Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.N12CCCN=C1CCCCC2.[Cl:24][C:25]1[C:40]([CH3:41])=[C:39]([N+:42]([O-:44])=[O:43])[C:28]([NH:29][C:30](OC2C=CC=CC=2)=[O:31])=[C:27]([F:45])[CH:26]=1.Cl>CN(C)C=O.O>[Cl:24][C:25]1[CH:26]=[C:27]([F:45])[C:28]([N:29]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:30]2=[O:31])=[C:39]([N+:42]([O-:44])=[O:43])[C:40]=1[CH3:41]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: Cc1c(Cl)cc(F)c(NC(=O)Oc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: -10 °C
Yield: 104.9 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (6.1 g, 33.1 mmol) was dissolved in dimethylformamide (47 ml) and stirred at −10 ° C. To this solution was slowly added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.3 g, 41.4 mmol) and solution stirred for 0.5 hr. To this solution was slowly added a solution of 4-chloro-2-fluoro-5-methyl-6-nitro-N-phenoxycarbonylaniline (8.5 g) in dimethylformamide (25 ml) followed by stirring at ambient temperature for 14 hr. Solution was then heated to 80 ° C. and stirred at this temperature for 4 hr. Water was added and pH adjusted to 4 by addition of dilute hydrochloric acid. Product was extracted with ethyl acetate followed by evaporation of the solvent to afford the crude product (10.1 g) which was subjected to N-methylation as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([I:34])[C:26]=1[C:27](O)=[O:28]>>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([I:34])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:28]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: O=C(O)c1c(F)cccc1I
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3c(F)cccc3I)cc21

Procedure:
Using the procedure of Preparation 21, the title compound (48 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2-fluoro-6-iodobenzoic acid. [LCMS (Method A, Mobile Phase I) RT=4.33 min, MH+ 530].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([NH:17][C:18]([C:20]3[N:21]([CH3:30])[N:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=3[Cl:25])=O)[CH:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[N:9]=2)[CH2:4][CH2:3]1>CC(O)=O.[Fe]>[C:26]([C:23]1[C:24]([Cl:25])=[C:20]([C:18]2[NH:14][C:13]3[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:9][C:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:40])[F:38])=[CH:11][C:12]=3[N:17]=2)[N:21]([CH3:30])[N:22]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(NC(=O)c3c(Cl)c(C(C)(C)C)nn3C)c2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc3nc(-c4c(Cl)c(C(C)(C)C)nn4C)[nH]c23)CC1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (300 mg, 0.517 mmol, prepared as described in the previous step) in AcOH (10 mL) was treated with iron powder (86.7 mg, 1.55 mmol) and heated to 100° C. for 5 h. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (25 mL), and extracted three times with EtOAc (30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=10 mL/min; Eluent=EtOAc-hexanes, 1:99 v/v for 5 min, then 1:99 to 3:17 v/v over 40 min) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(4-methyl-piperazin-1-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine as a tan solid. 1H-NMR (400 MHz, CDCl3) δ: 9.99 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.56-7.61 (m, 2H), 7.45-7.52 (m, 1H), 6.95 (s, 1H), 4.30 (s, 7H), 2.59 (t, J=4.9 Hz, 4H), 2.36 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C26H29ClF3N7: 532.2 (M+H); Measured: 532.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.Br[C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][N:29]=1.OC(C1C=CN=C(C2C=NC(N3C4C(=CC=C(C(N5CCOCC5)=O)C=4)C(SC)=C3)=NC=2)C=1)(C)C>>[Cl:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)=[O:18])[CH:15]=4)[C:10]([S:25][CH3:26])=[CH:9]3)=[N:6][CH:7]=2)[CH:33]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Clc1ccnc(Br)c1
Agent: CSc1cn(-c2ncc(-c3cc(C(C)(C)O)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3cc(Cl)ccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Coupling of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino) methanone and 2-bromo-4-chloropyridine analogously in an analogous manner as described for 289a). White solid. Yield: 1.7 g (79% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:22]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])=[N:13][CH:14]=1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(-c2ccc(Cl)cc2Cl)cn1)N1CCCCC1
Yield: 67.3 %

Procedure:
A solution of 0.23 g (1 mmol) of 5-(2,4-dichloro-phenyl)-pyridin-2-ylamine and 0.2 g (1.1 mmol) of piperidine-1-sulfonyl chloride (preparation: Bull. Soc. Chim. Fr.; 1936, p2143) in pyridine (10 ml) was heated to reflux until completion of reaction according to HPLC analysis (20 h). After concentration in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9/1 to 1/1) as eluent. Combination of the purified fractions and concentration in vacuo gave 0.26 g (67%) of the desired piperidine-1-sulfonic acid [5-(2,4-dichloro-phenyl)-pyridin-2-yl]-amide as a brown crystalline solid. ISN mass spectrum, m/e: 384 (M−1 calculated for C16H17Cl2N2O2S: 384).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CC[O:33]CC1.[OH2:37]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[O:37]=[S:16]1(=[O:33])[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][C:8]([NH:19][C:20]([C:22]3[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=3)=[O:21])=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: N#Cc1ccc(C(=O)Nc2ccc(N3CCSCC3)cc2N2CCCCC2)o1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: N#Cc1ccc(C(=O)Nc2ccc(N3CCS(=O)(=O)CC3)cc2N2CCCCC2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 21.5 mg (0.0542 mmol) 5-cyano-furan-2-carboxylic acid (2-piperidin-1-yl-4-thiomorpholin-4-yl-phenyl)-amide (as prepared in Example 6, step (b)) in 0.6 mL of acetone-water (3:1) was added 22.0 mg (0.163 mmol) of 4-methyl-morpholine N-oxide followed by 25 μL (0.0039 mmol) of a solution of osmium tetroxide (4.0 wt % in water). After stirring for 18 h at RT, 3 mL of water was added and the mixture extracted with EtOAc (2×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and concentrated. Chromatography of the resulting residue on a 5-g silica SPE column with 5-6% EtOAc-dichloromethane afforded 19.1 mg (82%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.48 (br s, 1H), 8.36 (d, 1H, J=8.9 Hz), ca. 7.28 (d, 1H, J=3.7 Hz), 7.23 (d, 1H, J=3.7 Hz), 6.77 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.80 (m, 4H), 3.14 (m, 4H), 2.84 (m, 4H), 1.82 (m, 4H), and 1.67 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O4S, 429.2 (M+H), found 429.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[N:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27]1)[C:21]#[N:22]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 21.6 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (150 mg, 0.684 mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (140 mg, 0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a clear dark brown solution. It was cooled to room temperature, diluted with DMSO (2 mL) and purified using preparative HPLC (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions containing product were concentrated in vacuo and crystallized with water (3 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (60.2 mg, 0.148 mmol, 21.65% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.03 (m, 3 H) 2.11-2.24 (m, 1 H) 2.44-2.49 (m, 4 H) 3.07-3.22 (m, 4 H) 3.34-3.42 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.97 (d, J=2.02 Hz, 1 H) 7.11 (t, J=8.72 Hz, 1 H) 7.56 (dd, J=8.46, 1.64 Hz, 1 H) 7.61 (d, J=2.02 Hz, 1 H) 7.69 (dd, J=13.39, 2.02 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C22H23FN6O, 407; found, 407; melting point 226° C.
Reaction SMILES: [CH:1]1[N:12]2[C:13]3[C:9]([C:10]4[CH2:16][CH2:15][CH2:14][C:11]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH:2]=1.B.C1COCC1>C(O)(C(F)(F)F)=O>[CH2:1]1[N:12]2[C:13]3[C:9]([CH:10]4[CH2:16][CH2:15][CH2:14][CH:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH2:2]1
Reactant: C1=Cn2c3c(c4cccc(c42)CN1)CCC3
Agent: B
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)C1CCCC1N3CCNC2
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of 3,4,9,10-tetrahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole (61 mg, 0.29 mmol) in TFA (2 mL) being cooled in an ice-bath, BH3.THF (0.7 mL, 0.7 mmol, 1 M THF) was added slowly under Ar. After 4 h, the reaction mixture was concentrated in vacuo then CHCl3 (3 mL) and 1 N HCl (3 mL) were added. The mixture was stirred for 1 h before separating the two layers. The aqueous layer was basified to pH 13-14 with 5 N NaOH then extracted with CHCl3 (3×3 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give 36 mg (58%) of the title compound as a thin white film.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccco2)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
6.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 200 ml. of methylene chloride and 10 ml. of triethylamine. The mixture, cooled to about 0° C., is treated while stirring with 3 ml. of furan-2-carboxylic acid chloride in 50 ml. of methylene chloride. After stirring for 1 hour, the mixture is diluted with 100 ml. of water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}-2-furamide having a melting point of 159°-162° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)O
Reactant: C1COCCN1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)N1CCOCC1
Temperature: -13 °C

Procedure:
To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13° C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.C(Br)C=C>CN(C)C=O>[CH2:30]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1)[CH:28]=[CH2:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCNCc1noc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 6 %

Procedure:
5.17 g (15 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 45 ml of N,N-dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred at room temperature for 1 hour. The reaction solution was evaporated and the residue was chromatographed on 250 g of silica gel while eluting with ethyl acetate. The uniform fractions having the smaller Rf value were evaporated. There was obtained 0.344 g (6%) of 3-(3-allylaminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 171°-174°.
Reaction SMILES: [CH3:1]Cl.[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[N:9][NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1>C(O)C>[ClH:3].[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[N:9][NH:10][C:11](=[NH:13])[S:12][CH3:1])=[CH:6][CH:5]=1
Reactant: CCl
Reactant: NC(=S)NN=Cc1ccc(Cl)cc1
Solvent: CCO
Product: CSC(=N)NN=Cc1ccc(Cl)cc1
Product: Cl

Procedure:
A 10% molar excess of methyl chloride is added to 2.14 g. of 4-chlorobenzaldehyde thiosemicarbazone and 25 ml. of a anhydrous ethanol in a pressure vessel. The reaction mixture is magnetically stirred and heated in an oil bath for 11/2 hour. The crystalline title compound separates on cooling and is filtered off and air dried.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20](OC)([CH3:22])[CH3:21].O.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH2:1]([O:8][C@H:9]([C@@H:13]1[C:14](=[O:16])[O:15][C:20]([CH3:22])([CH3:21])[O:17]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)[C@@H]([C@@H](OCc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2R,3R)-2-(Benzyloxy)-3-hydroxysuccinic acid (11.1 g, 46.2 mmol) was dissolved in 2,2-dimethoxypropane (46 mL, 374 mmol) and 4-methylbenzenesulfonic acid hydrate (0.0879 g, 0.462 mmol) was added and the reaction was stirred at ambient temperature for 4 hours. Water (30 mL) and NaHCO3 (0.0388 g, 0.462 mmol) were added and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to provide (R)-2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid. The crude product was taken on to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[C:2]([NH:1][S:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:27])=[O:28])[CH:7]=1
Reactant: ClCc1ncc[nH]1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1S
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ncc[nH]1)c1cc2ccccc2o1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].OO.[O:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH:12]1[C:13]([OH:15])=[O:14]>>[CH:16]([OH:11])([C:17]([OH:19])=[O:18])[CH:12]([OH:5])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Agent: OO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Thus free maleic acid is reacted in aqueous solution with hydrogen peroxide in the presence of alkali tungstates or molybdates, the intermediate epoxysuccinic acid formed hydrolyzed by boiling and then the racemic acid formed crystallized out of the hydrolysis solution, see Church and Blumberg, "Ind. Eng. Chem.", Vol. 43 (8) pages 1780 to 1786. The mother liquor of the racemic acid crystallization is again returned into the reaction step.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To 35.0 g of L-arginine were added 118.7 g of acetone and 200 g of water. Thereto were concurrently added dropwise 36.5 g of lauroyl chloride (“lauroyl chloride” manufactured by Nippon Oil and Fats Co., Ltd.) and 45 ml of 8N NaOH aqueous solution over a period of 2 hours with the pH being maintained at 11.5 to 12.0 and the reaction temperature being maintained at 15 to 25° C. After 2 hours of aging, the reaction mixture was adjusted to pH 5.0 with 6N sulfuric acid with cooling and then poured into about 300 ml of ice-water to precipitate crude crystals of mono-Nα-lauroyl-L-arginine, which were collected by filtration and then dried (yield 55 g). The crude crystals were washed by stirring in 300 ml of petroleum benzine and then filtered, and the crystals were dried under reduced pressure to obtain 51 g of mono-Nα-lauroyl-L-arginine (yield 85%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([F:20])[CH:14]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:26]2([OH:8])[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:15]([F:20])[CH:14]=1.[CH3:23][CH2:22][O:21][CH2:26][CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=COCCC1
Reactant: Oc1ccc(Br)cc1F
Solvent: CCCCCC
Product: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
p-Toluene sulfonic acid (0.40 g) was added to an ice-cooled solution of 4-Bromo-2-fluoro phenol (205.38, 1.075 mol) in dihydro-2H-pyran (452.23 g, 5.376 moles). The ice bath was removed after 30 min. and the mixture was stirred for two hours and then diluted with methylene chloride (500 ml). The methylene chloride solution was extracted with 10% aqueous KOH solution (3×500 ml), rinsed with water (3×500 ml), dried over MgSO4, filtered and rotavaped. The crude product was further dried overnight over a vacuum pump and then vacuum distilled. The first distillation fraction was unreacted phenol, (52.0 g) followed by a fraction of the protected phenol (212.29 g, 71.8%). The purified product was frozen in dry ice/acetone bath and then allowed to sit in the refrigerator over 2-3 days to obtain the Monomer IA2 intermediate as clear needle shaped crystals, mp=25-27° C., mp of the Monomer IA1 intermediate=62-63° C., TLC (1:1CH2Cl2/hexane), Rf=0.42.
Reaction SMILES: [Cl:1][C:2]#[C:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]#[C:2][Cl:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCCOCC#CCl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC#CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 79.1 %

Procedure:
To a mixture of 0.20 g of 4-(3-chloro-2-propynyloxy)butanol, 0.32 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.32 g of triphenylphosphine and 15 ml of tetrahydrofuran was slowly added dropwise 0.27 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-2-propynyloxy)butyloxy)benzene (yield, 71%), nD23.5 1.5511.