Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][CH3:35])=[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Yield: 83.5 %

Procedure:
To a stirred and cooled (10° C.) solution of 13.7 parts of intermediate 57, namely [4-amino-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone, in 147 parts of pyridine were added dropwise 7.14 parts of ethyl chloroformate. After stirring for 1 hour at 10° C., the reaction mixture was poured into 700 parts of water. The product was extracted with dichloromethane and the extract was washed with water (3×), dried, filtered and evaporated. The residue was co-evaporated with ethanol (3×) and was then crystallized from ethanol. The product was filtered off, washed with ethanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 14.05 parts (83.5%) of ethyl [4-benzoyl-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]carbamate; mp. 115.9° C. (interm. 58).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[CH3:12])[CH:14]=[CH:15][C:16]=12
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5nccn5c4)n3n2)c1
Temperature: 150 °C

Procedure:
(rac)-6-Chloro-3-(1-imidazo[1,2-a]pyridin-6-yl-ethyl)-imidazo[1,2-b]pyridazine (Example 292, 200 mg, 0.672 mmol) was dissolved in DME (3.36 mL) with 3-tolylboronic acid (91 mg, 0.672 mmol), 2 M Na2CO3 solution (1.21 mL, 2.418 mmol) and tetrakis(triphenylphosphine)palladium (38.8 mg, 0.034 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The white solid obtained was a repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 0.9 min (conditions 2), MH+=354).
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[CH3:11][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([S:13][CH3:14])[N:27]=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:26]=1
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Reactant: N=C(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1SC
Yield: 60.7 %

Procedure:
To a solution of ethyl 2-(bis(methylthio)methylene)-3-oxobutanoate (500 mg, 2 mmol) in ethanol was added benzamidine acetate (732 mg, 6 mmol) and triethyl amine (1.41 mL) and the reaction mixture was refluxed overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water and the organic layer washed with water and dried over Na2SO4 and the solvent evaporated in vacuum. The crude product was purified by column chromatography over silica gel using 1% ethyl acetate in petroleum ether as eluent to give the desired product (350 mg). 1H-NMR 400 Hz (CDCl3): δ 8.50 (d, J=7.6 Hz, 2H), 7.50-7.46 (m, 3H), 4.45 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 1.44 (t, J=7.2 Hz, 3H); MS m/z 288.7 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:41])([CH3:40])[C:8]1=[O:42])C.[OH-].[Na+].CO>C1COCC1>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([N:23]([CH:37]([CH3:39])[CH3:38])[C:21]([C:14]2[C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]3[O:10][C:9]([CH3:40])([CH3:41])[C:8](=[O:42])[N:7]([CH2:6][CH2:5][C:4]([OH:43])=[O:3])[C:12]=3[CH:13]=2)=[O:22])[CH2:25]1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCOC(=O)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCC(=O)O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (3R)-3-[{[4-(3-ethoxy-3-oxopropyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (350 mg) were added a 2N NaOH aqueous solution (5 ml), MeOH (5 ml) and THF (5 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was concentrated, and thereto was added dropwise a 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue (260 mg) was used in the subsequent reaction without a further treatment.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O-:9])[N:3]=[CH:2]1.[Na+].[Cl-].[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15]>>[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: [O-]CCCc1c[nH]cn1
Reactant: CCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(C)CCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1H-imidazol-4-yl)propanolate and 5 mmol of 3,3-dimethylbutane chloride are treated as described in Example 5.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[N:4]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)CN(S(=O)(=O)c2ccccn2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
100 mg (0.27 mmol) of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were initially charged in 1 ml of pyridine, and 88 mg (0.41 mmol) of 2-pyridylsulphonyl chloride hydrochloride were added. For workup, the mixture was concentrated fully and the residue purified by flash chromatography (100 g of silica gel/95:5 CH2Cl1:CH30H).
Reaction SMILES: N1C=CC=CC=1.N1CCCCC1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].[F:20][C:21]1[CH:28]=[CH:27][C:24](C=O)=[C:23]([CH3:29])[CH:22]=1>O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[C:23]([CH3:29])[CH:22]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(F)ccc1C=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cc(F)ccc1C=CC(=O)O
Temperature: 75 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a mixture of pyridine (0.035 mL) and piperidine (1.43 mL) was added malonic acid (30 g), and the mixture was heated to 75° C. To this mixture was added dropwise 4-fluoro-2-methylbenzaldehyde (20 g), and the mixture was stirred at 90° C. for 6 hr. The reaction mixture was cooled to room temperature, and diluted with water (100 ml), and concentrated under reduced pressure. The residue was suspended in 0.1N hydrochloric acid (250 mL), and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with 0.1N hydrochloric acid (250 mL) and water (50 mL, 0.3 times) and dried to give 4-fluoro-2-methylcinnamic acid (24 g, 93%) as a white powder.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[CH:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH:45]1[NH2:54])[CH2:51]2>CN(C)C=O.C(Cl)Cl>[CH:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH:45]1[NH:54][C:11]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9]=1[Cl:10])=[O:13])[CH2:51]2
Reactant: CC(C)(C)n1ncc(C(=O)O)c1Cl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a stirred solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (3.040 g; 15.0 mmol) in N,N-dimethylformamide/methylene chloride (1:4 ratio, 20 mL) at room temperature was added diisopropylethylamine (21.2 mL; 120.4 mmol). TSTU (5.420 g; 18.0 mmol) was then added. The resulting mixture was allowed to stir at room temp. for 2 hr and then 2-adamantylamine hydrochloride (2.844 g; 15.0 mmol) was added. The mixture was allowed to stir over the weekend at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting light yellow gum was triturated with diethyl ether to provide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (4.02 g, 80%) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[C:8]([NH2:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:9][C:8]([NH:16][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
2-Chloro-1-ethane sulfonyl chloride (51.3 mL, 0.49 mol) in dichloromethane (400 mL) was added dropwise over 2 hours to a solution of tert-octylamine (236.3 mL, 1.47 mol) and triethylamine (68.3 mL, 0.49 mol) in dichloromethane (400 mL) at −18° C. The mixture temperature was maintained between −18° C. and −9° C. during the addition. The mixture was allowed to warm to ambient temperature over 1 hour then washed with 1N HCl (400 mL) and distilled water (2×200 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The oil was dried under vacuum at 50° C. to give ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide, 96.0 g (90% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH:34]C(OCC1C=CC=CC=1)=O)[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH2:34])[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21
Reaction time: 5 h

Procedure:
878 mg of the compound of example 1, step d) were dissolved in 50 ml of methanol and 0.4 ml of acetic acid. Under a nitrogen atmosphere 350 mg of 10% palladium on charcoal were carefully added, and hydrogenation was performed under shaking of the reaction vessel. After 5 hours the reaction was complete. The solvents were removed after filtration of the catalyst Yield: 680 mg of a resinous product. MS (ES+): m/e=479.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([O:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33]
Reactant: [H][H]
Reactant: COc1cccc2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Agent: [Pd]
Solvent: CCNCC
Solvent: CO
Product: COc1cccc2c1c1c(n2CCO)CCCC1C(=O)O
Yield: 75.9 %

Procedure:
9-(2-Benzyloxy-ethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (10) (1.0 g, 2.1 mmol) in methanol (50 ml) was shaken with 10% palladium on charcoal (300 mg), and hydrogen gas excess for 18 h at 55° C. The reaction was then filtered through a pad of celite and the filtrate concentrated in vacuo to give 578 mg (100%) 9-(2-hydroxyethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (ii) as a foam. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.0, 14.4, 20.0, 22.0, 28.0, 36.4, 40.6, 42.0, 54.7, 60.6, 99.2, 102.6, 107.0, 116.7, 121.1, 136.1, 137.5, 138.0 153.5, and 175.7.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(C)C(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)CCc2ccc(O)cc21
Reaction time: 0.25 h

Procedure:
Under nitrogen, combined 1.3 g of 7-Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (6.8 mmol) with 18 ml of CH2Cl2. Added 15 ml of 1.0 M boron tribromide in CH2Cl2 (15.0 mmol) dropwise over 3 minutes. Stirred reaction for 5 hours, poured over ice-H2O, slurried for 15 minutes and filtered 818 mg of off-white solid (68%). 1H NMR (400 MHz, CD3OD) δ 2.56 (2H, t, J=7.88 Hz), 2.78 (2H, t, J=6.85 Hz), 3.29 (3H, s), 6.45 (1H, d, J=8.09 Hz), 6.54 (1H, d, J=2.07 Hz), 6.98 (1H, d, J=8.09 Hz). M/z (APCI+) 178.0 (M+1). HPLC (aqueous 200 mM ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 uM, 125×4 mm column) 2.826.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[CH:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].F[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[O:33].CC(=O)OCC>CS(C)=O.O>[F:12][C:3]([F:2])([F:11])[CH:4]1[CH2:10][CH2:9][N:8]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH2:7][CH2:6][NH:5]1
Reactant: FC(F)(F)C1CCNCCN1
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1N1CCNC(C(F)(F)F)CC1
Temperature: 160 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A mixture of 5-trifluoromethyl-[1,4]diazepane hydrochloride (1.17 g; 4.83 mmol; 1.2 eq.), sodium carbonate decahydrate (2.13 g; 20.14 mmol; 5 eq.) and 2-fluoro-benzaldehyde (500 mg; 4.03 mmol; 1 eq.) in DMSO (20 mL) and water (20 mL) was stirred at 160° C. for 4 hours. The solution was diluted EA and the organic layer washed with water (3×) then brine (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 33% EA in heptanes) afforded the title compound (350 mg, 32%) as a yellow oil. HPLC (max plot) 97.9%; Rt 5.23 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:16]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.[OH-].[Na+].CN(C)[CH:31]=[O:32]>C(O)(=O)C>[CH:31]([C:21]1[C:20]2[C:15](=[CH:16][C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:32]
Reactant: CCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1[nH]c2cc(C(=O)OC)ccc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (35 ml) in dimethylformamide (150 ml) was added to a solution of methyl 2-(n-heptyl)indole-6-carboxylate (67.5 g) in dimethylformamide (250 ml) and the resulting solution was stirred at between 70° and 85° C. for 2 hours. The mixture was then stirred for 30 minutes while the temperature dropped to 50° C. and was then poured into water (2 liters). Ice was added to reduce the temperature to 25° C. and a 50% w/v aqueous sodium hydroxide solution was added until the pH reached 11. After stirring for 10 minutes, acetic acid was added to pH 5 and the mixture was stirred until the product has solidified. Recrystallisation from methanol yielded methyl 3-formyl-2-(n-heptyl)indole-6-carboxylate (65.0 g) in the form of colourless, lustrous needles, m.p. 177°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:34][CH2:35][CH:36]([OH:38])[CH3:37])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Reactant: CC(O)CN
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF [(M+H)+]539.2451, observed 539.2447.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:1][CH2:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:30])[CH3:29]
Reactant: COc1ccc(CO)c(C(=O)NCc2cccnc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(C)=O)c(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of 710 mg of 2-hydroxymethyl-5-methoxy-N-(3-pyridylmethyl) benzamide and 317 mg of triethylamine in 10 ml of methylene chloride was chilled at 0° C., mixed with 320 mg of acetic anhydride and stirred at room temperature for 15 hours. The reaction mixture was washed with water and saturated brine in order. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 820 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([O:20][CH3:23])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(CO)c(O)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(CO)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To 190 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 3 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 200 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:19][CH:20]=1)\[C:13]([OH:15])=O)[C:8]#[CH:9].[NH2:41][CH:42]1[C:67](=[O:68])[N:44]2[C:45]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])=[C:46]([CH2:49][Cl:50])[CH2:47][S:48][C@H:43]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:50][CH2:49][C:46]1[CH2:47][S:48][C@@H:43]2[CH:42]([NH:41][C:13](=[O:15])/[C:12](=[N:11]\[O:10][CH2:7][C:8]#[CH:9])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[S:19][CH:20]=3)[C:67](=[O:68])[N:44]2[C:45]=1[C:51]([O:53][CH:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: C#CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (910 mg) was added to a solution of (Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-f) (1.7 g, 3.6 mmoles) in dichloromethane (30 ml). After stirring for 1 hour at room temperature, the mixture was added in one portion to an ice-cooled solution of (V) (1.98 g, 4.4 mmoles) and N,O-bis(trimethylsilyl)acetamide (1.5 ml) in dichloromethane (30 ml). After stirring for 1 hour, the reaction mixture was poured into 10% aqueous NaHCO3 (300 ml) and extracted with ethyl acetate (300 ml). The extract was washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with CHCl3 gave the title compound [VI-f] as an amorphous powder weighing 2.1 g (66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:28])[C:25]=4[CH:26]=[O:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]([Mg]Br)#[CH:30]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:28])[C:25]=4[CH:26]([OH:27])[C:29]#[CH:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C=O)cc3)cc2)CC1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)cnn1C

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 1-[4′-(5-Formyl-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and ethynylmagnesium bromide.