Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[C:29]([O:33][C:34](=[O:52])[CH2:35]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:32])([CH3:31])[CH3:30].[S:53]1[C:57]([CH:58]=O)=[CH:56][C:55]2[CH:60]=[CH:61][CH:62]=[CH:63][C:54]1=2>C1COCC1>[C:29]([O:33][C:34](=[O:52])[CH:35]=[CH:58][C:57]1[S:53][C:54]2[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=2[CH:56]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1cc2ccccc2s1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Potassium bis(trimethylsilyl)amide (5.4 g, 0.027 mol) was added to a solution of 18-Crown-6 (13.7 g, 0.052 mol) and (diphenoxy-phosphoryl)-acetic acid tert-butyl ester (9.4 g, 0.027 mol) in dry THF (120 mL) at −780C. After 30 minutes of stirring at this temperature, benzo[b]thiophene-2-carbaldehyde (4.0 g, 0.024 mol) was added and the reaction was stirred for 3 hours at −780C after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mix was allowed to come to room temperature and was extracted with ethyl acetate (3×200 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL), and dried over MgSO4. The solvent was evaporated in vacuo leaving the crude product that was purified by column chromatography (SiO2) using a 5-40% ethylacetate-hexane gradient to afford the subtitle compound (4.64 g, yield: 74%). MS calculated for C15H16O2S+H: 261, observed: 261.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:36]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:24]=2[CH3:36])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]OS(C)(=O)=O)[CH2:29][C@H:28]1[C:40]([O:42][CH3:43])=[O:41])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC1C(F)=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:29][C@H:28]1[C:40]([O:42][CH3:43])=[O:41])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H]1CN(CCOS(C)(=O)=O)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3-carboxylate (Intermediate 40) (1.93 mmol) as described for Intermediate 20 to give the product as a colorless hard foam, 538 mg (56%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][N:35]([CH2:40][CH:41]1[CH2:43][O:42]1)[S:36]([CH3:39])(=[O:38])=[O:37]>C(O)C>[CH3:31][O:32][CH2:33][CH2:34][N:35]([S:36]([CH3:39])(=[O:37])=[O:38])[CH2:40][CH:41]([OH:42])[CH2:43][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: COCCN(CC1CO1)S(C)(=O)=O
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CCOC)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 4.19 g (20 mmol) of N-(2-methoxyethyl)-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2d), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum, and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]#[N:16])[CH:9]=1.Br[CH:18]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C=O)C>[C:15]([C:10]1[CH:9]=[C:8]([Cl:7])[CH:13]=[CH:12][C:11]=1[O:14][CH:18]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])#[N:16]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: O=C(c1ccccc1)C(Br)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OC(OCc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of potassium carbonate (0.06 g, 4.0 mmol), 4-chloro-2-cyanophenol (0.25 g, 1.6 mmol) and ω-bromo-2-benzyloxy-acetophenone (0.49 g, 1.6 mmol) in dry DMF (10 ml) is stirred at room temperature for 20 h. After evaporating the solvent under reduced pressure the residue is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silical gel column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:15]([CH3:31])[C:16](=[O:30])[CH2:17][N:18]([CH2:27][C:28]#[N:29])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Li+].[OH-].FC(F)(F)C(O)=[O:37]>O1CCCC1.O>[NH2:29][C:28](=[O:37])[CH2:27][N:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:17][C:16]([N:15]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:31])=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CN(CC(N)=O)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 77 °C
Reaction time: 0.08 h

Procedure:
N1-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(cyanomethyl)-N2-(3,4-dichlorophenyl)-N1-methylglycinamide (6.1 g, crude) was dissolved in 25 mL of tetrahydrofuran and treated with a solution of LiOH (3.14 g, 74.9 mmol) suspended in 10.8 mL of water. The reaction was stirred vigorously and allowed to reflux at 77° C. for 24 hours before it was determined to be complete by LCMS (Eclipse XDB C18 (4.6×250 mm); trifluoroacetic acid: 1-99% B for 10 min, ES) Rt=7.8 min and m/e 543 [M+1]+. The solvent was removed by rotary evaporation and the crude residue was purified by silica gel chromatography (330 g Redisep column, silica, 40 um, 60 Å, 90 mL/min, A: methylene chloride, B: methanol, B: 0% for 5 min, 10% for 60 min; detection at 214 nm) to give 2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide (2.82 g, 5.2 mmol). MS (ES) m/e 543 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][CH2:28][C:29]#[N:30])[CH3:25]>>[C:29]([CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])#[N:30]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: CCNCCC#N
Product: CCN(CCC#N)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylamino-propionitrile LC-MS: rt=0.91 min, 417 (M+1, ES+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[CH3:8])[CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]([N:20]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:31])[NH:15]2>>[Cl:10][C:11]1[N:19]=[C:18]([N:20]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[N:17]=[C:16]2[C:12]=1[NH:13][C:14](=[O:31])[N:15]2[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8]
Reactant: CC(O)c1cccnc1
Reactant: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Product: CC(c1cccnc1)n1c(=O)[nH]c2c(Cl)nc(-n3cnc4ccc(C#N)cc43)nc21
Yield: 26 %

Procedure:
Yellow oil (26% yield based on 73% conversion). Synthesized using 1-pyridin-3-yl-ethanol and 3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.27 (s, 1H), 9.20-9.00 (br m, 1H), 8.86 (d, 1H), 8.88-8.77 (m, 1H, overlapping with 8.86 ppm), 8.68 (s, 1H), 8.13 (br s, 1H), 7.87 (d, 1H), 7.68 (d, 1H), 6.17 (q, J=7.1 Hz, 1H), 2.19 (d, J=7.3 Hz, 3H); MS (EI) m/z 417.1 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[CH:13]=[CH:12][C:7]4[N:8]=[CH:9][S:10](=[O:11])[C:6]=4[CH:5]=3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=S1C=Nc2ccc(CCBr)cc21
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=S1C=Nc2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc21

Procedure:
To a 100 ml round-bottomed flask with condenser and nitrogen inlet were added 1.0 gram (3.88 mmol) of 6-(2-bromoethyl)benzothiazolone, 822 mg (3.88 mmol) N-(1-naphthyl)piperazine, 410 mg (3.88 mmol) sodium carbonate, and 50 ml methylisobutlyketone. The reaction was refluxed for 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The resulting solid was treated with hot ethyl acetate to afford a white solid, m.p. 198°-220° C., 540 mg (36%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (50 mg, 145 μmol), 2,5-dichloropyrimidine (43 mg, 287 μmol), and DIPEA (75 mg, 431 mol) in isopropanol was stirred at 120° C. for 1 h in a microwave reactor. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H). 1H NMR (500 MHz, CDCl3) δ 8.25-6.85 (m, 7H), 5.55-2.65 (m, 8H), 1.95-0.85 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.S(=O)=O.[S:21](Cl)([Cl:24])(=[O:23])=[O:22]>CCOCC>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: O=S=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc2c(c1)OC(F)(F)O2
Temperature: -30 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 2.37 g (10 mmol) 5-bromo-2,2-difluoro-1,3-benzodioxole in 25 ml anhydrous ether, cooled to −30° C., and 4 ml (10 mmol) n butyllithium (2.5 M in hexanes) was added at −30° C., over 10 minutes. The mixture was stirred at −30° C. for 1 hour, then sulfur dioxide gas was passed through the mixture at −20° C. for 5 minutes. The mixture then was allowed to warm up to 20° C., and the precipitate was filtered and washed with 20 ml hexane. The solid was suspended in 20 ml hexanes, 1.35 g (10 mmol) sulfuryl chloride was added, the mixture was stirred at 20° C. for 48 hours. The mixture then was filtered and the filtrate was concentrated under reduced pressure to obtain 1.6 g (62%) title compound. The product was used in the next step without further purification. 1H-NMR (CDCl3): δ 7.27 (1H,d), 7.74 (1H,s), 7.88 (1H,d).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][CH2:21][CH2:20][CH2:19][Br:18])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCBr
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCCBr)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
To a solution of 2-(phenylmethoxy)benzoic acid (1.0 g, 4.4 mmol), 3-bromopropan-1-ol (0.35 mL, 4.0 mmol), and 4-(dimethylamino)pyridine (50 mg) in 20 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (1.3 g, 6.6 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl three times followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad, and concentrated under reduced pressure. Chromatography (silica gel, 1:9 ethyl acetate/hexane) of the residue afforded 0.8 g (58%) of 3-Bromopropyl 2-(phenylmethoxy)benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(COc2cccnc2N)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2-fluoro-4-methoxylbenzyloxy)pyridine (1.00 g, 0.004 mol), 4chlorophenyl isothiocyanate (0.68 g, 0.0048 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield0.86g(51%),m.p.138°-140° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C.C(OCC)(=O)C>[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[N:18]=1
Reactant: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1

Procedure:
A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate (0.30 g, 1.2 mmol) and thiourea (0.18 g, 2.4 mmol) in ethanol (5.0 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and brine successively; then dried; and then concentrated. The residue was triturated with ether followed by filtration to afford the product. LC-MS: 275.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH:17](O)=[O:18].C(OC(=O)C)(=O)C>COCCOC>[CH:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[N:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:18]
Reactant: O=CO
Reactant: Clc1ccc(NN=Cc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Product: O=CN(N=Cc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
6.91 g of 1A was dissolved in 37.5 ml of dry 1,2-dimethoxyethane and treated with 4.5 g of distilled mixed anhydride of formic acid and acetic acid prepared by mixing the appropriate amount of formic acid and acetic anhydride. The resulting mixture was left for 4 hours at room temperature and then heated up to boiling point and excess solvent removed in vacuo. The residue was triturated with 5% sodium bicarbonate solution, dried and crystallized from methanol to give 1, mp 122°-123° C.
Reaction SMILES: B(O)(O)O.[OH:5]O.S(=O)(=O)(O)O.[F:12][C:13]1[CH:14]=[C:15]([N+:23]([O-:25])=[O:24])[C:16]([OH:22])=[C:17](C(=O)C)[CH:18]=1>O1CCCC1.O>[F:12][C:13]1[CH:18]=[C:17]([OH:5])[C:16]([OH:22])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: OO
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Boric acid (20.45 g, 330.7 mmol), and hydrogen peroxide (35%, 36.8 mL) in tetrahydrofuran (150 ml) was treated with concentrated sulfuric acid (15 ml) and the mixture was stirred at rt for 30 min. 1-(5-Fluoro-2-hydroxy-3-nitrophenyl)ethanone (15 g, 75.4 mmol) in tetrahydrofuran (45 ml) was added and reaction heated for 48 h at 75° C. The reaction mixture was cooled to rt, diluted with water and extracted with DCM (3×500 ml). The combined organic phases were dried on magnesium sulphate, evaporated and the residue was subjected to column chromatography on silica gel using a 20%-80% EtOAc: 40-60 petroleum ether gradient to provide the desired compound (6.55 g, 50%), a 5:1 mixture of desired product and 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (4 g) and recovered 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (1.5 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O>[C:31]1([C:9]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][NH2:21])=[CH:29][CH:30]=3)=[N:11][C:12]3[CH:13]=[CH:14][N:15]4[C:3]([CH2:2][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:4][N:5]=[C:6]4[C:7]=3[CH:8]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccn4c(CCl)nnc4c3cc2-c2ccccc2)cc1
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: NCc1ccc(-c2nc3ccn4c(CN5CCCC5)nnc4c3cc2-c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of 26-1 (0.05 g, 0.1 mmol) in DMSO (1 ml) was added pyrrolidine. The solution was heated at 150° C. for 30 min. The reaction mixture was purified using reverse phase HPLC. The residue was dissolved in MeOH (0.5 ml) and was treated with 1N HCl (0.4 ml). The reaction mixture was stirred at 35° C. for 1 day. Solvent removal afforded the desired product 26-2 as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1CN1CCNCC1.[Li]CCCC.[CH2:39]([O:41][CH:42]=[C:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:40]>C1COCC1.O>[CH2:52]([O:51][C:49](=[O:50])[CH:43]([CH:42]([O:41][CH2:39][CH3:40])[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Li]CCCC
Agent: c1ccc(CN2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(OCC)C(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from 1-Pyridin-2-ylmethyl-piperazine according to the literature: J. Med. Chem. (1993), 36, 2984) (2.00 g, 7.21 mmol) in THF (15 mL) was added n-BuLi (1.6 M in hexanes, 5.0 mL, 7.9 mmol) at −78° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to −78° C. and a solution of diethyl ethoxymethylenemalonate (1.72 g, 7.93 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over 1 hour and stirred at 0° C. for 1 hour. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 8:1 to 1; 1) to give 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 67%) as a mixture of diastereomers. Diastereomer 1: 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=4.4 Hz, 1H), 7.63 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.16 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 5H), 3.75 (q, J=7.2 Hz, 2H), 3.52 (d, J=4.4 Hz, 1H), 3.38 (m, 4H), 2.67 (m, 2H), 2.44 (m, 2H), 1.40 (s, 9H), 1.22 (m, 6H), 1.44 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.61 min. Diastereomer 2: 1H NMR (CDCl3, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 7.59 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.15 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.91 (m, 1H), 4.16 (m, 5H), 3.53 (m, 1H), 3.22 (m, 6H), 2.50 (m, 2H), 2.19 (m, 2H), 1.34 (s, 9H), 1.24 (m, 6H), 0.69 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.62 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9](C#N)[C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc(C)cc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(CC(=O)CCC(=O)O)c(C)c1
Yield: 46 %

Procedure:
This acid was prepared by refluxing 106.5 g (0.390 mol) of ethyl 5-(2',4'-dimethylphenyl)-5-cyano-4-ketopentanoate in 350 ml of glacial acetic acid, 122 ml of water, and 122 ml of concentrated sulfuric acid. The procedure is described in Example I, Part B. The product was obtained as a dark-colored viscous oil, 39.2 g (46% yield).