J=11.0 Hz), 3.34 (2H, ddd, J=11.9, 6.1, 2.9 Hz), 3.08-3.19 (3H, m), 2.92-3.07 (2H, m), 2.43-2.62 (3H, m), 1.92-2.26 (6H, m), 0.97-1.11 (3H, m). Mass Spectrum (ESI) m/e=554.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:43]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CNC(=O)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In analogy to the procedure described under (d), from tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate by acylation with benzoyl chloride there was obtained crude tert-butyl (3RS,4RS)-4-[4-(benzoylamino-methyl)-phenyl]-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[F:1][C:2]1[C:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1-c1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Fc1cccc2[nH]c3cccc(F)c3c12
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 2,2′-difluoro-6-nitro-1,1′-biphenyl (0.740 g, 3.1 mmol) and triphenylphosphine (2.063 g, 7.9 mmol) in anhydrous 1,2-dichlorobenzene (1.5 mL) was heated to 175° C. in a microwave reactor for 3 hrs. The mixture was cooled to room temperature and purified by silica gel chromatography (5-50% methylene chloride/hexanes) to afford the product as a white solid (0.28 g, 44%). 1H NMR (CDCl3, 300 MHz) δ 8.26 (br s, 1H), 7.39 (tt, 2H, J=8.1, 2.4 Hz), 7.22 (d, 2H, J=8.1 Hz), 6.97 (dt, 2H, J=8.1, 5.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10]O)=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][Cl:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCl
Reactant: COc1cc(CO)cc(OC)c1Br
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CCl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of (4-bromo-3,5-dimethoxyphenyl)methanol (10.0 g, 40.6 mmol) and dichloromethane (100 mL) were added triethylamine (12.4 mL, 89.3 mmol) and methanesulfonyl chloride (3.46 mL, 44.7 mmol) in this order while cooling on ice, and the mixture was stirred at room temperature for 14 hours. To the mixture was added water, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.47 g, 9.30 mmol).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5.0 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 4-(4-fluorophenyl)-piperazine in 30 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature around 90° C. for approximately 4 hours. After cooling to approximately 20° C., 25 cm3 of water were added to the reaction mixture. The insoluble material was filtered off and washed with 2 times 25 cm3 of water. After recrystallizing once from 150 cm3 of dimethylformamide, 7.6 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 318-9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:15].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24]([CH3:27])(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:23][C:21]1[CH:22]=[CH:17][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([NH:15][CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=3[O:13][CH3:14])[CH2:5][CH2:6][CH2:7]2)[CH:20]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COc1ccc(OC)c2c1CCCC2N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c2c1CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Yield: 96.8 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine (1.1 g mL, 5.31 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.02 g, 5.31 mmol) and diisopropylethylamine (3.7 mL, 21.26 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried, and concentrated under reduced pressure to yield 1.95 g of a yellow oil. The residue was purified by PTLC (25% ethyl acetate in hexanes) to give 1.26 g (63%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, 1H), 6.73 (d, 1H), 6.66 (m, 2H), 6.44 (dt, 1H), 6.22 (br d, 1H), 4.79 (br s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 2.96-2.88 (m, 4H), 2.46-2.37 (m, 1H), 2.17-2.12 (br d, 1H), 1.92-1.84 (m, 1H), 1.78-1.60 (m, 2H). MS (ESI) m/z: Calculated: 379.13; Observed: 402.2 (M++23).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[C:14]3[S:19][C:18]([O:20]C)=[N:17][C:15]=3[N:16]=2)[CH3:9])=[N:6][CH:7]=1>[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@@H:23]([CH2:24][OH:25])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]3[S:19][C:18](=[O:20])[NH:17][C:15]=3[N:16]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1nc2nc(S[C@@H](C)c3ccc(F)cn3)nc(N[C@@H](CO)CC(C)C)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(F)cn2)nc2[nH]c(=O)sc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from (2R)-2-[(5-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol from the previous step using General method D, except that the reaction mixture was stirred at 50° C. for 3 h. After complete reaction the reaction mixture was diluted with Brine and extracted with DCM (three times). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo. The product was purified by flash chromatography (eluent DCM: methanol gradient). Further purification by preparative HPLC (column Chiralcel OJ, eluent: ethanol, flow: 8 mL/min) yielded 113 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.Cl.[NH2:22][CH2:23][C:24]([O:26]CC)=[O:25].CCN(CC)CC>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:8][CH2:9][C:18]([OH:20])=[O:19])=[O:14])[CH:10]1[CH:23]([C:24]([OH:26])=[O:25])[NH2:22])([OH:17])=[O:16]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NCC(=O)O
Reaction time: 8 h
Yield: 164.2 %

Procedure:
To a solution of ethyl (1SR, 2SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (190 mg, 0.55 mmol) in dry THF (3.5 mL) under argon was added ethyl glycinate hydrochloride (466 mg, 3.34 mmol), potassium cyanide (1.7 mg, 0.02 mmol) and Et3N (0.44 mL, 3.34 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 235 mg of the desired compound (95% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](SC)[C:5](=[O:12])[NH:6]2.ClN1C(=[O:21])CCC1=O.C1COCC1.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[C:5](=[O:12])[NH:6]2
Reactant: CSC1C(=O)Nc2ccc(C)c(Cl)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1Cl)C(=O)C(=O)N2
Yield: 80.9 %

Procedure:
This compound is prepared according to the procedure described in stage B of Preparation 1.10 from 0.72 g of 4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and 0.422 g of N-chlorosuccinimide in 72 ml of carbon tetrachloride and then from 58 ml of THF and 14 ml of water. The product obtained is chromatographed on silica gel, elution being carried out with DCM and then with the gradient of the DCM/AcOEt mixture up to (90/10, v/v). 0.5 g of the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[NH2:25][OH:26].[OH-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:9]3[C:14]([C:15]=2/[C:16](=[N:25]/[OH:26])/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(Cl)s2)n(-c2ccc(O)cc2)c2ccccc12
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N/C(=N\O)c1c(-c2ccc(Cl)s2)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
The compound 2-(5-chlorothiophen-2-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbonitrile (Example 86) was dissolved in DMSO (0.25 mL) and hydroxylamine (0.25 mL, 100 eq) was added from a 2M stock solution of hydroxylamine*hydrochloride neutralized with sodium hydroxide (pH=7.01 as measured with pH-meter). The mixture was stirred at 60° C. for 18 hours. The cooled mixture was diluted with brine and extracted with EtOAc and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 386.3 (M+H), 384.2 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.89 (m, 1H), 7.21-7.13 (m, 4H), 7.04 (m, 1H), 7.00-6.97 (m, 3H) and 6.91 (d, 1H, J=4.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([CH2:21][OH:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].S(=O)(=O)(O)O.[O-][Mn](=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+].[CH3:39][OH:40]>O>[C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:40][CH3:39])=[O:22])([F:19])[F:20])[F:17])([F:13])[F:14])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: CO
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 95 °C
Yield: 49.9 %

Procedure:
A 2 liter glass flask equipped with a thermometer, reflux condenser, dropping funnel and stirrer was used. 159 g of CF3O(CF2)3OCHFCF2CH2OH, 520 g water, and 100 g sulfuric acid were added to the flask. 190 g KMnO4 were added manually to the liquid over a period of 2 hours while stirring. The reaction temperature increased to 95° C. over time. After a post reaction time of two hours, an aqueous solution of sodium bisulfite was added until a clear solution was formed. 100 g of methanol and in total 400 g of 50% aqueous sulphuric acid were added. Flash distillation of the reaction mixture resulted in a two phase distillate. Fractionation of the lower phase (120 g) gave 85.5 g of CF3O(CF2)3OCHFCF2COOCH3 (bp 34-35° C./6 mbar; yield 50%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11](O)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:21]>>[C:1]1([C:7]2[N:12]=[C:11]([Cl:21])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Yield: 81 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].CC(C)([O-])C.[K+]>CN(C)C=O>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a microwave tube, 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 are introduced into 1 ml of N,N-dimethylformamide, 623 mg of 2-fluoroaniline and 378 mg of potassium tert-butoxide. 2 ml of N,N-dimethylformamide are then added. The tube is then microwave-heated at 150° C. for 20 minutes. The reaction mixture is concentrated under reduced pressure. 30 ml of water and 10 ml of ethyl acetate are added and the resulting mixture is thus stirred for 1 h 30. The precipitate formed is filtered off and rinsed with ethyl acetate, ethyl ether and then petroleum ether. The solid obtained is dried in a rotary evaporator and 93 mg of N-(2-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>ClC(Cl)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1ccsc1N
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1sccc1C(=O)OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Valeryl chloride (1.3 g) was added to a solution of methyl 2-aminothiophene-3-carboxylate (1.6 g) [Y. Kuwada et al. Chem. Abst. 82, 156252(1975)] and triethylamine (1.2 g) in dichloroethane (20 ml) under ice-cooling. The mixture was stirred for two hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (2.3 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Br

Procedure:
A mixture composed of 5.21 g (20 mmol) of (2-bromo-5-nitrophenyl)acetic acid (Zhumal Organicheskoi Khimii (1974) 10, 92-5), 80 ml of absolute ethanol and 0.1 ml of concentrated sulfuric acid is refluxed for 6 hours. After cooling, the reaction medium is concentrated under vacuum and taken up in ether. This organic phase is washed with saturated NaHCO3 solution and then with water, after which it is dried over Na2SO4. After concentrating under vacuum, 5.54 g of a beige solid are obtained.
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].BrC1SC(S(C[N:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[C:30]2=[O:36])(=O)=O)=CC=1.COC1C=CC(B(O)O)=CC=1>>[OH:35][C:31]1[C:30](=[O:36])[N:29]([CH2:2][S:3]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])[CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)CCl)s2)cc1
Reactant: O=c1c(O)cccn1CS(=O)(=O)c1ccc(Br)s1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Cn3cccc(O)c3=O)s2)cc1

Procedure:
The titled compound was synthesized in a similar manner as described in Example 60 by replacing 1-chloromethanesulfonyl-4-methyl-benzene with 2-chloromethanesulfonyl-5-(4-methoxy-phenyl)-thiophene (synthesized from 2-bromo-5-chloromethanesulfonyl-thiophene from Example 63 and 4-methoxy-phenyl boronic acid according the procedure described in example 52 Step A) in Example 60 Step B. MS (EI) 378 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].O>C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH2:16][Cl:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: CCOCC
Product: ClC/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Phenoxyphenyl)prop-2-en-1-ol (0.05 g) was dissolved in diethyl ether (2 cm3) which had been previously saturated with hydrogen chloride gas, and the solution was stirred at the ambient temperature for 2 hours. Water was added to the mixture and the products extracted into further diethyl ether. The combined ethereal layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support, eluted with hexane containing 5% by volume ethyl acetate, to give E-3-(3-phenoxyphenyl)-1-chloroprop-2-ene (0.03 g).
Reaction SMILES: [Li+].[BH4-].CO.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH2:17][CH3:18])[C:13](OC)=[O:14])=[CH:8][CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH2:17][CH3:18])[CH2:13][OH:14])=[CH:8][CH:7]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CO)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of LiBH4 (120 mg, 5.43 mmol) in THF (5 mL) was added MeOH (174 mg, 5.43 mmol) and a solution of methyl 2-(4-chlorophenyl)-2-(4-(N-((2-(trimethylsilyl)ethoxy)methyl)methylsulfonamido)-1H-indazol-1-yl)butanoate (600 mg, 1.09 mmol) in THF (8 mL) followed. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as a pale yellow solid. LC/MS m/z=524.2 [M+H]+.