Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccccc1
Yield: 70.1 %

Procedure:
An amount of 2 g (20 mmol) of 2,2-difluoro-1-chloroethane and 4.5 g (41 mmol) of benzylamine are heated in 62 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 50 ml of water and 50 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 2.4 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 66.2%, based on 2,2-difluoro-1-chloroethane used.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[CH:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[NH2:27][S:28]([NH:31][CH2:32][C:33]1[N:34]2[CH:40]=[N:39][CH:38]=[C:35]2[S:36][CH:37]=1)(=[O:30])=[O:29]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([CH2:32][NH:31][S:28]([NH2:27])(=[O:29])=[O:30])[N+:34]4=[CH:40]3)[CH:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)C(C)[C@H]12
Reactant: NS(=O)(=O)NCc1csc2cncn12
Product: CC1C(Cn2cc3scc(CNS(N)(=O)=O)[n+]3c2)=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Yield: 12.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 88 mg of allyl (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 87 mg of 3-(aminosulfonyl)aminomethylimidazo[5,1-b]thiazole were used, thereby obtaining 14.2 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.BrC1C=CC(C=CC2C=CC(Cl)=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:8]=[CH:9][C:10]3[C:11]([C:6]=2[CH:7]=1)=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3
Reactant: COc1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: Clc1ccc(C=Cc2ccc(Br)cc2)cc1
Product: COc1ccc2ccc3ccc(Br)cc3c2c1

Procedure:
This phenanthrene was prepared as described in Step 2 of Example 36, substituting 1-bromo-4-[2-(4-methoxyphenyl)vinyl]benzene from Step 1 above for 1-bromo-4-[2-(4-chlorophenyl)vinyl]benzene and performing the irradiation for 4 days.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(CCNc3ccncc3)cc2)cc1
Yield: 117.8 %

Procedure:
A solution of 1.495 g (5.2 mmol) of N-(4-pyridyl)-4-biphenyl-acetamide in 30 mL of THF was added dropwise to a rapidly stirred suspension of 0.49 g of lithium aluminum hydride (13 mmol) in 30 mL of THF at room temperature. Once the addition was complete, the mixture was heated to reflux and was refluxed for approximately 17 hours. The mixture was then cooled in an ice bath and quenched by the dropwise addition of 30 mL of saturated ammonium chloride followed by 2 mL of 15% sodium hydroxide. The mixture was filtered and the phases separated. The aqueous phase was extracted with ethyl ether (2×75 mL). The combined organic phases were then dried, filtered, and concentrated to give 1.68 g of a yellow solid. This was chromatographed on silica gel, eluting with 90% CHCl3 /10% CH3OH. Removal of solvent left 1.20 g. of a light yellow solid. This was recrystallized from hexane/ethyl acetate and vacuum oven dried to give 0.773 g of a very light yellow solid. M.P. 140.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14]([OH:17])=[C:13]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:12](=[O:29])[N:11]([CH3:30])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.BrC1SC2C(O)=C(C(NCC(OCC)=O)=O)C(=O)N(C)C=2C=1.FC1C=CC(B(O)O)=CC=1.O>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14]([OH:17])=[C:13]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:12](=[O:29])[N:11]([CH3:30])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2sc(-c3ccc(F)cc3)cc21
Agent: CCOC(=O)CNC(=O)c1c(O)c2sc(Br)cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Solvent: COCCOC
Solvent: O
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
tert-Butyl 2-(2-(4-fluorophenyl)-7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamido)acetate. A mixture of ethyl 2-(2-bromo-7-hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamido)acetate (0.20 g, 0.48 mmol, Method 7), 4-fluorophenylboronic acid (0.134 g, 0.959 mmol, commercially available from Aldrich), Pd(Ph3)4 (0.055 g, 0.048 mmol) in 1,2-dimethoxyethane (4 mL) and aqueous Na2CO3 (2M, 0.72 mL) was heated under N2 at 100° C. for 2 hours. The suspension was cooled to room temperature, poured into water, extracted with CHCl3, dried over MgSO4 and evaporated. The residue was rinsed with Et2O and dried in vacuo to give the title compound. MS (ESI) m/z: Calculated 432.4; Observed; 431.1. 1H NMR (400 MHz, CDCl3) δ ppm 10.72-10.672 (1H, m), 7.53 (1H, s), 7.35-7.30 (2H, m), 7.14 (2H, t, J=8.5 Hz), 4.12 (2H, d, J=5.3 Hz), 3.23 (3H, s), 1.50 (9H, s).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:30]2)(=[O:24])[CH3:23]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 34 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 325 mg of 5-acetamidomethylisoindoline hydrobromide, 536 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1H-NMR (CDCl3) δ: 8.74 (1H, s, C2 --H), 7.89 (1H, d, J=14Hz, C5 --H), 7.26-7.30 (3H, brs, ARM-H), 5.15 (4H, brs, 2 x --CH2N--), 4.47 (2H, d, J=6Hz, CH2NH2), 4.00 (1H, m, ##STR310## 2.06 (3H, s, --COCH3), 1.17-1.31 (4H, m, ##STR311##
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([NH:24][CH2:21][CH2:22][CH3:23])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: CCCN
Product: CCCNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Reaction time: 36 h
Yield: 72.8 %

Procedure:
A mixture of compound 6 (22.5 mg, 0.056 mmol) and n-propylamine (2 mL) was stirred at 85° C. for 36 h. After evaporation of volatiles, the residue was purified by preparative TLC (chloroform-methanol, 20:1) to give compound 13 (17.3 mg, 72.8%) as a slightly yellow solid. 1H NMR (DMSO-d6) δ 0.85 (pseudo t, J=7.5 and 7.3 Hz, 3 H, CH3), 1.47 (sextet, J=7.2 Hz, 2 H, CH2), 3.30 (m, 2 H, CH2), 3.54 (s, 3 H, 9-CH3), 4.58 (br s, 2 H, CH2), 6.33 (br s, 1 H, exchangeable with D2O, NH), 7.10 (pseudo t, J=8.0 and 7.7 Hz, 1 H, H-16), 7.36 (d, J=7.7 Hz, 1 H, H-17), 7.57 (d, J=8.2 Hz, 1 H, H-15), 7.66 (s, 1 H, H-13), 7.72 (s, 1 H, H-8), 7.80 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[S:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1.O.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[S:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (11) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (10) (284 mg, 0.69 mmol), lithium hydroxide monohydrate (66 mg, 2.76 mmol), THF (0.2 mL), methanol (0.4 mL), and water (0.8 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[N:8]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:10]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: Cc1ccc(N)nc1
Product: COc1ccc(-c2cn3cc(C)ccc3n2)cc1OC

Procedure:
The title compound, MS: m/e=269.2 (M+H+), was prepared in accordance with the general method of example 8 from 5-methyl-pyridin-2-ylamine and 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone.
Reaction SMILES: C[Mg]I.C(OCC)C.I[C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[CH:16][S:15][C:14]=12.[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]=[O:30])[CH2:27][C@H:26]([S:31][C:32]2[C@H:33]([CH3:56])[C@@H:34]3[C@@H:44]([C@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH3:46])[C:43](=[O:55])[N:35]3[C:36]=2[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH2:25]1)=[O:23])[CH:19]=[CH2:20].[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]([OH:30])[C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH2:27][C@H:26]([S:31][C:32]2[C@H:33]([CH3:56])[C@@H:34]3[C@@H:44]([C@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH3:46])[C:43](=[O:55])[N:35]3[C:36]=2[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH2:25]1)=[O:23])[CH:19]=[CH2:20]
Reactant: Ic1ncn2ccsc12
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 2 M methylmagnesium iodide/diethyl ether solution (1.30 ml) is diluted with 10 ml of anhydrous THF, and a solution of 650 mg of 7-iodoimidazo[5,1-b]thiazole in 10 ml of anhydrous THF is added dropwise to the diluted solution in an argon atmosphere over a period of 4 min. The mixture is stirred in this state at room temperature for additional 30 min. The internal temperature is lowered to −48° C., and the solution is added dropwise to a solution of 1.003 g of allyl(1R,5S,6S)-2-((3S,5S)-1-allyloxycarbonyl-5-formylpyrrolidin-3-yl)thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 10 ml of anhydrous THF over a period of 5 min. The mixture is stirred in this state at −48 to −40° C. for 40 min, and the temperature is then raised to −25° C. over a period of 50 min. Semi-saturated aqueous ammonium chloride (50 ml) is added thereto, the mixture is extracted with 90 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate, followed by filtration and the removal of the solvent by evaporation to give a yellow viscous material. This viscous material is successively purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and on silica gel (toluene:ethyl acetate=1:9) to give 491.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (a diastereomer mixture) as a yellow amorphous material.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.CO.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([C:20]#[N:21])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2cnc(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (200 mg), 5% Pd/BaSO4 (50 mg), and 20 mL methanol was stirred under 1 atm hydrogen for 18 h. 5 mL of CH2Cl2 was then added, as was an additional 50 mg Pd/BaSO4. After stirring overnight, the reaction was filtered, concentrated, and purified by flash chromatography (30% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: [CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3][C:4]([O:6]C)=[O:5].CO.[OH-].[K+]>O>[CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)C=C(C)/C=C\CC(C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)=CCCC(C)C/C=C\C(C)=CC(=O)O

Procedure:
A mixture of 1 g. of trans/cis methyl 3,7,11-trimethyldodeca-2,4,10-trienoate, 60 ml. of methanol, 0.5 g. of potassium hydroxide and 6 ml. of water is heated at reflux for about 8 hours. The mixture is then diluted with water, neutralized and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to yield trans/cis 3,7,11-trimethyldodeca-2,4,10-trienoic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.Br[CH2:14][CH2:15][O:16][CH3:17].O1CCCC1.[H-].[Na+]>O.CN(C)C(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH2:11][O:12][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][N:10]=1
Reactant: COCCBr
Reactant: OCc1cnc(C2OCCO2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCCOCc1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of [2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]methanol (1.02 g), 1-bromo-2-methoxyethane (1.14 g), tetrahydrofuran (6 mL) and N,N-dimethylacetamide (6 mL) was slowly added sodium hydride (60%, oil, 0.28 g) at 0° C. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and the title compound (0.40 g, yield 29%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). MS: 246 (MH+).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.O[NH:14][C:15](=[NH:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:16][C:15]1[N:17]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:1])[O:11][N:14]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=N)NO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2N)n1
Temperature: 180 °C
Yield: 69.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (3.5 g) in THF (35 mL) was treated with N-hydroxy-acetamidine (1.7 g), and DIEA (8 mL). The reaction mixture was microwave heated at 180° C. for 5 minutes, concentrated and purified by silica gel chromatography to afford 2.6 g of 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenylamine: 1H NMR (300 MHz, CDCl3) δ 8.0 (d, 1H), 7.4 (t, 1H), 6.9 (m, 2H), 6.0 (bs, 2H), 2.6 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[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]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][S:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:53])=[O:52])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CNS(=O)(=O)c2ccccc2)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and benzenesulfonylchloride (5.4 μL, 42 μmole, 1.05 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.44 (s, 2H), 8.17 (t, 1H), 7.72 (dd, 2H), 7.55 (m, 4H), 7.35 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.37 (s, 2H), 3.30 (water), 2.93 (t, 2H), 2.48 (DMSO), 2.44 (t, 2H), 1.61 (m, 4H), 1.21 (m, 1H), 1.11 (m, 1H), 0.51 (m, 4H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[Na].C(O)(=O)C.O>C(O)C>[C:12]1([C:9]2[N:10]=[CH:11][C:6]3[C:4](=[O:5])[NH:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:7]=3[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Nc1ccccc1N
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2ccccc2Nc2nc(-c3ccccc3)ncc21

Procedure:
78 g of 5-ethoxycarbonyl-4-(2-aminoanilino)-2-phenylpyrimidine are added to a freshly prepared boiling solution of 8 g (350 mmol) of sodium in 250 ml of absolute ethanol, while stirring. The suspension which has been formed thereby is heated under reflux for about 45 minutes until complete solution is effected. After cooling, the mixture is neutralized with 20 ml (350 mmol) of glacial acetic acid. 200 ml of ethanol and 200 ml of water are added, the precipitate is filtered off, washed with water and dried in vacuo; yield: 66 g (97%), with m.p. 260° to 261° C. (from dimethyl formamide/water).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:11]1[C:12]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:28]=[CH:27][C:21]([CH2:22][NH:23]C(=O)O)=[CH:20][CH:19]=2)=[N:15][CH:16]=1)(=[O:10])[NH2:9].O>C(OCC)(=O)C>[NH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:14]2[N:13]=[C:12]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[C:11]([C:8]([NH2:9])=[O:10])=[CH:16][N:15]=2)=[CH:28][CH:27]=1
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CNC(=O)O)cc3)ncc2C(N)=O)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 4 ml portion of 4 M hydrochloric acid-dioxane solution was added to 183 mg of tert-butyl ester of {4-[5-carbamoyl-4-(3-methylanilino)pyrimidin-2-ylamino]benzyl}carbamic acid, followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, the thus formed insoluble matter was removed by filtration and the filtrate was alkalified by adding 1 M sodium hydroxide aqueous solution. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue concentrated under a reduced pressure was recrystallized from a mixed solvent of ethyl acetate and n-hexane, thereby obtaining 44 mg of 2-(4-aminomethylanilino)-4-(3-methylanilino)pyrimidine-5-carboxamide (light yellow crystals).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([NH:25][NH2:26])([CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=1.ClC(OCC)=O.C(OC(OCC)=O)(=O)OCC>>[CH2:22]([O:21][C:19]([O:18][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([NH:25][NH2:26])([CH3:24])[C:3]([OH:27])=[O:2])[CH:11]=[CH:10][C:9]=1[O:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:20])[CH3:23]
Reactant: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OC)cc1OC(=O)OCC
Agent: CCOC(=O)Cl
Agent: CCOC(=O)OC(=O)OCC
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)O)cc1OC(=O)OCC

Procedure:
Following the procedure for preparation of 106, and substituting ethyl chloroformate and 108 with diethyl pyrocarbonate and 102, respectively, provided the title compound. 1H NMR (CD3OD, 400 MHz): 1.18 (t, 6H), 1.36 (s, 3H), 3.01 (dd, 2H), 3.80 (s, 3H), 4.17 (q, 4H), 7.08–7.17 (m, 3H). MS (ESI) m/z 371.24 (M+H+).
Reaction SMILES: C([O:8][CH2:9][C:10]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:37])[CH:20]([NH:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[C:28]([F:36])[CH:29]=[C:30]([F:35])[CH:31]=3)[CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][C:10]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:37])[CH:20]([NH:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[C:28]([F:36])[CH:29]=[C:30]([F:35])[CH:31]=3)[CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:11])[CH3:12]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)COCc2ccccc2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)CO)s1

Procedure:
A mixture of 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (300 mg) in ethyl acetate (20 mL) was treated with 600 mg of 10% Pd/C (50% water) and hydrogenated at 45 psi overnight. The mixture was filtered through celite, washed with ethylacetate. The combined filtrate was concentrated to dryness, added ethanol (10 mL), ethyl acetate (10 mL) and chloroform (5 mL) and treated with 1.4 g of 10% Pd/C (50% water) and hydrogenated at 50 psi overnight. The mixture was filtered through celite, washed with a mixture of methanol and chloroform. The filtrate was concentrated to give a light yellow oil. The oil was triturated with a 5:1 of hexane:chloroform to give 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide as an off-white solid, LC-MS RT=1.8 min, M+1=439.0.
Reaction SMILES: [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]([O:15]CC)=O.[Na].C(O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10](=[O:18])[CH2:11][CH2:12][C:13]1=[O:15]
Reactant: CCOC(=O)CCC(=O)Cc1ccc(C)cc1C
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C2C(=O)CCC2=O)c(C)c1
Yield: 49.2 %

Procedure:
Utilizing 21.46 g. (0.0864 mol) of ethyl 5-(2',4'-dimethylphenyl)-4-ketopentanoate, 4.00 g. (0.173 mol) of sodium, 125 ml of dry ethanol, 200 ml of toluene, and the procedure described in Example I, Part D, 8.60 g (49% yield) of 2-(2',4'-dimethylphenyl)-1,3-cyclopentanedione was obtained as a white, crystalline solid, m.p. 198.0°-200.5° C.