Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:25][C:26]([O:28]CC)=[O:27])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[F:49][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH2:25][C:26]([OH:28])=[O:27])[C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)C(F)(F)F)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(N(CC(=O)O)C(=O)C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 250 mg of ethyl (Z)-[(l-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-(trifluoroacetyl)amino]acetate in 5 ml of ethanol was added a solution of 100 mg of potassium carbonate in 2 ml of water, and the mixture was stirred at room temperature for three days. After evaporation of the solvent, water was added to the residue, and the mixture was washed with ethyl acetate (a washing A) The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated therefrom. The resulting residue was collected by filtration to give 60 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)(trifluoroacetyl)amino]acetic acid as a colorless amorphous powder.
Reaction SMILES: ClC1C(O[C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:31]([O:38][C:39](=[O:67])[C@H:40]([CH2:63][CH2:64][S:65][CH3:66])[NH:41]C(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39](=[O:67])[C@H:40]([CH2:63][CH2:64][S:65][CH3:66])[NH:41][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonylhexahydro-L-phenylalanine pentachlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonylhexahydro-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[OH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)C1CCCCC1O
Product: CC(C)(C)C1CCCCC1Oc1ccc(C#N)c(C#N)c1
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 4.7 grams of 2-t-butylcyclohexanol, there was obtained 1.41 grams of 1,2-dicyano-4-(2-t-butylcyclohexyloxy)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.41 grams of this compound and 0.42 gram of BBr3, there was obtained 0.77 gram of the end product (yield 50%, mp 162°-165° C.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].N>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.75 g 1-acetyl-6-chloro-2-indolinone (educt V.1) are placed in 40 ml concentrated sulphuric acid and at −10° C. 1.05 g of ammonium nitrate are added. The mixture is stirred for 1.5 hours at ambient temperature. After this time the mixture is poured onto ice water and stirred for a further 20 minutes. The solution is neutralised with concentrated ammonia, the precipitate formed is suction filtered and washed with a little ethanol and ether.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>ClCCl>[Cl:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: ClCCCNCCc1ccccc1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(CCCCl)CCc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of valeryl chloride (342 mg, 338 μl, 2.83 mmol) in dichloromethane (6 ml) and cooled to 0° C. is added a solution of (3-chloro-propyl)-phenethyl-amine (Starting material Q-01e, 560 mg, 2.83 mmol). The colourless solution turns yellow and after 2 min, a solid crystallizes out. Upon dropwise addition of Et3N (315 mg, 409 μl, 2.83 mmol) the solution turns colourless again and the solid dissolves instantaneously. The mixture is allowed to stir for 4 h at which time yet again a solid had crystallized out. Saturated aqueous NH4Cl solution is added and the organic phase is washed once with some saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is dried under high vacuum, yielding the title compound as an orange oil: tR=2.48 min (LC-2), ESI-MS (pos.): m/z 282.07 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 0.86-0.97 (m, 3H, CH3), 1.23-1.44 (m, 4H, CH2CH3), 1.55 (quint., 1H, CH2CH2CH3), 1.65 (quint., 1H, CH2CH2CH3), 1.95 (quint., 2H, CH2CH2N), 2.03-2.19 (m, 2H, CH2C═O), 2.90 (t, 2H, CH2Ph), 3.35-3.59 (m, 6H), 7.15-7.34 (m, 2Harom).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C.[C:45]([NH:55][C@H:56]([C:60](O)=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>ClCCl>[C:45]([NH:55][C@H:56]([C:60]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:10])=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Yield: 93.5 %

Procedure:
4-Methoxybenzyl 2-hydroxyphenylacetate 3 g, 11 mmol), N,N,-dichyclohexyl-carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine (0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolved in dichloromethane (50 ml). After the weekend the solid was filtered off, the solvent removed under reduced pressure and the crude product purified by chromatography (ethyl acetate, hexane, 1:2) to give the title compound (5.2 g, 93%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:36]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Nc1cccc(N2CCCC2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(N2CCCC2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(pyrrolidin-1-yl)aniline in step 1. MS: 396.6 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Br:19])[CH:13]=1)\[C:7]1[O:8][CH:9]=[CH:10][N:11]=1)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Br:19])[CH:13]=1)[C:7]1[O:8][CH:9]=[CH:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(/c1cc(F)cc(Br)c1)c1ncco1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1cc(F)cc(Br)c1)c1ncco1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
9.5 g (27.93 mmol) (Z)-3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-acrylic acid ethyl ester is dissolved in 200 ml acetic acid and 9.5 g Zinc dust (11 Ea)) is added slowly over a period of 30 minutes. The temperature of the reaction mixture is not allowed to reach >30° C. during the addition of the zinc dust. The resulting mixture is allowed to stir overnight. After filtration 200 ml EtOAc and 200 ml water are added and the organic phase is separated and washed with brine. After removal of the solvent the crude material is purified by column chromatography on silica gel using heptane/EtOAc=3:1 as eluent. 9.50 g of 3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid ethyl ester are isolated (yield=615)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][NH:23][CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)OC)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH:21]1(CO)C[CH2:22]1>C[O-].[Na+].C1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21]3)=[O:14])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: OCC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCC1CC1)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 12.8 parts of ethyl 4-(phenylmethoxy)benzoate, 180 parts of benzene and 5 drops of a sodium methoxide solution 30% was stirred and refluxed using a water separator. 10.8 Parts of cyclopropanemethanol in 90 parts of benzene was added dropwise during a period of 1 hour. Upon complete addition, stirring was continued for 4 hours at reflux. After cooling, the whole was washed with water, the organic layer was dried, filtered and evaporated, yielding 14 parts (100%) of (cyclopropylmethyl) 4-(phenylmethoxy)benzoate as a residue (int. 3).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]
Reactant: Cc1cc(Br)c2cnn(-c3ccc(F)cc3)c2c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Example 25 from 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18) and 4-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate 28). Purification was conducted by silica gel chromatography using the Flashmaster II (20 g cartridge) eluting with a 100:0 to 50:50 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound (26.7 mg)
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O.[OH-].[Na+]>O>[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:15]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(N)c1Cl

Procedure:
A solution of 1 ml. of concentrated hydrochloric acid in 5 ml. of 5% ethanol is slowly added to a refluxing mixture of 10.1 g. of 1-chloro-2,6-dinitrobenzene, electrolytically reduced iron and 20 ml. of 50% ethanol. The mixture is heated at reflux for two hours. The mixture is allowed to cool slightly and the pH is adjusted to 8 with sodium hydroxide solution. The iron products are removed by filtration. The solvent is removed from the filtrate to leave a solid which is dissolved in water and extracted with methylene chloride. Removal of the solvents leaves an oily solid which upon recrystallization of from Skellysolve B gives off-white crystals of 2-chloro-1,3-diaminobenzene having a melting point of 82°-83.5° C.
Reaction SMILES: [P:1]([O:6]C)([O:4]C)[O:2]C.[Cl:8][CH:9](Cl)[C:10](=[O:16])[C:11]([O:13]CC)=[O:12]>>[CH:9](/[Cl:8])=[C:10](/[O:16][P:1]([OH:6])([OH:4])=[O:2])\[C:11]([OH:13])=[O:12]
Reactant: COP(OC)OC
Reactant: CCOC(=O)C(=O)C(Cl)Cl
Product: O=C(O)/C(=C/Cl)OP(=O)(O)O
Reaction time: 1 h
Yield: 58 %

Procedure:
To trimethyl phosphite (10 mmol) cooled at 0-10° C. was added dropwise ethyl dichloropyruvate (10 mmol). After addition, the ice-bath was removed and the reaction was allowed to proceed at 70° C. for one hour to give the ethyl/dimethyl ester of 3-chlorophosphoenolpyruvate. It was purified by flash chromatography (hexanes/ethyl acetate, 1:1, v/v) to give 1.5 g (58% yield) of 4:1 mixture of the Z- and E-isomers.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([C:10]([CH3:12])=O)[C:7]([CH3:9])=O)=[O:5].[NH2:13][C:14]([NH2:16])=[O:15].Cl>C(O)C>[OH:15][C:14]1[N:16]=[C:10]([CH3:12])[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:7]([CH3:9])[N:13]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(O)nc1C
Temperature: 90 °C

Procedure:
A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to −20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)\[C:10]#[N:11])=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:10]#[N:11])/[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C(C#N)=C/c2ccc(O)cc2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(/C(C#N)=C/c2ccc(OC(C)=O)cc2)cc(OC)c1OC
Yield: 93 %

Procedure:
Compound 15 (1.20 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (1.27 g, yield: 93%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1.[CH2:35]([O:37]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:36].Cl>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:35]([C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1)(=[O:37])[CH3:36]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc2sc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A solution of 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (50 mg, 0.102 mmol), bis(triphenylphosphine)palladium(ii) chloride (7.16 mg, 10.2 μmol) and 1-ethoxyvinyltri-n-butyltin (0.103 mL, 0.306 mmol) toluene (3 mL) was stirred at 100° C. for 2 h. Cooled down to rt, 4N HCl in Dioxane (1 mL) was added and stirred for 1 h. Diluted with EtOAC, filtrated and evaporated. Purification by chromatography (0-10% EtOAc in CH2Cl2) gave the title compound 2-acetyl-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 25g (13 mg, 25.6%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.28 (s, 3H), 2.76 (s, 3H), 7.33 (d, J=8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.65 (s, 1H), 9.20 (s, 1H), 10.39 (s, 1H), 10.57 (s, 1H). (m/z)=498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[OH-].[Na+]>CO.O>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[N:10]=[CH:9][CH:8]=[C:7]2[NH:6][C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=1[F:25])([OH:19])=[O:18]
Reactant: COC(=O)c1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C(=O)O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-methoxycarbonylquinoline (1.79 g, 4.9 mmol), (prepared as described in Example 55), and sodium hydroxide (0.6 g, 15 mmol) in methanol (75 ml) and water (5 ml) was heated at 70° C. for 4 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The solid residue was suspended in water and acetic acid was added to adjust the aqueous suspension to pH5. The mixture was stirred for 15 minutes and the solid product was collected by filtration, washed with water and then acetone and finally ether, and dried to give 6-carboxy-4-(4-chloro-2-fluoroanilino)-7-methoxyquinoline (1.55 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1(N)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)C1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (cf. Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160° C. until there is no further reaction and after cooling it is evaporated to dryness. The residue is mixed with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.08 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH:16][CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:23].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:23][CH:16]2[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Yield: 44.8 %

Procedure:
A solution of 3-ethylidenepyrrolidine-1-carboxylic acid benzyl ester (Example A8, 0.65 g, 2.8 mmol) and 3-chloroperoxybenzoic acid (0.86 g, 5 mmol) in dichloromethane (15 mL) is stirred at room temperature for 3 hours. The excess peracid is decomposed by the addition of 10% sodium sulfite. The organic layer is washed with 5% sodium bicarbonate solution, dried over Na2SO4 and evaporated. The residue is purified by column chromatography (1:1 hexanes/ethyl acetate) to afford the title compound (0.310 g). 1H NMR (200 MHz, CDCl3): δ 7.36–7.26 (m, 5H), 5.14 (s, 2H), 3.73–3.55 (m, 3H), 3.34 (d. 1H), 3.20–3.13 (m, 1H), 2.26–2.11 (m, 1H), 1.90–1.62 (m, 1H), 1.33 (d, 3H).