Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([N:36]=[N+]=[N-])[C@H:27]([O:39][C:40](=[O:42])[CH3:41])[C@H:26]1[O:43][C:44](=[O:46])[CH3:45])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH2:36])[C@H:27]([O:39][C:40](=[O:42])[CH3:41])[C@H:26]1[O:43][C:44](=[O:46])[CH3:45])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 100 %

Procedure:
A solution of 1S (430 mg, 0.65 mmol) and 10% Pd/C (80 mg) in methanol (20 ml) was stirred under a hydrogen atmosphere for 30 min. The mixture was filtered through Celite and concentrated to give 413 mg (100%) of unstable glycosylamine 2S which was used without further purification in the next reaction.
Reaction SMILES: CC(C)N=C=NC(C)C.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([F:44])([F:43])[F:42])[CH2:37][CH2:36]2)[CH:32]=[CH:31][C:30]=1[NH:45][CH3:46])=S>CC#N>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:25][CH:26]1[NH:28][C:29]2[CH:34]=[C:33]([N:35]3[CH2:40][CH2:39][CH:38]([C:41]([F:44])([F:43])[F:42])[CH2:37][CH2:36]3)[CH:32]=[CH:31][C:30]=2[N:45]1[CH3:46]
Reactant: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CN1c2ccc(N3CCC(C(F)(F)F)CC3)cc2NC1Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C

Procedure:
DIC (130 μL, 0.8 mmol) was added to N-(4-chloro-3-{3-[2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)-phenyl]-thioureido}-benzyl)-2,2-dimethyl-propionamide (180 mg, 0.3 mmol) in MeCN. The reaction mixture was heated at 60° C.-80° C. for one week (additional DIC (2.5 ml) was added). The mixture was cooled to rt and concentrated. The residue was treated with MeCN, filtered and washed. The filtercake was diluted with dioxane and HCOOH and lyophilized to give the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])C.O1CCCC1.B.Cl.O>C1COCC1>[OH:11][CH2:10][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cccc(C(=O)O)c1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1cccc(CO)c1
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(3-ethoxy-3-oxopropyl)benzoic acid (2.99 g) in THF (100 mL) was added a 1.0 M solution of tetrahydrofuran-borane in tetrahydrofuran (26.9 mL) at 0° C., and the mixture was stirred in an ice bath for 18 hr. A 1.0 M solution of tetrahydrofuran-borane in tetrahydrofuran (20.0 mL) was added at 0° C., and the mixture was further stirred for 20 hr in an ice bath. 1N Hydrochloric acid (100 mL) and water were added at 0° C., and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.80 g) as a colorless oil.
Reaction SMILES: CN(C[CH2:11][CH2:12][N:13]([CH3:33])[C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[CH:17]=[C:16]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:15]=1)C(=O)OC(C)(C)C.N1(C2C3OC=CC=3C=C(N)C=2)CCC[CH2:36][CH2:35]1>>[N:13]1([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:12][CH2:11][CH2:36][CH2:35][CH2:33]1
Reactant: Nc1cc(N2CCCCC2)c2occc2c1
Reactant: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Product: O=S(=O)(Nc1cc(N2CCCCC2)c2occc2c1)c1ccccc1

Procedure:
The synthesis was performed according to the procedure of Intermediate 3 starting from 7-piperidin-1-yl-1-benzofuran-5-amine (Intermediate 6). Yield: 70 mg (39%). 1H NMR (400 MHz, CDCl3) δ ppm 1.57-1.62 (m, 2H), 1.70-1.78 (m, 4H), 3.16 (t, 4H), 6.39 (br s, 1H), 6.41 (d, 1H), 6.63 (d, 1H), 6.83 (d, 1H), 7.37-7.43 (m, 2H), 7.49-7.54 (m, 1H), 7.57 (d, 1H), 7.68-7.72 (m, 2H); MS (ESI+) for C19H20N2O3S m/z 357 (M+H)+; HPLC 97% (System A).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:14]([N:16](CC)CC)[CH3:15].C(Cl)(=O)OCC.C(N)C.O1CCCC1>O1CCCC1>[CH2:14]([NH:16][C:11]([C:10]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[S:8][CH:9]=1)=[O:13])[CH3:15]
Reactant: O=C(O)c1csc2c1CCCC2=O
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCNC(=O)c1csc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (the compound of Preparation Example 4) (98 mg) in tetrahydrofuran (2 mL) was added 0.11 mL of triethylamine (0.11 mL) and ethyl chlorocarbonate (58 μL) on an ice bath. After stirring for 30 minutes, a solution (1 mL) of 2M ethylamine-tetrahydrofuran was further added dropwise and the solution was stirred for 20 minutes. After the solution was extracted with water, then was extracted with ethyl acetate, and washed with saturated sodium chloride water. After the organic layer was dried with anhydrous sodium sulfate, the solvent was removed by evaporation and the title compound (100 mg) was obtained as a reddish-brown solid.
Reaction SMILES: [O-]CC.[Na+].[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1)[CH2:14][CH3:15].C(C1C=C(/C=C\C#N)C=CC=1)CC.Cl>C(O)C.O>[C:5]1([N:11]2[CH:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:13][CH2:14][CH3:15])[CH:17]=3)[CH2:23][C:24]([NH2:25])=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NNc1ccccc1
Reactant: CCCc1cccc(/C=C/C#N)c1
Agent: CCCc1cccc(/C=C\C#N)c1
Agent: CC[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCc1cccc(C2CC(N)=NN2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of sodium ethoxide (20 wt % in ethanol, 31 ml) in ethanol (66 ml) was stirred and added dropwise phenylhydrazine (6.4 ml) at room temperature, and then the mixture was stirred for 40 minutes. To this reaction solution was added dropwise a solution of the mixture of (E)-3-(3-propylphenyl)acrylonitrile and (Z)-3-(3-propylphenyl)acrylonitrile (11.1 g) in ethanol (33 ml), and then the mixture was stirred overnight at reflux. This reaction solution was cooled to room temperature, and water (30 ml) was added thereto. Next, pH of the reaction solution was adjusted to 7 by adding a 6M aqueous solution of hydrochloric acid under ice-cooling. This mixed solution was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added toluene, and the mixture was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue was added toluene, and again concentrated under reduced pressure to give a crude product of the titled compound (18.6 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4][CH2:3]1.S(OC)(O[CH3:14])(=O)=O.[OH-].[K+]>CCOCC>[CH3:14][O:9][C:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][CH2:7][N:6]=1
Reactant: CC1CCNC(=O)CC1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC1=NCCC(C)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-methylazepan-2-one (1.6 g) and dimethyl sulfate (2 g, 15.9 mmol) was stirred at 120° C. for 4 h. After it was cooled to room temperature, the reaction mixture was diluted with 10 mL ether and adjusted to pH 6 with aqueous KOH. The mixture was extracted with ether (2×50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.2 g) was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7]Cl)[O:4][N:3]=1.[CH3:9][N:10]([CH3:21])[C:11]([N:13]([CH3:20])[C:14]1[S:15][C:16]([SH:19])=[N:17][N:18]=1)=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:9][N:10]([CH3:21])[C:11]([N:13]([CH3:20])[C:14]1[S:15][C:16]([S:19][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[N:17][N:18]=1)=[O:12]
Reactant: Cc1cc(CCl)on1
Reactant: CN(C)C(=O)N(C)c1nnc(S)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CSc2nnc(N(C)C(=O)N(C)C)s2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
In a 100 ml round bottom flask were mixed 3-methyl-5-chloromethylisoxazole (1.5 g, 11 mmol), tetrahydrofuran (50 ml), 1,1,3-trimethyl-3-(5-mercapto-1,3,4-thiadiazol-2-yl) urea (2.5 g, 11 mmol) and triethylamine (5.1 g, 50 mmol). This was stirred at room temperature overnight. The reaction mixture was filtered and the solvent was stripped from the filtrate on a rotary evaporator. The residue was dissolved in dichloromethane and this was washed with water (2×60 ml) and the organic solution was dried over MgSO4. This was treated with decolorizing carbon, was filtered and the solvent was removed to give a pale tan oil which was dried in vacuo, 2.9 g, 84.1% yield. NMR: (CDCl3) 6.2 (S, 1H), 4.5 (S, 2H), 3.55 (S, 3H), 2.95 (S, 6H), 2.25 (S, 3H). IR (neat) 3120, 2960, 2930, 1660, 1600, 1480, 1440, 1410, 1370 1305, 1265, 1125, 1080, 1060 cm-1. Calcd: C, 42.16; H, 4.82; N, 22.35. Found: C, 42.06; H, 4.90; N, 22.10.
Reaction SMILES: N.[N+:2]([C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)([O-])=O>O>[NH2:2][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1
Agent: N
Solvent: O
Product: Nc1c[nH]c(=O)[nH]c1=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Into a 5-L 4-necked round-bottom flask were placed water (2.871 L), ammonia (116.1 mL) and 5-nitropyrimidine-2,4(1H,3H)-dione (180 g, 1.15 mol, 1.00 equiv). This was followed by the addition of Na2S2O2 (860 g, 6.06 mol, 4.30 equiv) in several batches. The pH value of the solution was adjusted to 8 with ammonia (25%). The resulting solution was stirred for 3 h (hours) at 75° C. The reaction mixture was cooled to 15° C. with an ice/water bath. The solid was collected by filtration. This resulted in 118 g (81%) of 5-aminopyrimidine-2,4(1H,3H)-dione 1 as a yellow solid (see Scheme 1).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[C:24]2[C:21](=[CH:20][CH:19]=1)[CH:22]=[C:2]1[C:1]([O:14][C:5](=[O:7])[C:4]3[C:3]1=[C:12]2[CH:11]=[CH:10][CH:9]=3)=[O:13]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3ccc(C(F)(F)F)cc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and p-(trifluoromethyl)benzaldehyde:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9]([CH:17](O)[CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9](/[CH:17]=[CH:18]/[C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC(O)c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1

Procedure:
A toluene (100 ml) solution of 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]-1-hydroxyethyl]-1,2,8-trifluoronaphthalene and p-toluenesulfonic acid (0.6 g) was refluxed with heating in an autoclave for 1 hour. The reaction solution was washed with water and brine, and concentrated. The crude production of (E)-7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]ethenyl]-1,2,8-trifluoronaphthalene (16.6 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)([O-])=O>C(O)C>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[NH2:1])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=[N+]([O-])c1ccncc1Oc1ccc2[nH]ccc2c1
Solvent: CCO
Product: Nc1ccncc1Oc1ccc2[nH]ccc2c1

Procedure:
A suspension of 5-[(4-nitro-3-pyridinyl)oxy]-1H-indole, N5 -oxide (10 g) in 250 ml ethanol containing 0.4 g PtO2 was hydrogenated at 50 psi for 25 hours and thereafter filtered through Celite and concentrated to 9 g oil. This oil was purified by HPLC (silica, 10% methanol in ethyl acetate) to give 3.5 g solid. This solid was recrystallized from acetonitrile to give 2.4 g crystals, m.p. 170°-172°.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CCCOc1cccc2cc(OB([O-])[O-])oc12
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1cccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 7-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(7-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 143) (213 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:30]\[OH:31])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing <5% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=413.0 [M−H]−.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:29]([OH:30])[C:28]4[C:23](=[N:24][CH:25]=[CH:26][N:27]=4)[C:22]3=[O:31])=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:29]([O:30][C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[C:28]4[C:23](=[N:24][CH:25]=[CH:26][N:27]=4)[C:22]3=[O:31])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: O=C(NC1CCCCC1)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 41.2 %

Procedure:
Cyclohexyl isocyanate (1.38 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (3.12 g.) in anhydrous acetonitrile (60 cc.) in the presence of triethylamine (1 cc.), and the reaction mixture is heated at the reflux temperature for 13 hours. After cooling, the insoluble product is filtered off and washed successively with acetonitrile (2 × 10 cc.) and diisopropyl ether (2 × 20 cc.). It is then dissolved in methylene chloride (300 cc.) and the solution obtained is stirred for 15 minutes with 1N sodium hydroxide solution (50 cc.). The organic layer is decanted, washed with water (2 × 50 cc.), dried over anhydrous sodium sulphate in the presence of decolourising charcoal, filtered and then evaporated to dryness under reduced pressure. The residue is recrystallised from acetonitrile (95 cc.) and the product obtained is heated for 10 minutes with ethanol (65 cc.) at the reflux temperature. The insoluble product is then isolated from the boiling solution by filtration, after which it is washed with boiling ethanol (2 × 10 cc.). After drying, 6-(7-chloro-1,8-naphthyridin-2-yl)-5-cyclohexylaminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (1.8 g.), melting at 264° C., is obtained.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21])=O)C1C=CC=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[CH3:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[NH2:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])ccc1N

Procedure:
Analogously to Example 7a), from 50 g. 2-methyl-4-nitroaniline is prepared 81.3 g. (88% of theory) N-benzyloxycarbonyl-2-methyl-4-nitroaniline which is reduced with sodium dithionite to give 44 g. 4-benzyloxycarbonylamido-3-methylaniline; m.p. 60°-62° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:25]([OH:27])=O.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[NH:36][NH2:37]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:25]([NH:37][NH:36][C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27]
Reactant: O=C(O)C(CCCCl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 64.8 %

Procedure:
IPEA (1.9 mL), HOBt (859 mg) and EDC (1.22 g) were added to a solution of 5-chloro-2-(3-fluorophenyl)pentanoic acid (734 mg) and tert-butyl carbazate (504 mg) in DMF (10 mL), and the reaction solution was stirred at room temperature for seven hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 711 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH2:14][Cl:15].[OH-].[Na+]>O>[Cl:15][CH2:14][CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: ClCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCCl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3-methyl-4-nitrophenol (10 g), 1-bromo-2-chloroethane (16 ml) and sodium hydroxide (2.9 g) in water (50 ml) was stirred under reflux for 16 h. The mixture was diluted with water and the product was extracted with methylene chloride. The organic extract was dried on sodium sulfate and concentrated in vacuo to give the title compound as an oil (10.81 g) NMR includes d 2.5 (s,3H,--CH3), 3.9 (t,2H,CH2 --O) and 4.3 (t,2H,--CH2 --Cl).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>CCOC(C)=O.Cl>[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:39])=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])(=[O:10])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](CCCCN)C(=O)O)cc12
Reaction time: 0.33 h
Yield: 15 %

Procedure:
Nα-[(4-Chloro-1-guanidino-7-isoquinolinyl) sulphonyl]-Nε-tert-butyloxycarbonyl-L-lysine tert-butyl ester (119 mg, 0.20 mmol) was dissolved in EtOAc (10 ml) and saturated with gaseous HCl. After 20 min, the resultant white precipitate was obtained by filtration and recrystallised from EtOH to give Nα-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-lysine (13 mg, 0.03 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])/[CH:6]=[C:7](\[C:9]([CH3:12])([CH3:11])[CH3:10])/[CH2:8][P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[CH3:2]
Reactant: C=C(C(O)C(NC=O)C(=O)OCC)C(C)(C)C
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(/CP(=O)(OC)OC)C(C)(C)C)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of 3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(3,3-dimethylbuten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 17 to 2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.