Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:22][CH2:23][CH2:24][OH:25])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.39 g (3.72 mmol) 3-(5-bromo-2-methoxyphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 2.69 mL (37.2 mmol) of 1,3-propanediol and 1.95 g (7.44 mmol) of triphenylphosphine in 25 mL of anhydrous tetrahydrofuran was added 1.17 mL (7.44 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 250 g of silica gel with 60% ethyl acetate-hexane to give a mixture of desired product and triphenylphosphine oxide. A second chromatography on 120 g of silica gel with 8% acetone-dichloromethane afforded 1.43 g (89% yield) of the pure title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 7.95 (d, 1 H, J=2.5 Hz), 7.70 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.62 (br s, 1 H), 6.52 (br s, 1 H), 6.46 (t, 1 H, J=2.0 Hz), 4.03 (t, 2 H, J=6.0 Hz), 4.00 (s, 3 H), 3.84 (q, 2 H, J=5.7 Hz), 2.26 (s, 3 H) and 2.00 (m, 2 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H1981BrO6S: 455.0 (M+Na). Found: 454.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:19])=[C:6]([C@@:8]([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)([C:10]([F:13])([F:12])[F:11])[OH:9])[CH:7]=1.[C:20](Cl)(Cl)=[O:21].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:19][C:20](=[O:21])[O:9][C@:8]([C:14]#[C:15][CH:16]3[CH2:17][CH2:18]3)([C:10]([F:12])([F:13])[F:11])[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
(S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH:32]=O)=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH2:42])=[O:41].C(O[BH3-])(=O)C.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH2:32][N:38]5[CH2:45][CH2:44][CH2:43][C@H:39]5[C:40]([NH2:42])=[O:41])=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: Cn1c(C=O)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(CN2CCC[C@H]2C(N)=O)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
2-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-3-methyl-3H-imidazole-4-carbaldehyde was dissolved in dichloromethane (5 ml) containing glacial acetic acid (0.03 ml). L-prolinamide (0.028 g) was added and the mixture stirred at 20° C. for 0.75 hours. Sodium acetoxyborohydride (0.08 g) was added and the reaction stirred at 20° C. for 18 hours. The mixture was partitioned between 2N sodium carbonate and ethyl acetate, the organic phase was dried over magnesium sulphate and concentrated in vacuo. Chromatography on silica gave the title compound (0.008 g) as a yellow solid; tlc (SiO2, CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.18; m/z (M+1)+ 534.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[N:27][CH:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl.CO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][CH2:31][C:29]3[CH:30]=[N:25][CH:26]=[N:27][CH:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: NCc1cncnc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cncnc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was charged along with dichloromethane (5 mL, 10V). The reaction mixture was cooled to −20° C. and then added pyrimidine-5-ylmethanamine (0.075 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 ml, 2 eq) dropwise into the reaction mixture. The reaction mixture was stirred at −20° C. for another 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was concentrated by rotary evaporation (25° C., 20 mm Hg) to afford crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collections (500 mL fractions). The compound started eluting from 4% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.2 g. Yield: 80%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH2:22][CH2:21]S[CH2:19][CH2:18]1.[OH2:23]>>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([N:17]2[CH2:22][CH2:21][O:23][CH2:19][CH2:18]2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: C1CSCCN1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1N1CCCCC1
Temperature: 140 °C
Reaction time: 40 h
Yield: 66 %

Procedure:
A mixture of 172 mg (0.715 mmol) 1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in Example 4, step (a)) and 360 μL (3.58 mmol) of thiomorpholine were heated with stirring under Ar at 140° C. for 40 h. After cooling to RT, the mixture was poured into water (50 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with water (3×50 mL) and brine (50 mL) and then dried (Na2SO4). Concentration and chromatography on a 10-g silica SPE column with 60% dichloromethane-hexane afforded 145 mg (66%) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C15H21N3O2S, 308.1 (M+H), found 308.1.
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[CH3:13].[CH2:16]([C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:17]>C(O)C.Cl.C(O)(C)C>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH2:8][CH2:24][C:23]([C:21]2[S:22][C:18]([CH2:16][CH3:17])=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:25])=[CH:6][C:5]=1[CH3:13]
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1CC(O)CO
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(CC(O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
A solution of 4-(2,3-dihydroxy-propyl)-3,5-dimethyl-benzaldehyde (64 mg, 0.308 mmol) and 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (50 mg, 0.218 mmol) in ethanol (2 mL) and 5 N HCl in isopropanol (0.5 mL) is stirred at rt for 5 days. The solvent is removed in vacuo and the residue is separated by prep. HPLC. Product containing fractions are treated with sat. aq. NaHCO3 and 3 M aq. NaOH (5 mL). The mixture is stirred at rt for 1 h, then extracted with DCM. The solvent of the organic extract is removed. The residue is dissolved in THF:methanol 1:1 (5 mL) and is treated with Pd/C. The slurry is stirred at it for 16 h under 1.5 bar of H2. The mixture is filtered over celite and the filtrate is evaporated to give 3-[4-(2,3-dihydroxy-propyl)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (20 mg) as a colourless oil, LC-MS: tR=1.04 min, [M+1]+=423.28.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>O>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[N:11][C:12]=1[OH:13]
Reactant: COC(=O)c1sccc1N
Reactant: NC(N)=O
Solvent: O
Product: Oc1nc(O)c2sccc2n1
Temperature: 180 °C

Procedure:
A solid mixture of methyl 3-aminothiophene-2-carboxylate (40.0 g, 254 mmol) and urea (99.4 g, 163 mmol) was stirred and heated to 180° C. for 5 h. The now semi-fluid mixture was cooled to 75-80° C. before water (800 ml) was added. After stirring at room temperature for 2 h the formed precipitate was filtered off, washed with further water and dried at 40° C. i. vac. Thieno[3,2-d]pyrimidine-2,4-diol was obtained as cream-coloured powder (37.15 g, 87% yield) of >95% purity.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C(Cl)Cl.[I:15]N1C(=O)CCC1=O>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([I:15])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 16 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A 50-L jacketed reactor was charged with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (950 g, 5053 mmol) and DCM (16 L). The resulting tan suspension was cooled to 16° C., and N-iodosuccinimide (1598 g, 7104 mmol) was added portionwise over 20 min. The reaction mixture was stirred at room temperature for 16 h, after which time TLC analysis (2:1 hexane/ethyl acetate) indicated complete reaction. The resulting precipitate was filtered, washed with DCM (3×1.5 L), and dried under reduced pressure at 40° C. for 64 h to afford 1447 g (Yield: 91%) of target compound as a beige solid. MS (ESI) m/z 314.0 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5](I)[CH:4]=1)=[O:2].[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([C:17]#[C:16][CH2:15][CH2:14][OH:18])[CH:4]=1)=[O:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C=O)cc1C#CCCO
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.810 g, 2.82 mmol) in DMF (25 mL) and triethylamine (5 mL) were added PdCl2(PPh3)2 (0.10 g, 0.14 mmol) and copper (I) iodide (0.16 g, 0.85 mmol). A degassed solution of but-3-yn-1-ol (0.27 g, 0.29 mmol) in DMF (8 mL) and triethylamine (2 mL) was added at 80° C. over a period of 1 hour under nitrogen. After the addition, the reaction mixture was stirred at 80° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave N-[4-formyl-2-(4-hydroxy-but-1-ynyl)-phenyl]-acetamide as a brown solid. Crude yield: 0.85 g (100%). The crude material was used in next step without further purification.
Reaction SMILES: [OH2:1].Cl.[C:3](NO)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1>[C:3]([O:1][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: ONC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc(C(OC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C

Procedure:
First, to a flask charged with THI (21.20 mmol, 4.88 g) is added water (25 ml) and 1N aqueous HCl (21.2 ml, 21.2 mmol). After all solids dissolved, a solution of trityl hydroxylamine (25.44 mmol, 7.00 g) in dioxane (55 ml) was added and the reaction was maintained at 50° C. for 4 h. At completion, the reaction was cooled room temperature and the solution was adjusted to pH=7 by addition of 1N aqueous NaOH. The neutralized solution was then concentrated to a plastic mass, which was purified by flash chromatography on silica gel [10% MeOH/1% NH4OH (5% wt. solution in water) in DCM] to provide the trityl-ether as clear plastic. Treatment of the plastic mass with hexane and concentration provided a white foam, which could be dried under vacuum to a flakey solid (10.00 g, 97% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[OH:39][CH:37]([CH3:38])[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CC(O)CN
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(C)O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (2RS)-1-amino-2-propanol, the title compound was obtained in 90% purity by HPLC. MS(ESI+): m/z=410.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][N:18]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1F)[C:32]([N:34]1[CH2:37][CH2:36][CH2:35]1)=[O:33]>C(#N)C>[N:34]1([C:32]([C:31]2[CH:38]=[CH:39][C:40]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[S:15][C:16]([CH3:19])=[CH:17][N:18]=3)=[O:12])=[C:29]([F:28])[CH:30]=2)=[O:33])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)s1
Temperature: 160 °C
Yield: 11.9 %

Procedure:
Potassium carbonate (143 mg, 1.04 mmol) was added to a mixture of 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(5-methyl-1,3-thiazol-2-yl)benzamide (160 mg, 0.52 mmol) and 1-(3,4-difluorobenzoyl)azetidine (102 mg, 0.52 mmol) in acetonitrile (5.0 mL), and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 15 hours. The mixture was allowed to reach ambient temperature and pressure and reduced in vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate, to give the desired compound (30 mg)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1([OH:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C1C=CC=CC=1.CCOCC>[C:1]([O:25][C:13]1([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)(=[O:3])[CH3:2]
Reactant: CC1(O)CCCCC1C1CCCCC1
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC1(C)CCCCC1C1CCCCC1
Temperature: 40 °C

Procedure:
A mixture of 360 ml of acetyl chloride and 153 ml of acetic acid anhydride is added dropwise at 0° C., whilst stirring, to a solution of 576 g of crude 1-methyl-2-cyclohexyl-cyclohexanol in 750 ml of N,N-dimethylaniline. The mixture is then allowed to come to room temperature, after which is heated to 40° C. for 36 hours. Thereafter, the reaction mixture is poured onto ice and diluted with 1 liter of ether, and the organic phase is separated off and concentrated on a Rotavapor apparatus. The residue is then taken up in 2 liters of ether and the solution is washed with three times 200 ml of cold 2-N HCl and then with saturated bicarbonate solution and water until neutral, and is dried with anhydrous MgSO4 and evaporated in vacuo. 646 g of crude 1-acetoxy-1-methyl-2-cyclohexyl-cyclohexane are obtained.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:28][N:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=[CH:30]1.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.CO.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>[CH3:28][N:29]1[C:33]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:32][N:31]=[CH:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cncc1-c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg, 0.16 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (120 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) and lithium chloride (68 mg, 1.6 mmol) in 1,4-dioxane (3 mL) was degassed and flushed with nitrogen and the reaction heated at 100° C. for 16 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in methanol)) to afford a residue that was purified by preparative HPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale orange solid (13 mg, 20%). 1H NMR (DMSO-D6, 400 MHz): 12.26 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=0.9 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.58 (d, J=0.9 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.72 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.0 Hz, 1H), 3.96 (s, 3H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D): KT=6.54 min, M+H+=423.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[OH:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:33][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 48 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol), trans-4-aminocyclohexanol hydrochloride (226 mg, 1.5 mmol), and triethylamine (0.42 mL, 3 mmol) were combined in THF (15 mL) and stirred under Ar at 50° for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 158-160°, LC MS m/z=481 (MH+) Retention time=2.08 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:15]=3[CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:27][N:11]1[C:12]2[C:17](=[CH:16][C:15]3[CH2:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2[nH]c1=O)CCC3
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.5 %

Procedure:
To a mixture of ethyl 4-(2-methylphenyl)-2-oxo -1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (3.0 g), potassium carbonate (1.43 g) and DMF (30 ml) was added methyl iodide (0.65 ml) dropwise. The mixture was stirred at room temperature for 10 hours, after which water was added to the reaction mixture to give crystals of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-l,2,7,8-tetrahydro-6H-cyclopenta [g]quinoline-3-carboxylate (2.95 g, 94.6%). Recrystallization from ethyl ether-isopropyl ether gave colorless needles, m.p. 134°-135° C.