Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([OH:14])(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C=C>>[C:4]([O:14][CH2:1][CH2:2][OH:3])(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)CCCCC(=O)O
Reactant: C1CO1
Agent: C=C
Product: CC(C)(C)CCCCC(=O)OCCO
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a one liter stainless steel autoclave, equipped with a mechanical stirrer, heater, cooling coils, automatic temperature controller, and a tared ethylene oxide cylinder, in a series of runs is added 500 grams neononanoic acid and 2.0 g of the selected catalyst. The reactor is heated to approximately 100° C. and a gaseous N2 purge of the reactor is introduced to remove both oxygen and water. With continued N2 purging its temperature of the neo acid/catalyst solution is gradually raised to 150° C. Upon reaching temperature, the N2 purge is stopped and the reactor vents are sealed. Ethylene oxide is then slowly added to the reactor until a pressure of 60 psig is obtained. The ethylene oxide flow is then stopped. As the reaction between the neo acid and the ethylene proceeds, the pressure of the reactor vessel will slowly decrease. When the pressure reaches 20 psig, ethylene oxide is again slowly charged to the reactor until a pressure of 60 psig is obtained. The ethylene oxide flow is then decreased to the point where a steady reactor pressure of 60 psig is obtained. The addition of ethylene oxide continues until the desired quantity of ethylene oxide has been added to the reaction. The flow of ethylene oxide is then stopped. The reaction mixture is stirred for an additional 20 minutes, until the reactor pressure decreases to 15 psig. Total reaction time, from the start of ethylene oxide addition is about 55 minutes. The reactor is then vented, a gaseous nitrogen purge is introduced, and the reaction product is cooled to room temperature. The crude ethylene glycol mononeononanoate product mixture thereby obtained was characterized by gas chromatography and found to have the following characteristics:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH:4]([CH2:5]2)[N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([N:7]2[CH:6]3[CH:4]([CH2:5]3)[N:3]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[C:2]2=[O:1])[CH:24]=[CH:23][N:22]=1
Reactant: COc1cc(Br)ccn1
Reactant: O=C1NC2CC2N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(N2C(=O)N(C(=O)OCc3ccccc3)C3CC32)ccn1
Yield: 41.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, benzyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (50 mg, 0.215 mmol) was reacted with 4-bromo-2-methoxypyridine (44.5 mg, 0.237 mmol), xantphos (11 mg, 0.019 mmol), Pd2(dba)3 (6.0 mg, 0.006 mmol), cesium carbonate (105 mg, 0.32 mmol) and 1,4-dioxane (3.0 mL) in seal tube at 100° C. for 2.5 hours. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded (35% ethyl acetate in hexane) afforded 30 mg of the product (41% yield).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (422 mg, 55%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18][N:19]=[C:20]([C:22]3[CH:39]=[CH:38][C:25]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]4)=[CH:24][CH:23]=3)[NH2:21])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:19]=[C:20]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:24][CH:23]=4)[N:21]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NOC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol) in acetonitrile (30 mL) was added a 1M solution of TBAF in tetrahydrofuran (3.99 mL, 3.99 mmol), and the reaction mixture was allowed to stir at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (521 mg, 0.962 mmol, 72.4% yield) as a colorless solid. HPLC ret. time=3.63 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=542.22. 1H NMR (500 MHz, CDCL3) δ ppm 1.46 (s, 9H), 3.25-3.31 (m, 3H), 3.52-3.58 (m, 2H), 3.69 (s, 2H), 7.43 (d, J=8.25 Hz, 2H), 7.47 (m, 5H), 7.91 (s, d, J=1.65 Hz, 1H), and 8.09 (d, J=8.25 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (5.11 g, white solid) from 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (4.62 g, 16.2 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[CH3:15][O:16][CH2:17][C:18](Cl)=O>O1CCOCC1>[CH3:15][O:16][CH2:17][C:18]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COCC(=O)Cl
Solvent: C1COCCO1
Product: COCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
To a mixture of 0.01 mole of 3-hydrazino-6-phenylpyridazine in 25 ml. of dioxane is added 0.005 mole of methoxyacetyl chloride. The mixture is refluxed for 2 hours to give the product of the Example, m.p. 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1N
Product: COC(=O)c1sc(C2(O)CCOCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-(4-hydroxytetrahydropyran-4-yl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 312.39 (C14H20N2O4S) was obtained in this way; MS (ESI): 313 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.CCN(CC)CC.[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>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.O1CCOCC1>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:2]2[C:3]3[C:4]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[O:32]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(B4OC(C)(C)C(C)(C)O4)c3c2CC1
Yield: 92.4 %

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.51 g, 4.12 mmol) and dioxane (26 mL) were combined at rt under N2. Et3N (3.43 mL, 2.49 g, 24.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.28 mL, 1.05 g, 8.21 mmol) were added to the mixture by syringe. trans-Dichlorobis(triphenylphosphine)palladium(II) (0.147 g, 0.209 mmol) was added and Ar was bubbled through the reaction mixture for 15 min. The reaction mixture was refluxed under N2 for 16 h. The cooled reaction mixture was concentrated and the residue was combined with toluene (50 mL), brine (20 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted with toluene (2×50 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered and concentrated. The crude product (1.90 g) was chromatographed (SiO2 60 g, eluted with 2:2:1 heptane:CH2Cl2:Et2O) to give tert-butyl 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.57 g) in 93% yield. MS (ESI+) for C23H33BN2O4 m/z 413.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH3:1][CH:2]([NH:11][CH3:12])[CH:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Solvent: ClCCl
Product: CNC(C)C(O)c1ccccc1

Procedure:
A mixture of d,l-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid (136.6 g., 0.44 mole) and l-ephedrine (72.5 g., 0.44 mole) is dissolved in methylene chloride (500 ml.). The methylene chloride is then removed in vacuo to yield the 1-ephedrine salt of d,l-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid as an oil, [α]D25 =-20.0 (c=1.0, CHCl3). Addition of ether (1500 ml.) causes crystallization of a white solid which is separated by filtration and dried (102 g.), m.p. 114°-116° C. Recrystallization from ethyl acetate/hexane (1:1) affords 71.1 g. (34%) of the l-ephedrine salt of l-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid; m.p. 126°-127° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:7]([Cl:17])=[CH:6][C:3]=1[C:4]#[N:5].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C.N1C=CC=CC=1N>C(O)CCC>[Cl:17][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:9][C:2]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Agent: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(C#N)cc2Cl)n[nH]1
Temperature: 150 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a 10-ml microwave vessel was added, 2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method 60, 8 mmol), [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine (Method 33, 8 mmol, 97 wt % solution in dioxane), DIEA (0.3 ml, 1.66 mmol), and n-butanol (4 ml). The vessel was then sealed and subjected to microwave heating at 150° C. for 3 hours. After 3 hours, more 2-pyridyl amine (100 mg, 0.69 mmol) was added. The resulting mixture was purified by silica gel chromatography (Biotage Horizon System) using an isocratic system of 15:0.5:0.5% of DCM/EtOAc/MeOH to give 312 mg of the title compound. 1H NMR: 12.04 (br s, 1H), 8.41-8.63 (m, 2H), 7.84 (s, 1H), 7.56-7.71 (m, 1H), 7.40 (dd, J=8.67, 4.14 Hz, 1H), 7.28 (s, 1H), 5.86 (s, 1H), 5.06-5.25 (m, 1H), 2.17 (s, 3H), 1.51 (d, J=7.54 Hz, 3H). MS: Calcd.: 371/373. Found: [M+H]+ 372/374.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:30][CH3:31])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:30][CH3:31])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([C:26]([CH3:27])([CH3:29])[CH3:28])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nn2c(Cl)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
0.67 g (7.7 mmol) of piperazine in 10 ml of DMF was added to a solution of 1.23 g (3.1 mmol) of 3-benzenesulphonyl-5-tert-butyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.25 g (18%) of 3-benzenesulphonyl-5-tert-butyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 236-237°.
Reaction SMILES: N1CCC(C2C3C(=C(C(N)=O)C=C(C4SC=CC=4)C=3)NC=2)CC1.[NH2:24][C:25]([C:27]1[CH:28]=[C:29]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[C:32]2[CH:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1)=[O:26].Cl>CO>[NH:39]1[CH2:40][CH2:41][CH:36]([C:32]2[C:31]3[C:35](=[C:27]([C:25]([NH2:24])=[O:26])[CH:28]=[C:29]([C:49]4[CH:53]=[CH:52][S:51][CH:50]=4)[CH:30]=3)[NH:34][CH:33]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Agent: Cl
Agent: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CO
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12

Procedure:
The title compound was prepared according to the general procedure for intermediate 17. Thus, 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-(3-thienyl)-1H-indol-3-yl]-1-piperidinecarboxylate (460 mg, 1.08 mmol) and HCl (4.0M in dioxane, 10 mL) in MeOH (5 mL) was reacted to form the desired product without further purification (260 mg, 74%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>C1C=CC=CC=1.C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:16])[CH3:17])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
2.1 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 57) were dissolved in a mixture of 20 ml of benzene and 2 ml of acetic acid, and the compound was reduced for 10 hours at room temperature, in the presence of 0.1 g of 10% w/w palladium-on-carbon, and under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with benzene, to give the title compound as a slightly brown oil.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S([CH:14]([CH2:18][C:19](O)=O)[C:15](O)=O)(O)(=O)=O>O>[CH2:1]([O:9][CH2:15][CH2:14][CH2:18][CH2:19][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(C(=O)O)S(=O)(=O)O
Reactant: CCCCCCCCO
Solvent: O
Product: CCCCCCCCOCCCCCCCC
Reaction time: 7 h

Procedure:
206 kg (1581.8 moles) of n-octanol were heated to 190°-210° C. together with 2.94 kg of sulfosuccinic acid (70% by weight). The water of reaction formed was distilled off. After 7 hours, 10.3 g of 50% by weight sodium hydroxide were added to the cooled reaction mixture for neutralization, after which the crude product was washed until neutral and then distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.6 %

Procedure:
0.341 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one and 0.669 g of chlorotriphenylmethane were dissolved in 5 ml of N,N-dimethylformamide; 0.414 ml of N-ethyldiisopropylamine was added, followed by stirring at room temperature for 2 days. After water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (2:1). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration, washed with diethyl ether, and dried, to yield 0.591 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>ClCCCl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([OH:40])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
tert-Butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (300 mg, 0.504 mmol) was dissolved into DCE (5 mL) and then TFA (700 μl, 9.09 mmol) was added (reaction became green) and the reaction was stirred at rt for 1 h (˜70% conversion by LCMS). More TFA (700 μl, 9.09 mmol) was added and the reaction was stirred 1 h (complete by LCMS). The reaction mixture was concentrated on a rotary evaporator, diluted with diethyl ether and reconcentrated twice to yield 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid trifluoroacetate (362 mg, 0.55 mmol, quant.) as a dark yellow solid. Used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-2.13 (m, 21H), 2.68-2.86 (m, 1H), 3.36-3.50 (m, 2H), 3.90 (s, 3H), 4.11-5.35 (m, 2H), 7.14 (s, 1H), 7.18-7.28 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.21 (br s, 1H), 9.55 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC-MS retention time: 2.50 min; 538 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11]([CH:13]=[CH2:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:14][C:13]([CH:11]=[O:12])=[CH:4]2
Reactant: O=Cc1cc(O)ccc1O
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(O)ccc2OC1

Procedure:
3 g (21.7 mmol) of 2,5-dihydroxybenzaldehyde and also 2.2 ml (32.6 mmol) of acrolein are added to a suspension of 6 g (43.5 mmol) of potassium carbonate in 50 ml of 1,4-dioxane; the medium is then heated at reflux for 12 hours. The salts are filtered off over Celite; the solvent is then evaporated in vacuo. The residue obtained is taken up in water; the aqueous phase is then extracted with ether. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the crude product is triturated in dichloromethane to yield the title compound in the form of a yellow solid.