Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[C@H:11]([C:21](=[O:42])[NH:22][C@H:23]([C:38]([O:40]C)=[O:39])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:27][CH:26]=1)[C@@:12]([OH:20])([CH2:16][CH2:17][O:18][CH3:19])[C:13]([OH:15])=[O:14].O.C(N(CC)CC)C.[Br-].[Li+]>C(#N)C>[C:38]([C@@H:23]([NH:22][C:21]([C@@H:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:50])([F:1])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:12]([OH:20])([CH2:16][CH2:17][O:18][CH3:19])[C:13]([OH:15])=[O:14])=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:27][CH:26]=1)([OH:40])=[O:39]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccc2F)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccc2F)cc1)C(=O)O)[C@@](O)(CCOC)C(=O)O
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 83.5 %

Procedure:
No. 5538573, (E)-(2S,3S)-12,12-difluoro-3-[(S)-2-(2′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (8.2 mg, 0.0116 mmol) was dissolved in acetonitrile (0.328 mL), and water (0.0011 mL, 0.0611 mmol), triethylamine (0.0097 mL, 0.0696 mmol), and anhydrous lithium bromide (20.1 mg, 0.231 mmol) were then added at room temperature. The reaction mixture was stirred at 50° C. for 3.5 hours, cooled to room temperature, and then purified by preparative HPLC to obtain 6.7 mg of the title compound (0.00969 mmol, 83% yield).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[CH2:5]([N:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH3:6]>C(#N)C>[CH2:5]([N:7]([CH2:11][CH3:12])[C:8]([S:1][C:2]#[N:3])=[O:9])[CH3:6]
Reactant: CCN(CC)C(=O)Cl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)C(=O)SC#N
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
A suspension of sodium thiocyanate (3.30 g, 40.7 mmol) in dry acetonitrile (25 mL) at 80° C. was treated dropwise with a solution of N,N-diethyl carbamoyl chloride (5.0 g, 36.9 mmol) in dry acetonitrile (15 mL). The reaction mixture was stirred at 80° C. for 50 min, cooled to room temperature, then filtered through a fine glass frit. The resulting filtrate was used as a 0.9 M solution of N,N-diethyl carbamoyl thiocyanate in acetonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:83])[C@@H:67]([NH:75]C(OC(C)(C)C)=O)[CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:83])[C@@H:67]([NH2:75])[CH2:68][S:69][S:70][C:71]([CH3:72])([CH3:73])[CH3:74])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSC[C@H](N)C(=O)NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 55) (12 mg, 10.38 μmol) in dichloromethane (0.4 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((R)-2-amino-3-(tert-butyldisulfanyl)propanamido)hexanoate (Lys(Cys(StBu))-pdCpA) (Compound 48) (9.3 mg, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[C:13]1([C:2]2[N:7]=[C:6]3[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]3=[N:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2ncc(Cl)nc2n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.00 g of 3-chloropyrido[2,3-b]pyrazin-6-ylamine (5.54 mmol), 743 mg of phenylboronic acid (6.09 mmol), 640 mg of tetrakis(triphenylphosphine)palladium(0) (0.55 mmol) and 1.76 g of sodium carbonate (16.6 mmol) were initially charged in 100 ml of dimethylformamide/water (1:1) under nitrogen as a protective gas and stirred at 80° C. for 2 h. Once the reaction had ended, the mixture was filtered off with suction and the filtrate was poured onto 800 ml of distilled water. The aqueous phase was extracted repeatedly with ethyl acetate. The organic phase was freed of solvents under reduced pressure. The resulting solid was purified by means of column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]3[CH2:19][CH2:20][N:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][C:17]=3[S:16][C:10]=2[NH:11][C:12](=[O:15])[CH2:13][N:14]=1.[H-].[Na+].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]3[CH2:19][CH2:20][N:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][C:17]=3[S:16][C:10]=2[N:11]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:12](=[O:15])[CH2:13][N:14]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCC(=O)N3)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCC(=O)N3CCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
18 g of ethyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-8-carboxylate (4.46 mmol) is solubilized under argon, in 180 ml of anhydrous dimethylformamide. Sodium hydride at 60% (1.784 g, 4.46 mmol) is added then the reaction medium is heated for approximately 30 minutes at 50° C. until there is no more release. The reaction medium is cooled down to a temperature around 20° C. then 2-bromoethylbenzene (6.2 ml, 4.46 mmol) is added with a syringe. Agitation is carried out for 16 hours at 23° C. then the reaction medium is poured into a saturated solution of ammonium chloride (400 ml). Extraction is carried out with ethyl acetate (2×500 ml). The organic phase is dried over magnesium sulphate then the solvent is evaporated off with a rotary evaporator. After purification by chromatography on a silica column (eluent ethyl acetate-heptane: 0-100 to 20-80), the fractions containing only the product are evaporated and the desired product is obtained in the form of a white amorphous powder (20.3 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:9]1([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:18][CH2:17][CH2:16][O:15]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCO
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2(c3ccccc3)OCCO2)cc1

Procedure:
In 1300 milliliters of toluene in a flask equipped with a Dean-Stark tube are dissolved 100 grams of p-bromobenzophenone; and to this solution is added 150 grams of ethyleneglycol and 4.4 grams of p-toluenesulphonic acid. This mixture is refluxed until no further water collects in the Dean-Stark tube. After distilling off the toluene and recrystallization from methanol one obtains 2-phenyl-2-(p-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:12][CH2:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:24]=[C:18]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1cc(F)c(F)c(F)c1
Product: CN1CCCn2c1cc(OCCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(3,4,5-trifluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:34]([F:35])=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)[CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([C:29]1[CH:33]=[C:34]([F:35])[C:26]([F:25])=[CH:27][C:28]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:32]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1cc(F)c(F)cc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 336, (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]([OH:25])=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([C:23]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Reactant: CN1CCNCC1
Product: CC(C)N1CCC(Oc2ccc(C3(C(=O)N4CCN(C)CC4)CCOCC3)cc2)CC1
Yield: 48 %

Procedure:
The title compound (60 mg, 48%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid and N-methyl piperazine similarly to the procedure used for example 150. 1H NMR (400 MHz, CDCl3) δ 1.05 (d, 6H), 1.79-1.81 (m, 2H), 2.00-2.03 (m, 7H), 2.15 (s, 3H), 2.18-2.22 (m, 2H), 2.37-2.42 (m, 2H), 2.77-2.79 (m, 3H), 2.99 (m, 1H), 3.27-3.56 (m, 4H), 3.78 (t, 2H), 3.87-3.89 (m, 2H), 4.28 (m, 1H), 6.88 (d, 2H), 7.14 (d, 2H).
Reaction SMILES: OC1N=C2C=C(OCC3SC=C(C(C)C)N=3)C=CN2C(=O)C=1/C=C/C(OC(C)(C)C)=O.[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:44]2[CH:72]=[CH:71][N:47]3[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[C:50]([N:52]4[CH2:57][CH2:56][CH2:55][C@H:54]([O:58]C=O)[CH2:53]4)[N:51]=[C:46]3[CH:45]=2)=[O:43])[S:39][CH:40]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:44]2[CH:72]=[CH:71][N:47]3[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[C:50]([N:52]4[CH2:57][CH2:56][CH2:55][C@H:54]([OH:58])[CH2:53]4)[N:51]=[C:46]3[CH:45]=2)=[O:43])[S:39][CH:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@H](OC=O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Agent: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@H](O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Yield: 73.2 %

Procedure:
Reactions were performed in the same manner as in Example 1, (K) by using tert-butyl (E)-3-{8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-2-[(3S)-3-formyloxyhexahydro-1-pyridinyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (630 mg, 1.083 mmol) to obtain 439 mg (73%) of the title compound as an orange oily substance.
Reaction SMILES: [Na].N.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([C:10]([CH2:18][CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:9]=1.Cl[CH:22](Cl)[C:23]([O-:25])=[O:24].[K+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:20][CH:22]([C:23]([OH:25])=[O:24])[O:11][C:10]([CH2:18][CH3:19])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=1
Reactant: CCC(O)(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C([O-])C(Cl)Cl
Agent: N
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
4.8 g of sodium were added in small amounts to a stirred mixture of 250 ml of condensed liquid ammonia and 100 mg of ferric nitrate and then a solution of 26.2 g of 5-chloro-α-ethyl-2-hydroxy-α-phenyl-benzene-methanol [prepared by Step A of Example 23 using ethyl bromide] with a melting point of 85° C. in 200 ml of anhydrous toluene was added thereto at 28°-30° C. over 90 minutes. The temperature was raised to disengage the ammonia and the mixture was then refluxed for 3 hours. 100 ml of toluene was added thereto followed by addition of 18 g of potassium dichloroacetate at 50° C. The mixture was refluxed overnight and 9 g of potassium dichloroacetate were added thereto. The mixture was refluxed for 2 more hours and was cooled and poured into water. The organic phase was decanted and the aqueous phase was acidified and extracted with ether. The ether extracts were washed 3 times with 500 ml of water and was extracted 3 times with 300 ml of sodium bicarbonate solution. The combined aqueous phases were washed twice with 500 ml of ether, were acidified with concentrated hydrochloric acid and extracted 3 times with 500 ml of ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 27 g of raw 6-chloro-4-ethyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid. (mixture of two racemates diastereoisomers).
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[CH3:14][Si:15]([CH3:46])([CH3:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37](O)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:32]=1>C(OCC)(=O)C>[CH3:46][Si:15]([CH3:14])([CH3:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
The [4-(trialkylsilylalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For example, ethyl 5-[4-[14-(trimethylsilyl)tetradecylamino]phenyl]-2,4-pentadienoate is obtained by the Wittig reaction of 4-[14-(trimethylsilyl)tetradecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-trialkylsilylalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-[4-[14-(trimethylsilyl)tetradecylamino]phenyl]-3-hydroxypropionate to yield ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[O:9]1[CH2:10][CH2:11][O:12][C:13]2[C:4]([NH2:1])=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A suspension of 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (8 g, 0.044 mol) and palladium on carbon (10%, 2 g) in methanol (250 mL) was stirred vigorously under an atmosphere of hydrogen overnight at room temperature. The mixture was filtered through a pad of Celite and then concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 9/1) to afford the product 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (6.5 g, yield 97%). 1H NMR (400 MHz, CDCl3) δ ppm 6.61-6.65 (t, 1H, J=8.0 Hz), 6.30-6.33 (dt, 2H, J=1.2 Hz, 2.4 Hz), 4.22-4.27 (m, 4H), 3.75 (s, 2H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=[C:12]([Cl:24])[C:11]=1[NH:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[C:33]([O:39][CH2:40][CH:41]([F:43])[F:42])[C:34]([C:36]([OH:38])=O)=[CH:35][C:28]=2[N:27]=1.[Cl:44][C:45]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:46]=1[NH2:47].N1C=CC=CC=1>C(#N)C>[Cl:44][C:45]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:46]=1[NH:47][C:36]([C:34]1[C:33]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:32][C:29]2[N:30]([CH3:31])[C:26]([NH:25][C:11]3[C:12]([Cl:24])=[CH:13][CH:14]=[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[C:10]=3[Cl:9])=[N:27][C:28]=2[CH:35]=1)=[O:38]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(Cl)cc3Cl)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (53 mg, 0.10 mmol) in 1.0 mL acetonitrile and it is stirred 15 min at rt. The crude acid chloride solution is added to a mixture of 2,4-dichloroaniline (16 mg, 0.10 mmol), pyridine (24 μL, 0.30 mmol) and acetonitrile (1.0 mL) and it is stirred over the weekend at 60° C. The solvent is removed in vacuo and the residue is dissolved in 2 mL of a 9:1 DMF/water-solution and is purified via preparative HPLC.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:24])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
To a suspension of phenylalanine methyl ester hydrochloride (2.15 g, 10.0 mmols) in methylene chloride (40 mL) at -30° C. was added N-methylmorpholine (2.2 mL, 20 mmols) followed by p-nitrophenyl chloroformate (2.01 g, 10 mmols). The resulting mixture was stirred at -30° C. for 15 minutes, then for 15 minutes at 25° C., after which it was washed sequentially with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried, and concentrated. The residue (2.96 g) was crystallized from acetonitrile to give the title A compound (1.22 g), m.p. 130°-131° C., [α]D +88° (c=1.5, CHCl3). The mother liquor was chromatographed on silica gel (90 g), eluting with benzene:ethyl acetate (9:1) to give an additional 760 mg of the title A compound (total yield 1.98 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2cccnc2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-boronobenzoic acid (4.15 g, 25 mmol) and 3-bromopyridine (4.3 g, 27.5 mmol) in acetonitrile (60 mL) and water (60 mL), potassium carbonate (13.8 g, 100 mmol), bis(triphenylphosphine)palladium(II) chloride (1.75 g, 2.5 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 hours. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 4 g of white solid of 4-(pyridin-3-yl)benzoic acid. (Yield: 80%. LC-MS (ESI) m/z: 200 (M+1)+). Thionyl chloride (10 ml) was added to 4-(pyridin-3-yl)benzoic acid (4 g, 20 mmol) and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum. 4.5 g of crude 4-(pyridin-3-yl)benzoyl chloride was obtained. To a solution of methyl 3-amino-2-hydroxybenzoate (2.9 g, 17 mmol) and pyridine (4 g, 52 mmol) in toluene (50 ml) were added 4-(pyridin-3-yl)benzoyl chloride (4.5 g, 20.4 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(4-(pyridine-3-yl)enzamido)benzoate as a yellow solid (5 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.