Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1CCC(N=C=NC2CCCCC2)CC1.[O:35]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCCC1>[OH:35][NH:1][C:2]1[CH:3]=[C:4]([O:11][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1O
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NO)cc1ON1C(=O)CCC1=O
Reaction time: 0.01 h

Procedure:
4-Amino salicylic acid (2.07 g, 13 mM), N-hydroxy-succinimide (2.07 g, 18 mmol) and DCC (3.44 g, 19 mmol), which had been dried over night over phosphorus pentoxide in vacuum, were dissolved sequentially in anhy. tetrahydrofuran (150 mL) in a round bottom flask. A vacuum was then applied for 30 seconds, the flask sealed and the reaction allowed to proceed for 7 hours at 1°-0° C., maintaining continuous stirring. After this time, the solvent was removed under vacuum and the residue re-dissolved in 15 mL CHCl3 /acetonitrile (CH3CN) (98:2). This solution was chromatographed using 80 g silica gel, eluting sequentially with 300 mL each, CHCl3 /CH3CN (95:5), CHCl3 /CH3CN (90:10) and CHCl3 /CH3CN (50:50). HASA began eluting in the tail end of CHCl3 /CH3CN (95:5) and continued throughout the elution with 10% CH3CN. A total of 2.4 g (70%) of purified HASA (XXXII) was obtained, Rf =0.64 (CHCl3 /CH3CN, 20.3).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.CO.[ClH:18]>C(Cl)Cl.O1CCOCC1>[ClH:18].[CH3:8][C@H:7]1[CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:2][OH:1]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1CCN[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate from step 3 was dissolved in a 1:1 mixture of methylene chloride:methanol. Excess 4N HCl in dioxane was added, and the reaction stirred at room temperature for 1 hour, concentrated under reduced pressure, and then used in the final step (see Scheme 1a (g) to (h)). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.2 Hz, 3 H) 1.5 (m, 1 H) 2.1 (m, 2 H) 3.1 (m, 1 H) 3.3 (m, 1 H) 3.4 (m, 1 H) 4.5 (dd, J=12.1, 8.1 Hz, 1 H) 4.7 (dd, J=12.3, 3.1 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:32]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:47][CH2:48][CH2:49][CH3:50]>CC#N.ClCCl>[CH2:47]([O:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCI
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCOc1cccc(/C(CC)=C(\c2ccc(/C=C/C(=O)OCC)cc2)c2ccc3c(cnn3C3CCCCO3)c2)c1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (53 mg, 0.38 mmol) was added to (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl) -1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (101 mg, 0.19 mmol) in CH3CN (1 mL). After stirring for 15 min, iodobutane (24 μL, 0.21 mmol) was added. The reaction was stirred at rt for 15 h. Additional iodobutane (24 μL, 0.21 mmol) was added, and the reaction was stirred at 60° C. for 10 h and then at rt for 48 h. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and purified by silica gel chromatography (0-20% EtOAc in hexanes) to give 97 mg of (E)-ethyl 3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenypacrylate as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.73 (d, 1H), 7.64 (s, 1H), 7.49 (d, 1H), 7.41 (d, 2H), 7.24 (dd, 1H), 7.12 (t, 1H), 6.91 (d, 2H), 6.76 (d, 1H), 6.67-6.72 (m, 2H), 6.48 (d, 1H), 5.86 (d, 1H), 4.15 (q, 2H), 3.86-3.94 (m, 1H), 3.72-3.80 (m, 3H), 2.38-2.46 (m, 3H), 1.96-2.10 (m, 2H), 1.70-1.82 (m, 1H), 1.52-1.63 (m, 4H), 1.31-1.37 (m, 2H), 1.22 (t, 3H), 0.85-0.92 (m, 6H); LCMS: 495 [(M-THP+H)+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH3:10])=[CH:2][CH:3]=2)[N:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: CCOc1ccc(B(O)O)cc1F
Product: CCOc1ccc(-c2cc(I)ncn2)cc1

Procedure:
The compound was prepared according to Example 1 using 3-fluoro-4-ethoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27](Cl)[C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].ClCC1ON=C(C2N=CN3C4C=CC([F:53])=CC=4C(=O)N4CCC4C=23)N=1.C(NCCC)CC>CN(C)C=O>[CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:53])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Reactant: O=C1c2cc(F)ccc2-n2cnc(-c3noc(CCl)n3)c2C2CCN12
Solvent: CN(C)C=O
Solvent: CCCNCCC
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 85 %

Procedure:
1.8 g (5 mmol) of (S) 1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with mmol) of dipropylamine and 20 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.8 g (85%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][N:16]3[C:20]([CH:21]=O)=[C:19]([C:23]([O:25]CC)=O)[N:18]=[CH:17]3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[C:20]4[CH:21]=[N:3][N:2]([CH3:1])[C:23](=[O:25])[C:19]=4[N:18]=[CH:17]3)=[CH:28][CH:29]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cn1ncc2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of methylhydrazine (472 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-formylimidazole-4-carboxylate (1.03 g) in ethanol (20 ml) was refluxed for 3 hours. After cooling to room temperature, concentrated sulfuric acid (0.2 ml) was added and the mixture was further refluxed for 21 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developer; chloroform:methanol=19:1) to provide the title compound as white powder (66 mg, yield 7%). 1H-NMR (CDCl3) δ: 3.90(3H,s), 5.47(2H,s), 7.31(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.92(1H,s), 8.00(1H,s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: N#Cc1ccc(B(O)O)cc1
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: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80° C. overnight. DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column (Petroleum Ether/EtOAc 50:1) on silica gel to give [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.02-8.07 (m, 2H), 7.95 (d, J=8.4 Hz, 1H), 7.71-7.79 (m, 3H), 7.37-7.44 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: CC(C)C[O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[C:18]([CH2:21][NH:22][C:23]1[C:24]([I:39])=[C:25]([C:29]([I:38])=[C:30]([NH:33][CH2:34][C:35](=[O:37])[CH3:36])[C:31]=1[I:32])[C:26](Cl)=[O:27])(=[O:20])[CH3:19]>CC(N(C)C)=O>[C:35]([CH2:34][NH:33][C:30]1[C:29]([I:38])=[C:25]([C:26]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:4])=[O:16])=[CH:14][CH:13]=2)=[O:27])[C:24]([I:39])=[C:23]([NH:22][CH2:21][C:18](=[O:20])[CH3:19])[C:31]=1[I:32])(=[O:37])[CH3:36]
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CC(C)COC(=O)CCCc1ccc(N)cc1
Solvent: CC(=O)N(C)C
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCC(=O)O)cc2)c1I
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 4-aminobenzenebutyric acid 2,2-dimethylethyl ester IXb (2.0 g, 7.5 mmol) in dimethylacetamide (DMA 25 mL), was added 3,5 bis(acetylmethylamino)-2,4,6 triiodobenzoyl chloride X (1.98 g, 3 mmol), and the mixture stirred at 90-95° C. for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (200 mL). The organic extract was washed with saturated sodium bicarbonate (250 mL), water and saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuum and the residue purified by a silica gel column (150 g) using hexane/EtOAc to obtain the title compound XIb (1.98 g, yield 74%). (MS: m/e 858 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].C([O-])(O)=[O:49].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[C:3]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37]([S:40]([CH3:41])=[O:49])=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:14][CH2:15]1)=[O:8]
Reactant: COc1ccc(-c2ccc(SC)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(S(C)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of methyl sulfide 209 (75 mg, 0.11 mmol) and NaHCO3 (46 mg, 0.55 mmol) in DCM (3 mL) at 0° C. is treated with a solution of m-chloroperbenzoic acid (20 mg, 0.12 mmol) in DCM (1 mL) dropwise over 2 minutes. After stirring 2 h at RT, the reaction is diluted with aqueous Na2SO3 (10 mL) and extracted into DCM (3×10 mL). The combined DCM phases are then dried (Na2SO4) and reduced in vacuo. The residue is purified by column chromatography (gradient elution—10-90% EtOAc in heptane with 0.5% triethylamine) to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>ClCCl.C(=O)=O.CC(C)=O>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Reactant: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Benzyl Alcohol 3 (0.500 g, 1.759 mmole) was dissolved in dichloromethane (50 mL) and cooled to −78° C. in dry ice/acetone bath. To this solution, boron tribromide (1.0 M in dichloromethane), (7.04 mL, 7.05 mmole) was added drop wise over 15 minutes. After 30 minutes, the dark orange solution was allowed to come to room temperature and reacted for an additional 4 hours. The solution was concentrated and added to saturated sodium bicarbonate and extracted with ethyl acetate. Organic layers were combined and washed with water, brine, and dried over magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.495 g (88%) of benzyl bromide 4 as a white solid: Mp=337-339° C.; 1H NMR (DMSO-d6) δ 7.90 (s, 2 H),), 7.74 (d, 2 H, J=8.8 Hz), 7.06 (s, 1 H), 6.89 (d, 2 H, J=8.7 Hz), 6.86 (d, 1 H, J=2.5 Hz), 6.77 (d, 1 H, J=2.2 Hz); MS 317/319 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)[CH:6]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.61) (0.16 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.043 g, 26%). MS (ISP) 398.1 [(M+H)+]; mp 255.5° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]([CH2:32][CH3:33])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[C:23]([O:30][CH3:31])[CH:22]=3)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[C:28]([C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:30][CH3:31])=[CH:24][CH:25]=2)[N:20]([CH2:32][CH3:33])[C:19]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[CH:17][CH:16]=1)#[N:29]
Reactant: CCn1c(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c(C#N)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(-c2cccc(NC(N)=S)c2)c(C#N)c2ccc(OC)cc21
Temperature: 50 °C
Yield: 96.4 %

Procedure:
A suspension of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) is stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) is added. The reaction mixture is heated to 50° C. for 17 h. The reaction mixture is concentrated to remove methyl alcohol. Water is added to the mixture and the solid is filtered, washed with water and dried to give 179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:14]3[CH:15]([CH2:19][C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:30]([CH3:32])[CH3:31])[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C(#N)C.O>[NH3:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:14]3[CH:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:30]([CH3:32])[CH3:31])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1[C@@H](C)c1ccc(Cl)cc1)C(CC(=O)OCc1ccccc1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(C)c1nc2c(n1[C@@H](C)c1ccc(Cl)cc1)C(CC(=O)O)CCC2
Product: N
Reaction time: 8 h

Procedure:
Intermediate 66 (177 mg) was dissolved in methanol (4 mL). NaOH (2 mL, 6.60 mmol) was added to the stirred reaction mixture as a 3.3 N aqueous soln and the reaction mixture. After stirring overnight the reaction mixture was conc in vacuo and taken up in acetonitrile/water. The soln was taken to pH4-5 by the addition of 2 M aqueous HCl and loaded onto an SCX column. After washing with water and acetonitrile, the product was eluted with 2 M ammonia soln in methanol. The washing were conc in vacuo to afford the ammonium salt of the desired product. LC/MS, MH+ 361, Rt 2.01 mins (5 min system).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+].S([O-])([O-])=O.[Na+].[Na+].[OH2:30]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:19])=[O:30]
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)c(F)c1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 3-fluoro-4-(phenylthio)nitrobenzene (5.65 g, 22.7 mmol) in glacial acetic acid (200 mL) was added potassium permanganate (4.30 g, 27.2 mmol) in distilled water (75 mL). The dark brown mixture was stirred at room temperature for 1 hour, then treated with solid sodium sulfite until the solution clarified. The mixture was diluted with water and filtered to yield an off-white solid. Recrystallization from absolute ethanol yielded the title sulfone (4.80 g, 75%) as an off-white solid; mp 124°-125° C. 1H-NMR (300 MHz, DMSO-d6): 7.68-7.73 (m, 2H, aromatic) 7.79-7.84 (m, 1H, aromatic) 8.00 (d, 2H, J=8.2 Hz, aromatic) 8.28-8.38 (m, 3H, aromatic). MS (CI, CH4): 282 (M+1).
Reaction SMILES: [Br-].[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])=[CH:10][CH:11]=2)[C:6]([CH3:35])([CH3:34])[CH2:5][CH2:4]1.C([Li])CCC.[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CCCCCC>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([CH3:14])=[CH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:10][CH:11]=2)[C:6]([CH3:34])([CH3:35])[CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCN2C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=Cc1ccccc1)c1ccc2c(c1)C(C)(C)CCN2C
Temperature: -20 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
5.1 g of [1-(1,2,3,4-tetrahydro-1,4,4-trimethyl-6-quinolinyl)ethyl]triphenylphosphonium bromide were suspended in 40 ml of tetrahydrofuran and treated at -20° C. with 5.9 ml of a 1.6 molar solution of n-butyllithium in hexane. After stirring at -20° C. for 1 hour, 1 g of benzaldehyde was added thereto and the mixture was stirred at room temperature for an additional 1 hour. After working-up in analogy to Example 49 and recrystallization from hexane, there were obtained 1.2 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-6-(α-methylstyryl)quinoline, melting point 69°-71° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:13](Cl)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OC(C)C)(C)C.Cl>C1COCC1.CN(C)C1C=CN=CC=1>[C:13]([CH:1]([OH:5])[CH2:2][CH2:3][OH:4])(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)C(O)CCO
Temperature: 30 °C

Procedure:
1,3-Propanediol, 153 g (MW 76.1; 2 mol) is dissolved in 1 l of THF and, after addition of 60 g of triethylamine (MW 101.2, 0.6 mol) and 7.3 g of 4-dimethylaminopyridine (MW 122.2, 0.06 mol), equilibrated at 20° C. in a water bath. While stirring continuously, 178 g of erucoyl chloride (MW 357.0; 0.5 mol) in 500 ml of THF are slowly added dropwise so that the temperature in the reaction mixture does not exceed 30° C. The dropwise addition is followed by warming at 30° C. for 30 minutes and then addition of 1.5 l of diisopropyl ether and 1.5 l of 1N HCl. After vigorous shaking and phase separation, the upper ether phase is washed once again with 1% NaCl solution and evaporated in vacuo at 45° C. The residue is taken up in 2 l of hexane and cooled to −20° C. The white crystals are filtered off with suction and dried in vacuo. The yield of pure erucoyl-1,3-propanediol is 123 g (MW 396.7; 62%). The substance is pure by thin-layer chromatography (Rf value 0.3 in ether/pentane/acetic acid 200/200/2 parts by volume).