Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[NH2:9])=[CH:4][C:3]=1[F:16].CCN(C(C)C)C(C)C.[OH:26][CH2:27][C@@H:28]([NH:30][C:31]1[N:40]=[CH:39][C:38]2[C:33](=[CH:34][C:35]([C:41](O)=[O:42])=[CH:36][CH:37]=2)[N:32]=1)[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[NH:9][C:41]([C:35]2[CH:34]=[C:33]3[C:38]([CH:39]=[N:40][C:31]([NH:30][C@@H:28]([CH3:29])[CH2:27][OH:26])=[N:32]3)=[CH:37][CH:36]=2)=[O:42])=[CH:4][C:3]=1[F:16]
Reactant: C[C@@H](CO)Nc1ncc2ccc(C(=O)O)cc2n1
Reactant: Cn1cc(C(N)c2ccc(Cl)c(F)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ncc2ccc(C(=O)NC(c3ccc(Cl)c(F)c3)c3cnn(C)c3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
To a stirred solution of the hydrochloride salt of 40c (140 mg, 0.506 mmol), and DIPEA (88.1 μL, 0.506 mmol) and DMF (5 mL) under nitrogen was added 70 (125 mg, 0.506 mmol) and HBTU (211 mg, 0.556 mmol) and the reaction was stirred at RT for 18 h. The reaction was poured into water and extracted with EtOAc. The combined extracts were dried (MgSO4) and evaporated and the crude material was purified by reverse phase chromatography (SP4) eluting with a MeCN/H2O gradient (10 to 95% MeCN) to afford 83.5 mg (35.2%) of N-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((S)-1-hydroxypropan-2-ylamino)quinazoline-7-carboxamide (I-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]1COCC1.[CH3:16][N:17]1[CH:21]([CH3:22])[CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:29](=[O:39])/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[C:18]1=[O:40]>C1COCC1.C1(C)C=CC=CC=1.[Zn+2].[I-].[I-]>[CH3:16][N:17]1[CH:21]([CH3:22])[CH:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:19]([C:29](=[O:39])[CH2:30][C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:11][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]1=[O:40]
Reactant: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccc(F)c2)C(=O)N1C
Reactant: COc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H](CC(=O)N2C(=O)N(C)C(C)C2c2ccccc2)c2cccc(F)c2)cc1
Temperature: -20 °C

Procedure:
A solution of 4-methoxyphenylmagnesium bromide in THF (0.31 M, 14.7 mL, 4.56 mmole) was added dropwise to a stirred suspension of (4 R, 5 S)-3,4-dimethyl-1-[(E)-3-(3-fluorophenyl)prop-2-enoyl]-5-phenylimidazolidin-2-one (514 mg, 1.52 mmole), CuBr.DMS complex (229 mg, 1.06 mmole), and ZnI2 (582 mg, 1.82 mmole) in THF/toluene (10 mL) at −15° C. After 1.5 hr the reaction was quenched with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was taken up in 1:1 Et2O/hexanes and cooled at −20° C. for 18 hr. The solid was collected, washed with 1: Et2O/hexanes, and dried in vacuum to afford a first crop of the title compound. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (30% EtOAc/hexanes) to afford additional title compound as a yellow oil that solidified in vacuum. The total yield of the title compound was 0.62 g(91%): 1HNMR (300 MHz, CDCl3) δ 6.75-7.37 (m, 13 H), 5.10 (d, J=8.5 Hz, 1 H), 3.80 (s, 3 H), 3.65-3.85 (m, 1 H), 3.63 (dd, J=16.7, 9.6 Hz, 1 H), 3.36-3.41 (m, 1H), 3.14 (dd, J=16.7, 4.9 Hz, 1 H), 2.72-2.88 (m, 2 H), 2.79 (s, 3 H), 0.74 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:8]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: COC(=O)c1ccccc1C1=NOC(c2ccccn2)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Product: COC(=O)c1ccccc1-c1cc(-c2ccccn2)on1
Yield: 34.8 %

Procedure:
A mixture of 11.0 g (0.039 mol) of methyl 2-[5-(2-pyridyl)-2-isoxazolin-3-yl]benzoate and 9.76 g (0.043 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 200 ml of chlorobenzene was held at reflux for 3 hours; the mixture was allowed to cool, was filtered, and was concentrated under vacuum to 12.0 g of residue. The residue was chromatographed on 400 g of silica gel with 20% ether in benzene to give 3.8 g (35%) of solid, mp 54°-57° C. Recrystallization of a small sample gave solid with mp 58°-60.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1>CCO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(C#Cc3ccc(OCOC)cc3C)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCOC)cc3C)cc12
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][1,7]naphthyridin-8-yl)propanoate (6-11) (1.0 equiv.) in EtOH/THF (3:1, 0.16 M) was flushed with nitrogen. Then, 10% wt Pd/C (0.20 equiv. by weight) was added. The reaction was flushed with hydrogen (2×) and stirred under a hydrogen balloon. After 24 hours, the reaction was filtered through a pad of celite, washing with 5% MeOH in DCM. The filtrate was checked for the presence of starting material using LCMS. The hydrogenation reaction was repeated until no more of the alkyne starting material or alkene intermediate was detected. The crude product was purified by Combiflash using 0-4% MeOH in DCM to give ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-12) as a white solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[C:28]([C:33]1[N:34]=[C:35]([CH:39]=O)[N:36]([CH3:38])[CH:37]=1)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:39]([C:35]2[N:36]([CH3:38])[CH:37]=[C:33]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[N:34]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: CC(C)C(=O)c1cn(C)c(C=O)n1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(C(=O)C(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-isobutyryl-1-methyl-1H-imidazole-2-carbaldehyde. 536 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@H:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C@@H:35]1[C@@:63]2(C)[C:39](=[CH:40][CH2:41][C@@H:42]3[C@@H:62]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC(=O)C)C(C)C)C[C@@H](OC(=O)C)C1)(=O)C>>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@H:17]([O:21][C:2](=[O:1])[C:27]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:35](=[O:34])[C:63]2[CH:62]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: CC(C)[C@@H](O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1

Procedure:
The 1α,3β,24(S)-trihydroxycholesta-5,7-diene obtained in Example 16 was benzoylated in quite the same way as in Example 22, (A) to form 1α-hydroxy-3β,24(S)-dibenzoyloxycholesta-5,7-diene. 15 mg of this product was treated in quite the same way as in Example 25 to afford 1.5 mg of a product whose properties corresponded with 1α,24(S)-dihydroxycholecalciferol. From this, it was confirmed that the product obtained after the isomerization was 1α-hydroxy-24(S)-benzoyloxycholecalciferol-3β-benzoate.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]1.[CH3:23]O>>[CH3:23][O:20][C:19](=[O:21])[CH:18]([C:8]1[CH:9]=[CH:10][C:11]([N:12]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]2)=[C:6]([Cl:5])[CH:7]=1)[CH3:22]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 86.9 %

Procedure:
100 ml of thionyl chloride are added to 28.51 g (0.1 mole) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid and heated to the boil for half an hour. The solution is concentrated in a vacuum, and 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid chloride is thus obtained. 500 ml of absolute methanol are added; and, again, heating to the boil for half an hour and concentrating are effected, followed by taking up in benzene, washing with water and sodium hydrogen carbonate solution, drying of the organic solution and distilling to produce 26 g (86.9% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid methyl ester (b.p. 126° to 127° C./10-2 mm Hg).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70][CH3:71])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(OC(C)C)(C)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70][CH3:71])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([OH:53])=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cn3cnc4cc(O)c(O)cc43)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(/C=C/Cn3cnc4cc(O)c(O)cc43)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-3-(5,6-dihydroxybenzimidazol-1-yl)-1-propen-1-yl]-3-cephem-4-carboxylate (XIn) (171 mg, 0.175 mmol), anisole (0.5 ml) and TFA (4 ml) was stirred for an hour at room temperature. The mixture was diluted with isopropyl ether to precipitate a crude product. The product was chromatographed on a column of Prep C18 (Waters, 20×300 mm), and the column was eluted successively with 10% MeOH/H2O, 15% MeOH/H2O and 25% MeOH/H2O. The eluate was monitored by UV absorption at 254 nm and the fractions showing UV absorption were further checked by HPLC.*The fractions containing the desired product were combined and concentrated in vacuo. The concentrate was freeze-dried to give 52 mg (52% yield) of the title product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.F[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=1[N+:40]([O-:42])=[O:41]>CN(C=O)C.CCOC(C)=O>[O:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][C@@H:2]([NH:1][C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=2[N+:40]([O-:42])=[O:41])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of (R)-3-amino-1-morpholino-4-(phenylthio)butan-1-one (INTERMEDIATE 72, 375.5 mg, 1.34 mmol) in DMF (2.5 ml) and DIPEA (1.20 Ml, 6.87 mmol) was added 4-fluoro-3-nitrobenzenesulfonamide (INTERMEDIATE 18, 325.8 mg, 1.48 mmol), and the resulting dark solution was stirred at 50° C. overnight, under a nitrogen atmosphere. The mixture was diluted with EtOAc (50 ml) and washed with water and brine (30 ml each), dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM) to give the title product (532.5 mg, yield: 83%).
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][C@@H:25](C)[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C@H:19]1[C@@:36]2([CH3:37])[C:23]([C:22](=[CH2:21])[C@@H:25]([CH3:24])[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:18]1
Reactant: CCOCOCC
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β,7α-dimethyl-16α-fluoroandrost-4-ene-3,17-dione (0.896 g, 2.7 mmol) is stirred at reflux for about 5 hrs, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline. The organic layer is separated, washed to neutrality with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluant. Thus the pure 1β,7α-dimethyl-16α-fluoro-6-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.56 g).
Reaction SMILES: [NH2:1][C:2]1C=C[C:5]([CH:8](O)CC)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[C:14]=1/[CH:21]=[CH:22]/[C:23](/[CH3:33])=[CH:24]/[CH:25]=[CH:26]/[C:27](/[CH3:32])=[CH:28]/[C:29]([OH:31])=O.C(Cl)CCl.C1C=CC2N(O)N=[N:44]C=2C=1>CN(C=O)C>[CH3:32]/[C:27](/[CH:26]=[CH:25]/[CH:24]=[C:23](\[CH3:33])/[CH:22]=[CH:21]/[C:14]1[C:15]([CH3:19])([CH3:20])[CH2:16][CH2:17][CH2:18][C:13]=1[CH3:12])=[CH:28]\[C:29]([NH:44][C:4]1[CH:3]=[CH:2][N:1]=[CH:8][CH:5]=1)=[O:31]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: On1nnc2ccccc21
Reactant: CCC(O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccncc2)C(C)(C)CCC1

Procedure:
Coupling of (4-amino)phenylpropanol (453 mg; 3 mmol) and retinoic acid (600 mg, 2 mmol) in anhydrous DMF (4 mL) using standard EDC/HOBt coupling condtions yielded the desired amide as a pale, yellow solid (600 mg, 69%). EIMS m/z: 434 ([M+1]+). The amide (510 mg, 1.2 mmol) was dissolved in CH2Cl2 (4 mL) and added with triethylamine (276 □L, 2 mmol) and DMAP (10 mg). The reaction mixture was then treated with p-toluenesulfonyl chloride (324 mg, 1.7 mmol) and stirred at room temperature overnight. The reaction mixture was then diluted with CH2Cl2 (10 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4. The solvent was removed in vacuo to afford tosylate which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:24])[C:11]([CH:16](C#N)[C:17](OCC)=[O:18])([C:14]#[N:15])[C:12]([CH:13]=1)=[C:5]23.C(O)(=[O:27])C>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:24])[C:11]4([CH2:16][C:17](=[O:18])[NH:15][C:14]4=[O:27])[C:12]([CH:13]=1)=[C:5]23
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)C1(C#N)C(=O)N2CCOc3cc(Cl)cc1c32
Agent: O=S(=O)(O)O
Product: O=C1CC2(C(=O)N1)C(=O)N1CCOc3cc(Cl)cc2c31
Temperature: 0 °C

Procedure:
A solution of ethyl 2-(8-chloro-6-cyano-2,3-dihydro-5-oxopyrrolo[1,2,3-de]-1,4-benzoxazine-6-yl)-2-cyanoacetate (1 g) in sulfuric acid (0.5 ml)-acetic acid (10 ml) was heated under reflux for 2 hours. The reaction mixture was poured into ice water, and the resulting precipitate was collected by filtration. Recrystallization from acetic acid afforded colorless crystals (0.48 g, 57%), mp 271° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([O:15]C)=[O:14]>CO.O>[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cnccc1-c1cnccn1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnccc1C1CNCCN1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-(2-pyrazinyl)-3-pyridinecarboxylate (400 mg; may be prepared as described in Intermediate 19) in methanol (20 mL) and water (3 mL) LiOH was added (44.5 mg). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered to remove the inorganic salts and evaporated in vacuo. The residue was dissolved in MeOH (20 ml), Pd/C (300 mg) was added and the reaction mixture was placed under hydrogen at 3 bar for 2 days. The reaction was monitored by LCMS which showed complete conversion of starting material. Then the catalyst was filtered by means of a celite plug and the filter was washed with MeOH. Then the solvent was evaporated in vacuo and the residue dissolved in 25 ml of MeOH to give a solution of the title compound, used directly in subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1.[CH3:20]SC1C(C2C=NC=CC=2)=NNC=1>>[F:19][C:2]([F:1])([F:18])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:20])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: FC(F)(F)CCCSc1c[nH]nc1-c1cccnc1
Product: CN1CCC=C(c2n[nH]cc2SCCCC(F)(F)F)C1

Procedure:
Compound 21B (0.3 g, 1.49 mmol) was converted to compound 22B, using the methodology described for the conversion of 21A to 22A. Yield 0.131 g (amorphous, 72% overall). LCMS (method A); Rt: 1.64 min, ([M+H]+=306). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.67-6.60 (bs, 1H), 3.43-3.39 (m, 2H), 2.71-2.62 (m, 4H), 2.49 (s, 3H), 2.48-2.43 (m, 2H), 2.28-2.19 (m, 2H), 1.81-1.75 (m, 2H).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9].C(OC=O)=O>C1COCC1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1F
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To anhydrous acetic acid (0.63 ml) was added formic acid (0.31 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (10 ml). In THF (10 ml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (510 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-ethoxy-3-fluoropheny)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (490 mg, 89%) as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9].[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:43])[NH2:27])=[CH:24][CH:25]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CCc3ccc(C#N)cc3)nc2c1)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 95 %

Procedure:
Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 95% of theory, C26H25N5O3S (487.58); Rf value: 0.20 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=488.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:23][N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:15]([NH:17][CH:18]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH2:40][C:39]([N:38]([CH3:43])[CH3:37])=[O:42])[CH2:28][CH2:29]4)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH2:13]3)[CH2:6]1)[CH2:14]2)=[O:4]
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)C(CN1CCNCC1)NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CN1CCN(CC(=O)N(C)C)CC1)NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reaction time: 4 h

Procedure:
Methyl 2-(3-Methoxycarbonyladamant-1-ylcarbonylamino)-3-(piperazin-1-yl)propionate (114 mg, 0.28 mol) was dissolved in anhydrous dichloromethane (10 mL) and Et3N (3.0 eq) and N,N-dimethyl 2-chloroacetamide (3.0 eq) were added. The reaction mixture was refuxed at 50° C. for 4 hours. The solvent was then evaporated under reduced pressure and the crude material was purified by column chromatography (silica gel; CHCl3/MeOH 9:1) to afford the title compound.