Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])/[CH:5]=[CH:6]/[Sn](CCCC)(CCCC)CCCC)[CH3:2].[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1I>CN(C)C=O.O>[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1/[CH:6]=[CH:5]/[Si:4]([O:3][CH2:1][CH3:2])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](/C=C/[Si](OCC)(OCC)OCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1I
Solvent: CN(C)C=O
Solvent: O
Product: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Temperature: 90 °C
Reaction time: 120 h
Yield: 5.4 %

Procedure:
Tetrakis triphenylphosphine palladium(0) (160 mg, 0.14 mmol, 0.10 equiv) and (E)-triethoxy(2-(tributylstannyl)vinyl)silane (990 mg, 2.1 mmol, 1.5 equiv) were sequentially added to a stirred solution of methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-iodopyrimidine-4-carboxylate (600 mg, 1.4 mmol, 1.0 equiv) in N,N-dimethylformamide (5.5 mL) at room temperature. The heterogeneous yellow mixture was heated at 90° C. and stirred for 5 d. The cooled reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by acid free reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to provide the title compound as a yellow glass (38 mg, 6% yield): IR (thin film) 3315 (w), 3069 (w), 2974 (w), 1657 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=9, 8 Hz, 1H), 7.29 (d, J=18.5 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 6.06 (d, J=18.5 Hz, 1H), 5.39 (br s, 2H), 3.98 (d, J=1 Hz, 3H), 3.92 (s, 3H), 3.89 (q, J=7 Hz, 6H), 1.26 (t, J=7 Hz, 9H); ESIMS m/z 500 [(M+H)+].
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10](Br)[N:11]=1)[CH2:2]2.C(O)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=3[F:23])[N:11]=1)[CH2:2]2
Reactant: Brc1csc(N2CC3CC3C2)n1
Reactant: OB(O)c1ccc(F)cc1F
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: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2csc(N3CC4CC4C3)n2)c(F)c1
Temperature: 92.5 °C
Yield: 77.4 %

Procedure:
To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-bromothiazole (Step-1 of compound 66, 0.29 g, 1.16 mmol) in a mixture of toluene: ethanol (4 ml:16 ml) were added (2,4-difluorophenyl) boronic acid (0.20 g, 1.28 mmol) and potassium carbonate (0.32 g, 2.32 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.067 g, 0.058 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite; residue was washed with ethyl acetate (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.25 g, 77.0%). MS: m/z 279 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9]>CCOCC>[CH2:6]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=C=O
Reactant: NCCCN
Solvent: CCOCC
Product: CCCCNC(=O)NCCCN

Procedure:
30 grams 1,3 diaminopropane in 30 mls ether was slowly (1 hour) reacted with 10 gms butyl isocyanate and refluxed for one-half hour. The precipitate was filtered and washed with ether and dried in vacuum oven, melting point 201°-202°C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](N2CCCCC2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:10]3[CH2:37][CH2:36][CH:7]([CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCCCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(bis(4-fluorophenyl)methylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 64% overall yield. FDMS m/e=476 (M+ of free base). α[D]589 =-9.85 (c=0.89, methanol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29]I)[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[C:9]([O:8][CH2:7][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[C:27](=[O:28])[CH2:26][O:25][CH2:24][CH:23]2[CH2:29][O:4][C:1](=[O:3])[CH3:2])[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:41][O:42][C:43](=[O:45])[CH3:44])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2C(=O)COCC2CI)c1I
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2C(=O)COCC2COC(C)=O)c1I

Procedure:
To a solution of N,N'-Bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-2,4,6-triiodo-5-[3-(iodomethyl)-5-oxo-4-morpholinyl]-1,3-benzenedicarboxamide of example 7b (2.01 g, 1.83 mmol) in glacial acetic acid (35 ml), was added silver acetate (0.67 g, 4 mmol) and the mixture refluxed for 14 hours. The solvent was removed in vacuo at 40°, and the residue extracted with ethyl acetate (200 ml). The organic extract, after washing with saturated aqueous sodium bicarbonate (3×25 ml) and water (3×25 ml), was dried over anhydrous sodium sulfate. Removal of the solvent followed by purification of the crude product by column chromatography over silica gel, yielded analytically pure N,N'-Bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[3-[(acetyloxy)methyl]-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white fluffy solid (1.5 g, 82% yield), m.p. 208°-210°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=1
Reactant: OCCOc1ccc(-c2ccccc2F)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(-c2ccccc2F)nc1
Reaction time: 7 h

Procedure:
217.1 mg (1.89 mmol) of methanesulfonyl chloride were added dropwise with cooling to 340 mg (1.46 mmol) of 2-(6-(2-fluorophenyl)pyridin-3-yloxy)ethanol and 442.5 mg (4.37 mmol) of triethylamine in 25 ml of methylene chloride. After 7 h at room temperature, the mixture was extracted with water, and the organic phase was separated and concentrated. Yield: 394 mg (87%).
Reaction SMILES: C1(OC(=S)O[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[F:25][C:19]1[CH:18]=[C:17]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: N#Cc1ccc(C(OC(=S)Oc2ccccc2)c2cccnc2)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: N#Cc1ccc(Cc2cccnc2)cc1F

Procedure:
To a solution of thiocarbonic acid O-[(4-cyano-3-fluoro-phenyl)-pyridin-3-yl-methyl]ester O-phenyl ester (as described in Step A above) (0.5 g, 1.37 mmol) in benzene (2.0 mL) was added AIBN (0.18 g, 1.1 mmol) and tri-n-butyltinhydride (1.09 mL, 4.0 mmol) and the solution was heated to refluxed for 2 hr. The solvents were removed in vacuo to obtain the title compound after chromatography (silica gel, CH2Cl2:MeOH 99:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[C:15]1N=C(C)C(C)=CC=1.[Li+].CC([N-]C(C)C)C.C(=O)(OCC)OCC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc(Cl)ccc1C

Procedure:
Following the same procedure described for the preparation of ethyl (6-chloro-2-pyridinyl)acetate (Example 469) and starting from 6-chloro-2,3-dimethylpyridine (0.35 g, 2.5 mmol), LDA (5.17 mmol), and diethyl carbonate (0.75 mL, 6.2 mmol) in THF (10 mL), the title compound was obtained (0.15 g, 29%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42 (d, 1H), 7.15 (d, 1H), 4.18 (q, 2H), 3.84 (s, 2H), 2.29 (s, 3H), 1.27 (t, 3H); LC-MS: RT=2.30 min, (M+H)+ 214.2.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][S:13][CH2:14][S:15]([CH3:17])=[O:16].CO.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O1CCCC1.C(O)(=O)C.O>[CH3:17][S:15]([C:14]([S:13][CH3:12])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: CSCS(C)=O
Reactant: CN(C)c1ccc(C=O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CSC(=Cc1ccc(N(C)C)cc1)S(C)=O
Yield: 60.8 %

Procedure:
p-Dimethylaminobenzaldehyde (12.953 g) was dissolved in 30 ml of tetrahydrofuran, and 18.428 g of FAMSO and 12 ml of a 40% methanol solution of trimethylbenzylammonium hydroxide were added. The mixture was heated under reflux for 40 hours. Water was added, and the reaction mixture was acidified with acetic acid and then extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride/ethyl acetate as an eluant, and then recrystallized from diethyl ether to afford 13.492 g of 1-methylsulfinyl-1-methylthio-2-(p-dimethylaminophenyl)ethylene.
Reaction SMILES: C1[O:15][C:4]([CH3:14])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=2)OC1.[CH3:16][O-:17].[Na+].[I-].[Na+]>CO>[CH3:16][O:17][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:15])[CH3:14])=[CH:11][CH:10]=1
Reactant: CC1(Cc2ccc(CBr)cc2)OCCO1
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(CC(C)=O)cc1
Reaction time: 1 h

Procedure:
1-(4-Bromomethylphenyl)propan-2-one ethylene ketal (1.35 g) in methanol was added to sodium methoxide (from sodium (0.11 g)) in methanol containing a trace of sodium iodide. The mixture was refluxed for 1 hour. Methanol was removed, the residue partitioned between water and ether and the combined organic extracts dried. Removal of the solvent gave an oil which was dissolved in methanol-2 N hydrochloric acid and left for 1 hour at room temperature. Extraction with ether gave the title compound, bp 106°/0.7 mm. τ(CDCl3) 7.9 (3H, s), 7.63 (3H, s), 6.33 (2H, s), 5.54 (2H, s), 2.8 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[S:48][C:47]([NH:49][C:50]([C:52]2[CH:56]=[CH:55][NH:54][N:53]=2)=[O:51])=[C:46]([C:57](=[O:59])[NH2:58])[CH:45]=1.[C:60]1([CH2:66][SH:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.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]>[CH2:66]([S:67][C:44]1[S:48][C:47]([NH:49][C:50]([C:52]2[CH:56]=[CH:55][NH:54][N:53]=2)=[O:51])=[C:46]([C:57](=[O:59])[NH2:58])[CH:45]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: NC(=O)c1cc(Br)sc1NC(=O)c1cc[nH]n1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(SCc2ccccc2)sc1NC(=O)c1cc[nH]n1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
A mixture of Pd2(dba)3 (20 mg, 0.022 mmol) and Xantphos (51 mg, 0.087 mmol) in 1,4-dioxane (5 mL) is degassed, put under N2 and sonicated. This mixture is then added to a degassed mixture of 1H-Pyrazole-3-carboxylic acid (5-bromo-3-carbamoyl-thiophen-2-yl)-amide (345 mg, 1.09 mmol), phenyl-methanethiol (135 μL, 1.15 mmol) and DIEA (380 μL, 2.18 mmol) in 1,4-dioxane (5 mL). Resulting mixture is stirred at 100° C. under N2. After 75 min, the reaction is diluted with DCM and washed with aqueous NaHCO3. The organic is then dried over MgSO4, filtered and evaporated to an oily residue. This residue is triturated in di-isopropylether, separated by filtration, the cake is dried, and the resulting the solid is used as such.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].C(N(CC)CC)C.O>CN(C=O)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: CCNCC
Reactant: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C#N
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
A mixture of 2,6-dichloro-4-(3-isopropyl-phenyl)-quinoline-3-carbonitrile (128 mg, 375 μmol, Eq: 1.00), diethylamine (54.9 mg, 78.4 μl, 750 μmol, Eq: 2) and triethylamine (114 mg, 157 μl, 1.13 mmol, Eq: 3) in DMF (1 ml) was heated first to 120° C. for 20 min and then to 180° C. for additional 20 min in a microwave. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 90:10 to 85:15) to afford the title compound as yellow oil (128 mg). MS (ESI): 377.1 (M−H)−.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=[O:17])[NH:6][C:7]3[CH:8]=[C:9]([C:14](O)=[O:15])[CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[OH:15][CH2:14][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]3[CH2:1][CH2:2][CH2:3][CH:4]3[C:5](=[O:17])[NH:6][C:7]=2[CH:8]=1
Reactant: O=C(O)c1ccc2c(c1)NC(=O)C1CCCC21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1Nc2cc(CO)ccc2C2CCCC12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
A solution of 150 mg (0.65 mmol) of 1,2,3,3a,5,9b-hexahydrocyclopenta[c]-quinolin-4-one-7-carboxylic acid in 20 ml of THF is mixed with 0.10 ml (0.70 mmol) of triethylamine and 0.07 ml (0.70 mmol) of ethyl chloroformate at room temperature. After 10 minutes, 76 mg (2.0 mmol) of sodium borohydride is added, and within 20 minutes, 10 ml of methanol is added in drops to it. The batch is stirred for 15 hours at room temperature, diluted with ethyl acetate (100 ml), washed with 20% citric acid (50 ml) and saturated NaCl (50 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 65 mg of product.
Reaction SMILES: C[O-].[Na+].[NH2:4][C@H:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8].[O:16]1[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17]1.Cl>CO>[OH:16][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][NH:4][C@H:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCCC1CO1
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCC(O)CN[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.9 %

Procedure:
27.01 g of sodium methoxide and 82.6 g of (S)-3-amino-3-phenylpropionic acid were dissolved in 800 ml of methanol. After adding 92 g of 1,2-epoxydodecane, the solution was stirred at room temperature for 20 h. Subsequently, the pH of the solution was adjusted to pH 6 with methanolic hydrochloric acid and the sodium chloride which crystallized out filtered off. After the methanol was distilled off, an oily residue remained, which crystallized in the course of stirring with 700 ml of acetone. This resulted in 153.4 g of colorless crystals. 1H NMR (DMSO) δ (ppm): 0.85 (t, 3H), 1.13-1.31 (m, 18H), 2.28/2.60/2.70/2.86 (m, 2H), 3.02 (m, 1H), 3.34 (m, 1H), 3.66-3.78 (m, 1H), 4.57 (m, 1H), 5.20/5.29 (s, br., 1H, OH), 7.42 (m, 3H), 7.60 (m, 2H), 9.40 (s, br., 2H, NH2+), 12.56 (s, 1H, CO2H)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C@@H:23]([CH3:27])[C:24](O)=[O:25].C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:24](=[O:25])[C@@H:23]([N:14]2[C:13](=[O:12])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:22])[CH3:27])=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: NCC(O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NCC(O)c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-amino-1-(4-chlorophenyl)ethanol (1000 mg, 5.83 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (1280 mg, 5.83 mmol) in THF (20 ml) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 1322 mg, 6.41 mmol) and allowed to stir at ambient temperature for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Used crude directly in the next step. 2 g of white solid. HRMS(B) tR=1.04 min; MS m/z 373.1
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N#N>C(O)(C)C.C1(C)C=CC=CC=1.CCOCC>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(O)c1sccc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccsc2C(=O)O)c1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
3-Bromothiophene-2-carboxylic acid (600 mg; 2.9 mmol) was dissolved in isopropanol (7 ml)/toluene (7 ml), followed by the addition of K2CO3 solution (aq; 2M; 9 ml) and 3-methoxybenzeneboronic acid (440 mg; 2.9 mmol). The reaction mixture was deoxygenized with N2 (g) for 3 minutes followed by the addition of tetrakis-(triphenylphosine)-palladium and subsequently heated to 80° C. for 14 h. The mixture was cooled to rt, ether was added and the organic layer was extracted with 2M NaOH-solution. The aq. layer was acidified by the addition of 2M HCl. The product precipitated and was filtered off and dried at high vacuum to give 470 mg of 3-(3-methoxy-phenyl)-thiophene-2-carboxylic acid; LC-MS: tR=0.94 min; [M−H]+=235.27.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[N:11]1[NH:12][C:13](=[O:17])[CH:14]=CC=1>>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]2[CH:1]=[CH:14][C:13](=[O:17])[NH:12][N:11]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2ccc(O)cc2)n[nH]1

Procedure:
50 g of 4-hydroxyacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[NH:20][N:19]=[C:18]([C:21]5[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=5)[CH:17]=4)[NH:13][C:12]=3[CH:28]=2)[CH2:4][CH2:3]1.[N:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>CS(C)=O.CC#N>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:17]=[C:18]([C:21]5[CH:27]=[CH:26][C:24]([NH:25][C:30]([NH:29][C:32]6[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=6)=[O:31])=[CH:23][CH:22]=5)[NH:19][N:20]=4)=[N:13][C:12]=3[CH:28]=2)[CH2:4][CH2:3]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CS(C)=O
Product: CN1CCN(c2ccc3[nH]c(-c4cc(-c5ccc(NC(=O)Nc6ccc(OC(F)(F)F)cc6)cc5)[nH]n4)nc3c2)CC1
Yield: 50.2 %

Procedure:
To a solution of 4-{5-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-3-yl}aniline (45 mg, 0.12 mmol) in DMSO (2 mL) were added 1-isocyanato-4-trifluoromethoxybenzene (36.6 mg, 0.18 mmol), triethylamine (36.4 mg, 0.36 mmol) in CH3CN (1 mL) at room temperature. The reaction mixture was monitored by LC-MS until reaction was complete (1 h). The resulting mixture was concentrated in vacuo and separated by preparative HPLC (0.1% TFA/CH3CN, 0.05% TFA/water). The corresponding fractions were concentrated and dried. The resulting solid was dissolved in MeOH (1 mL) and was added 4N HCl (0.5 mL). The solution was concentrated and repeated three times to afford product (24%, 34.7 mg) as light yellow solid as the hydrochloride salt: 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.68 (d, 2H), 7.79-7.57 (7H, m), 7.38-7.29 (m, 3H), 7.17 (s, 1H), 3.90 (m, 2H), 3.46 (m, 2H), 3.21 (m, 4H), 2.85 (m, 3H) MS (EI) for C29H27F3N8O2: 577.3 (MH+).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:7]([C:13]([O:15]CC)=[O:14])[CH:6]=[N:5]1.Cl>O.O1CCOCC1>[CH3:3][N:4]1[C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:7]([C:13]([OH:15])=[O:14])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1cnn(C)c1S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)O)c1S(C)(=O)=O
Reaction time: 8 h
Yield: 64 %

Procedure:
Add a solution of LiOH (22 mg, 0.90 mmol) in H2O (1 mL) to a rapidly stirring solution of ethyl 1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxylate (175 mg, 0.75 mmol) in 1,4-dioxane (3 mL) at ambient temperature. Treat the reaction mixture with additional LiOH (5 mg, 0.21 mmol), and stir overnight. Acidify to pH 2 with 1 N HCl, and extract twice with CH2Cl2. Combine the organic layers, dry over MgSO4, filter, and concentrate under reduced pressure to yield the title compound as a white solid (98 mg, 64%). ES/MS m/z 202.9 (M−1).