Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:16][CH:15]=1.Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:21]([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[C:30]([F:32])[CH:31]=[C:10]([F:9])[CH:11]=3)=[CH:28][CH:27]=2)[C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1

Procedure:
5.7 g of freshly distilled phenylsulfenyl chloride in 10 ml of toluene are added dropwise at 0° to +5° C. in the course of 30 minutes to a solution of 12 g of ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 40 ml of pyridine, with stirring. After this, the mixture is stirred for 4 more hours at room temperature. The reaction mixture is poured into 300 ml of 2N hydrochloric acid and ice, and the mixture is extracted twice using diethyl ether. The combined organic phases are washed to neutrality with water and sodium chloride solution and dried over sodium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography on silica gel (eluent: hexane/diethyl ether, 20:1), which gives pure ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, nD20 : 1.5700.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13](N(CC)CC)C.C(OCC)(=O)CC(C)=O.Cl>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[CH2:13][C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(=O)CC(C)=O
Product: O=C1CC(=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4-bromo phthalic anhydride (4.15 g; 0.018 mole) in acetic anhydride (10 g) containing triethylamine (4 g) was treated at room temperature with ethyl acetoacetate (2.38g; 0.02 mole). After 24 hrs. with stirring, crushed ice (20 g) and concentrated hydrochloric acid (10 ml) were added and the precipitated red solid filtered. Addition of a hot (70°-80°C) solution of hydrochloric acid (150 ml) in water (750 ml) to this solid resulted in decarboxylation and generation of 5-bromo indane-1,3-dione as red plates, m.p. (acetone) 152°-3°C. (Found; C, 48.04; H, 2.17; Br, 35.63; C9H5Br O2 requires; C, 48.05; H, 2.24; Br, 35.52%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8](OCC=CC)=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:16]>C1C2C(=CC=CC=2)CCC1>[CH3:1][C:2]1[CH:10]=[C:9]([CH:3]([CH3:4])[CH:2]=[CH2:1])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:16]
Reactant: CC=CCOc1ccc(C)c2c1C(=O)CC2
Solvent: c1ccc2c(c1)CCCC2
Product: C=CC(C)c1cc(C)c2c(c1)C(=O)CC2

Procedure:
8 Grams of 4-methyl-7-crotyloxy-1-indanone was suspended in 50 ml of tetrahydronaphthalene. The suspension was refluxed by heating for 9 hours under argon gas atmosphere. The reaction mixture was purified by means of a silica gel column chromatography (eluent: n-hexane, then a mixture of n-hexane: dichloromethane=2:1) and was recrystallized from a mixture of dichloromethane with n-hexane to obtain 5.44 g of 4-methyl-6-(1-methyl-2-propenyl)-1-indanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)[CH2:10][C:11](N2[C@H](C3C=CC=CC=3)[C@H](C)N(C)C2=O)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Li+]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]([CH:27]2[CH2:28][CH2:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32]2)[CH2:10][CH:11]=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C[C@@H](c2cc(F)cc(F)c2)C2CCS(=O)(=O)CC2)C(=O)N1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CC[C@@H](c1cc(F)cc(F)c1)C1CCS(=O)(=O)CC1
Temperature: 60 °C

Procedure:
To a solution of (4S,5R)-1-[(3R)-3-(3,5-difluorophenyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoyl]-3,4-dimethyl-5-phenylimidazolidin-2-one (618 mg) in anhydrous THF (15 ml) was added lithium borohydride (1.3 ml of 2M solution in THF). The resulting mixture was heated to 60° C. for 2 hours. The mixture was cooled and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3×50 ml). The organic extracts were dried (MgSO4) and evaporated to a solid to give the title compound, which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[C:12]([CH3:44])[CH:11]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][NH:34][CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[C:12]([CH3:44])[CH:11]=1
Reactant: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)c(C)c1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-1 (2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.25 g, 0.50 mmol) in CH2Cl2 (2.0 mL) under N2 and stirred for 1 h. The reaction mixture was made basic with saturated NaHCO3 solution and the resolution solution was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 40 column volumes) yielded the title compound (0.16 g, 80%) as an off-white film: 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.38 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.07 (dd, J=8.5, 2.0 Hz, 1H), 6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.23 (dd, J=7.0, 1.5 Hz, 1H), 4.09 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.77 (t, J=5.5 Hz, 2H), 2.27 (t, J=6.0 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14](=[O:27])[N:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[O:25][CH3:26])[CH3:16])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14](=[O:27])[N:15]([C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([Br:1])=[C:19]([CH3:24])[C:18]=1[O:25][CH3:26])[CH3:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1c(C)cc(C)cc1N(C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1c(N(C)C(=O)OC(C)(C)C)cc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92 %

Procedure:
N-Bromosuccinimide (326 mg, 1.83 mmol) was added to a solution of (2-methoxy-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (456 mg, 1.72 mmol) in dichloromethane (1.8 ml) at 0° C., and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with dichloromethane and adjusted to pH 9 and washed with water and a 1 N aqueous NaOH solution (1 ml), and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-2-methoxy-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester as a colorless solid (545 mg, 92%).
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].S(=O)=O.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:5])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: O=S=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
P-acetoxy benzoic acid 180.16 g (1.0 mol) was added to thionylchloride 500 ml, and dimethylformamide (DMF) 1 ml was dropped in as a catalyst and stirred, and when generation of hydrogen chloride and sulfur dioxide stopped and the reaction liquid cleared, p-acetoxy benzoic acid 180.16 g (1.0 mol) was added another 5 times, i.e. a total of 6.0 mol was added. After all 6.0 mol of the p-acetoxy benzoic acid was added and when the generation of hydrogen chloride and sulfur dioxide stopped, and the reaction liquid cleared, it was heated at reflux for 3 hours, then it was distilled and purified (at 173° C., 10 mmHg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH3:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[C:16]([Cl:22])[N:15]=1>C1COCC1>[Cl:22][C:16]1[C:17]([CH3:21])=[C:18]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:19]=[C:14]([CH3:13])[N:15]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 2,4,6-trimethylphenol (2.720 g, 20 mmol) in 60 ml of dry THF was treated with NaH (60% in oil, 1,200 g, 30 mmol) at room temperature. After stirring at room temperature for 15 minutes, 2,5-dimethyl-4,6-dichloropyrimidine (3.34 g, 20 mmol) was added and the resulting mixture was heated at reflux for 15 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 5.4528 g of beige solid. The solid was recrystallized from isopropanol to give 5.1345 g of pale yellow solid. mp 86-87° C.; high MS (C15H17ClN20) calc. 276.1025, found 276.10359. 1H NMR (CDCl3) δ 6.87 (s, 2H), 2.37 (s, 6H), 2.28 (s, 3H), 2.01 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: Clc1cccc2[nH]c(C3CC3)nc12
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4c(Cl)cccc43)cc2COc2cc(F)ccc21
Yield: 65.7 %

Procedure:
Using 4-chloro-2-cyclopropyl-1H-benzo[d]imidazole (EP1988091; 64 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (105 mg, 67%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:15]=[C:14]([O:29][CH3:30])[N:13]=2)=[CH:8][C:4]=1[CH:5]=[N:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:15]=[C:14]([O:29][CH3:30])[N:13]=2)=[CH:8][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(CCNc2cc(-c3ccc(OC)c(C=NO)c3)nc(OC)n2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCNc2cc(-c3ccc(OC)c(C#N)c3)nc(OC)n2)cc1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde oxime [0.49 g, 1.2 mmol, Example 26(c)], and triphenylphosphine (0.63 g, 2.4 mmol) in DCM (20 mL) is added N-chloro-succinimide (0.32 g, 2.4 mmol) at 10° C. After 2 hours at 20° C., the mixture is concentrated, and subjected to chromatography on silica gel eluting with 5% to 10% MeOH in DCM to afford 2-methoxy-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzonitrile [0.4 g, 85%, Example 55]. LCMS: RT=2.75 minutes, MS: 391 (M+H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]([C:63](O)=[O:64])=[N:55][CH:54]=1>C(Cl)Cl>[F:28][C:26]([F:29])([F:27])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[C:15]([N:9]1[CH2:10][CH2:11][C@H:12]([NH:14][C:63]([C:56]2[C:57]3[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:53]=[CH:54][N:55]=2)=[O:64])[CH2:13][C@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: O=C(O)c1ncnc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1)c1ncnc2ccccc12

Procedure:
Analogously to Example 1, 252 mg (1.45 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-4-piperidineamine in 5 ml of methylene chloride are reacted with 368 mg (1.45 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride, 440 mg (4.35 mmol) of triethylamine and 566 mg (1.32 mmol) of quinazoline-4-carboxylic acid. The title compound is obtained in the form of white crystals. M.p.: 92-172° C.; TLC: hexane/ethyl acetate (1:1) Rf =0.37, FD-MS: M+ =586; [alpha]D=+1.3 (c=0.98, methylene chloride). ##STR16##
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=[C:19]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[N:16][CH:15]=[N:14][CH:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:29]=[C:23]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cncnc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cncnc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-(pyrimidin-5-yloxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].[CH2:16](N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH2:9][C@@H:10]([OH:14])[C:11]([O:13][CH3:16])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC(=O)C(=O)O)cc(C)c1N
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)Cc1cc(C)c(N)c(C)c1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 20.0 g (82.1 mmol) 3-(4-amino-3,5-dimethyl-phenyl)-2-oxo-propionic acid and 25.7 mL (189 mmol) triethylamine in 400 mL THF was cooled to −35° C. Then a solution of 40.0 g (125 mmol) (1R)—B-chlorodiisopinocampheylborane in 100 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C. The reaction mixture was kept for 1 h at this temperature, the cooling bath was removed and the reaction mixture was stirred overnight at RT. THF was evaporated down i.vac., the residue was combined with methanolic HCl (1.25 M) and stirred for 2 h at RT. It was evaporated down i.vac., the residue was taken up in 2 M HCl and extracted exhaustively with EtOAc. The aqueous phase was made alkaline with semiconc. NaOH and exhaustively extracted with EtOAc. The combined organic phases were dried over Na2SO4, suction filtered through activated charcoal and evaporated down. The product was obtained as a brown oil.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:22])(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44](O)[CH3:45])=[C:39]([F:47])[C:38]=2[F:48])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(OC1C=CC(C2C=CC=C(F)C=2F)=CC=1)CCCCCC.C1OC1C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([O:21][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:45])=[C:39]([F:47])[C:38]=2[F:48])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC(C)O)c(F)c2F)cc1
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1CO1
Agent: CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(CC(C)OC(=O)CCCC)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 0° C., 0.1 mol of DCC, dissolved in methylene chloride, is added with exclusion of moisture to a mixture of 0.1 mol of pentanoic acid, 0.1 mol of optically active 4'-heptyloxy-2,3-difluoro-4(2-hydroxypropyl) biphenyl [sic] (which can be prepared by customary metallation of 4'-heptyloxy-2,3-difluorobiphenyl and reaction with optically active propylene oxide) and a catalytic amount of DMAP in 200 ml of methylene chloride. When the addition is complete, the mixture is stirred at room temperature for 12 hours, the precipitate is filtered off with suction, and the product is worked up in a customary manner. The product is purified by chromatography, to give optically active 4'-heptyloxy-2,3-difluoro-4-(2-valeroyloxypropyl)biphenyl.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1.Br[CH2:23][CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[N+:18]([C:17]1[CH:16]=[CH:15][C:14]([O:21][CH2:25][CH:24]=[CH2:23])=[CH:13][CH:12]=1)([O-:20])=[O:19]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
Potassium carbonate (49.7 g, 0.36 mol) was added to an N,N-dimethylformamide (250 ml) solution of p-nitrophenol (25.0 g, 0.18 mol) under nitrogen atmosphere and suspended, and 3-bromopropene (21.7 g, 0.18 mol) was dropwise added thereto. After finishing dropwise adding, the solution was stirred at a room temperature for 5 hours, and then extracting practice with diethyl ether was carried out after adding water to the solution. The organic layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was refined by means of silica gel chromatography (eluent solvent: toluene). Toluene was distilled off under reduced pressure, and then the resulting residue was recrystallized from ethanol to obtain allyl p-nitrophenyl ether (25.7 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.C[O-:16].[Na+]>CO>[OH:16][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]cc(-c2ccncn2)cc1O

Procedure:
A mixture of 5.0 g of 3-bromo-5-(4-pyrimidinyl)-2-(1H)-pyridone, 6.0 g of sodium methoxide and 100 ml of methanol is autoclaved at 200° for twelve hours. The solvent is distilled off in vacuo and the residue treated with water. The aqueous mixture is neutralized with acetic acid and the resulting solid collected, washed with water and dried. Recrystallization from dimethylformamide with a hot filtration yields the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1)=[O:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of 5.00 g 2-(2-amino-5-chlorophenyl)-2,3-dihydro-1H-indole in 70 ml CH2Cl2 at 10° C. were added 3.14 ml triethylamine and then dropwise 2.52 ml trimethylacetylchloride. The resulting solution was stirred for one hour at 10° C. and then quenched with water. The organic phase was separated, washed with 7.5% NaHCO3 and saturated NaCl, dried (MgSO4), and concentrated to yield 5.67 g solid. Recrystallization from cyclohexane yielded 3.09 g solid, m.p. 195°-198° C.
Reaction SMILES: F[C:2]([F:20])(F)[C:3](=[N:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4]#[C:5][C:6]([O:8][CH3:9])=[O:7].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:3]2[C:2]([F:20])=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:27]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)C#CC(=Nc1ccc(OC)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
In a typical reaction, methyl 5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate is mixed with about a 2.5 to 3 fold excess of 4-chlorobenzyl amine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous terahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude methyl 4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4,5-diaminopyrimidine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [C:1]1([CH2:6][OH:7])([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>COCCOC.O>[Si:14]([O:5][CH2:4][C:1]1([CH2:6][OH:7])[CH2:3][CH2:2]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of cyclopropane-1,1-diyldimethanol (3.7 g) dissolved in ethylene glycol dimethyl ether (50 mL) was treated with 60% sodium hydride (1.449 g) at 0° C. under nitrogen. The resulting mixture was stirred at 20° C. for 1 h, treated with tert-butylchlorodimethylsilane (5.46 g) and stirred at room temperature overnight. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (2×250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution 100% DCM). Pure fractions were evaporated to dryness to afford the subtitle compound (5.50 g) as an oil.