Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:13])[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].Cl[CH:15]([CH:18]=O)[CH:16]=[O:17].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH:16]([C:15]1[S:13][C:2]([CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:4])=[N:1][CH:18]=1)=[O:17]
Reactant: O=CC(Cl)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C=O)s1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-1-thioxopropan-2-ylcarbamate (6.9 g, 0.03 mol), 2-chloromalonaldehyde (5.2 g, 0.049 mol) and magnesium carbonate (2.76 g, 0.03 mol) in 1,4-dioxane (400 mL) was heated at 60° C. for 3 hours and further at room temperature overnight. The reaction mixture was concentrated and the residue purified by column chromatography (50-80% EtOAc/hexane) to afford tert-butyl 1-(5-formylthiazol-2-yl)ethylcarbamate (5.5 g, 64%). LC-MS: (FA) ES+ 257.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:43])[CH:11]([CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])C1C=CC=CC=1>[Pd].[OH-].[OH-].[Pd+2]>[O:41]=[C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:42])[N:32]1[CH2:31][CH2:30][CH:11]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:10]([NH:9][OH:8])=[O:43]
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)NO)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
A mixture of N-benzyloxy-α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (58 mg, 0.10 mmol) and 5% Pd/C (20 mg) is stirred for 1.5 hours at room temperature under an atmosphere of hydrogen. Palladium hydroxide on carbon (10 mg) is added and the mixture is stirred under hydrogen at room temperature for 6 hours. The mixture is filtered and the filtrate is concentrated. Purification by column chromatography (5% MeOH/EtOAc) gives 39 mg of an oil which is crystallized from EtOAc/hexane to give 29 mg (59%) of the title compound as a white solid (mp 158°-159° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].O.NCC(O)=O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:10]([C:9]#[N:13])[C:11]#[N:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: N#CCC#N
Agent: NCC(=O)O
Solvent: CCO
Solvent: O
Product: N#CC(C#N)=Cc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-thiophenecarboxaldehyde (6.92 g, 36.2 mmol) and malononitrile (2.39 g, 36.2 mmol) were dissolved in 100 mL 1:1 EtOH:H2O. A small spatula of glycine was added and the reaction was stirred at ambient temperature for 30 min. The precipitated product was collected by suction filtration, washed with water, and dried under vacuum overnight. The result was 8.38 g (97% ) 4bromo-2-(2,2-dicyanoethenyl)thiophene as a light green solid. MS 238/240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: COc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Product: COc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 81A in analogy to the synthesis of the compound of Example 1. 31 mg (84% of theory) of the title compound are obtained.
Reaction SMILES: N1C(C([O-])=O)=C[N:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.[OH-:15].[Na+]>C(O)C>[CH2:13]([O:12][C:10]([C:3]1[N:4]=[N:4][C:3]([C:10]([OH:11])=[O:15])=[CH:2][CH:2]=1)=[O:11])[CH3:14]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc(C(=O)[O-])cn1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.15 g of ethyl pyrazine-3,6-dicarboxylate was dissolved in 34.5 mL of ethanol, and 5.64 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitated salt was collected by filtration and dissolved in a small amount of water, and then this solution was acidified (pH=2) with a 1 M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 435 mg of 6-(ethoxycarbonyl)pyridazine-3-carboxylic acid.
Reaction SMILES: C(N(CCCCCCCCC)[C:7](=[O:16])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])C(C)(C)C.C(NCCCCCCCCC)C(C)(C)C.[CH2:41]([NH:51][CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:41]([N:51]([CH:52]([CH3:53])[CH3:54])[C:7](=[O:16])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCN(CC(C)(C)C)C(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CCCCCCCCCCNC(C)C
Agent: CCCCCCCCCNCC(C)(C)C
Product: CCCCCCCCCCN(C(=O)N[C@H]1CCCC[C@@H]1O)C(C)C
Yield: 88 %

Procedure:
The same procedure for preparing (1S,2S)-2-(3-neopentyl-3-nonylureido)cyclohexanol as in Example 3 was repeated except that the neopentylnonylamine employed in Example 3 was replaced by decylisopropylamine, whereby (1S,2S)-2-(3-decyl-3-isopropylureido)cyclohexanol was obtained in a yield of 88%.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1](=[O:10])(=[O:2])[NH2:11])=[CH:8][CH:7]=3)=[O:26])[CH2:22][CH2:23]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from sulfanilamide (Aldrich) and [4-(4-fluoro-benzyl)-piperidin-1-yl]oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 201-203° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5](OC)=[O:6]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:22])[CH3:23])[CH:14]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(OC)c(C(C)C)c2)c(Br)c1
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Br)cc(CO)cc2Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Methyl 3,5-dibromo-4-(4-methoxy-3-isopropyl-phenoxy)-benzoate (Example 1a) (4.6 g) was treated with a 1 M solution of diisobutyl aluminium hydride(DIBAL) in THF (40 ml) at 0° C. and then warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into an ice-cold 1 M HCl solution and extracted with ethyl acetate 3 times. The organic layer was washed (brine), dried, filtered and concentrated to dryness affording 3,5-dibromo-4-(4-methoxy-3-isopropylphenoxy)benzylalcohol (4.15 g, 96%) as oil which became a white solid after standing.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[C:11](=[O:15])[NH:12]2)=[CH:8][C:7]=1[N+:18]([O-])=O)=O>[Pd].C(O)C>[CH3:16][C:10]1([CH3:17])[C:9]2[C:13](=[CH:14][C:6]3[NH:5][C:3]([C:2]([F:22])([F:21])[F:1])=[N:18][C:7]=3[CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(C(F)(F)F)nc3cc21

Procedure:
Analogously to Example 5, 4.50 g. (0.014 mole) 6-trifluoroacetamido-5-nitro-3,3-dimethylindolin-2-one in 500 ml. ethanol are hydrogenated in the presence of 0.5 g. 10% palladium on charcoal at normal pressure and at ambient temperature. After filtration, the filtrate is evaporated to dryness in a vacuum and the residue is dissolved in dichloromethane/ethyl acetate and treated with active charcoal. After filtration, the filtrate is evaporated to dryness in a vacuum and the residue is recrystallised from ethyl acetate, there being obtained 3.8 g. (95% of theory) of the title compound in the form of the monohydrate; m.p. 175°-177° C.
Reaction SMILES: N.N[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[C:11]([OH:13])(=[O:12])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N
Product: O=C(O)/C=C/c1ccccc1
Yield: 70 %

Procedure:
L-phenylalanine ammonia-lyase (PAL; EC 4.3.1.5.), is an enzyme found in several plants and also in yeast. It catalyzes the deamination of L-phenylalanine to give trans-cinnamic acid. In 1981, Yamada et al in Applied and Environmental Biology, 42:773-778 (1981) described the use of PAL for the rapid conversion of trans-cinnamic acid to L-phenylalanine, with a conversion yield of above 70%. This publication opened the way to investigate and apply commercially, the use of PAL for the production of phenylalanine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2].CCO.O.NN>CCO.C1COCC1.[Ni]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of tert-butyl 4-[3-(ethylamino)-4-nitrophenyl]-1-piperazinecarboxylate (1.028 g, 2.93 mmol) in 40 mL EtOH:THF (4:1) solvent system was added Raney-Ni (1 mL of a EtOH suspension) followed by addition hydrazine hydrate (0.734 g, 14.67 mmol). The mixture was stirred vigorously for 3 hours and then filtered through a Celite pad pretreated with water. The filtrate was concentrated and then purified by column chromatography on silica using CHCl3/MeOH/NH3 9:1:0.4% as eluent to give 0.877 g (93%) of a red oil. The oil was used immediately in the next reaction. HPLC purity>90 %; MS (posEI) m/z=320 (M+);
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:31])([F:30])[C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:27]5[CH2:28][CH2:29][C@@H:25]([C:24]([F:31])([F:30])[F:23])[CH2:26]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: FC(F)(F)[C@H]1CCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC[C@@H](C(F)(F)F)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-(trifluoromethyl)pyrrolidine (1.2 equiv) to give 213 (15.8 mg, M+1 435.1)
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][N:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:20][CH2:19]1.Cl.[OH-].[Na+]>C(O)C.C(N(CC)CC)C.CCOCC>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:1][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]3=[N:4][N:3]=2)[CH2:23][CH2:22]1
Reactant: FC(F)(F)c1cccn2c(S)nnc12
Reactant: Fc1ccc(N2CCN(CCCl)CC2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(N2CCN(CCSc3nnc4c(C(F)(F)F)cccn34)CC2)c(F)c1
Yield: 58.9 %

Procedure:
A solution of 13 g of 3-mercapto-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine, prepared in Example 18, and 15.5 g of 1-chloro-2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethane as the base, freed from its hydrochloride, prepared in Example 7, by the addition of sodium hydroxide and extraction with ether, in 75 ml of ethanol containing 10 ml of triethylamine is heated under reflux for 6 hours. The reaction mixture is then concentrated in vacuo and the residue is taken up with methylene chloride, which is washed carefully with water, dried and then evaporated. The residue crystallizes when taken up in a mixture of ethyl ether and isopropyl ether. The crystals obtained are filtered off, washed with isopropyl ether and then dried to give 15.5 g of 3-[2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethylmercapto]-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 119°-120° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][C:44]([CH:51]=[CH2:52])([C:48]([OH:50])=[O:49])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][C:44](/[CH:51]=[CH:52]/[C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]4)=[O:16])[CH3:13])=[N:9]3)=[CH:4][CH:3]=2)([C:48]([OH:50])=[O:49])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)CN(C(=O)OC(C)(C)C)CCO1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)CN(C(=O)OC(C)(C)C)CCO4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (95 mg, 0.178 mmol), 2-vinyl-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (45.7 mg, 0.178 mmol), tri(o-tolyl)phosphine (11 mg, 0.036 mmol) and triethylamine (0.08 mL, 0.534 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018 mmol). After stirring at 100° C. for 50 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 711.3 [M+H], Tr=2.14 min.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](O)=[O:19])(=O)[CH3:10].P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:9]1[N:4]([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Br:1])[C:18](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[N:12]=1
Reactant: CC(=O)Nc1ccsc1C(=O)O
Reactant: Nc1ccccc1Br
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc2ccsc2c(=O)n1-c1ccccc1Br
Temperature: 105 °C
Yield: 42.7 %

Procedure:
To a mixture of pyridine (6 mL), 2-bromoaniline (1.03 g, 6 mmol), and 3-acetamidothiophene-2-carboxylic acid (0.555 g, 3 mmol) was added phosphorus trichloride (0.03 mL, 3.45 mmol). The reaction was heated to 105° C. for 4 hours, cooled to ambient temperature and partitioned between chloroform and water (an insoluble precipitate was removed by filtration). Phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to a dull yellow film. This residue was flash chromatographed on silica gel (30×125 mm) eluting with 15-25% ethyl acetate/hexane to afford 0.411 g (47%) of 2-methyl-3-(2-bromophenyl)-3H-thieno[3,2-d]pyrimidin-4-one as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][OH:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][C@@H:35]3[CH2:39][OH:40])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: OC[C@H]1CCCN1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC[C@@H]4CO)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 182.6 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) then (R)-(−)-2-pyrrolidinemethanol (0.516 g) was added and the mixture heated to 110° C. for 50 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.341 g) as a pale yellow gum; NMR Spectrum: (CDCl3) 1.761 (m, 3H), 1.88 (m, 1H), 2.12 (m, 2H), 2.30 (m, 1H), 2.48 (m, 1H), 2.63 (m, 1H), 3.04 (m, 1H), 3.21 (m, 1H), 3.39 (dd, 1H), 3.46 (s, 3H), 3.64 (dd, 1H), 3.98 (s, 3H), 4.25 (m, 2H), 4.35 (s, 2H), 6.07 (s, 2H), 7.01 (s, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.28 (s, 1H), 8.62 (s, 1H). Mass Spectrum: M+H+ 555/557.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-methylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-176).
Reaction SMILES: Cl.[O:2]1CCOCC1.C([C:12](=[O:25])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)(C)(C)C>O1CCOCC1>[CH2:23]([O:22][C:20]([CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][C:12]([OH:25])=[O:2])[CH2:19][CH2:18]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1CCN(CC(=O)C(C)(C)C)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)C1CCN(CC(=O)O)CC1
Temperature: 60 °C

Procedure:
At room temperature, 3.0 ml of 4 M hydrogen chloride/1,4-dioxane was added to 8 ml of 1,4-dioxane solution containing 543 mg of ethyl 1-(2-tert-butyl-2-oxoethyl)piperidine-4-carboxylate, and stirred at 60° C. for 8Hours. The thus formed solid was collected by filtration to obtain 300 mg of [4-(ethoxycarbonyl)piperidin-1-yl]acetic acid as a white solid. EP: 216.