Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7]>C1C=CC=CC=1>[CH:6]([N:9]([CH:1]=[CH:2][CH2:3][CH3:4])[CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7]
Reactant: CCCC=O
Reactant: CC(C)NC(C)C
Solvent: c1ccccc1
Product: CCC=CN(C(C)C)C(C)C
Yield: 64.6 %

Procedure:
6.25 ml (69.3 mmol) of butyraldehyde and 19.44 ml (139 mmol) of diisopropylamine were dissolved in 30 ml of benzene, and the mixture was heated under reflux, while removing the water produced, until the production of water stopped (about 15 hours). The solvent was then removed by distillation under reduced pressure, and the residue was distilled under atmospheric pressure. Those fractions of the distillate having a boiling point of from 140 to 160° C. were collected, to give 6.95 g of the title compound as a pale yellow oily substance (yield 65%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13].[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([N+]([O-])=O)[C:27]=1[C:28]#[N:29])([O-:25])=[O:24]>>[C:28]([C:27]1[C:26]([N+:23]([O-:25])=[O:24])=[CH:33][CH:32]=[CH:31][C:30]=1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])=[O:13])#[N:29]
Reactant: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1O
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1Oc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 126c from (±)-3-((2-hydroxycyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide (Example 129d) and 2,6-dinitrobenzonitrile as a brown solid (100%). MS 454 (MH+).
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[Cl-].[CH3:14][C:15](=[CH2:22])[C:16]([O:18]CC[NH3+])=[O:17]>O1CCCC1>[N:8]1([C:6]([NH:3][CH2:2][CH2:1][O:18][C:16](=[O:17])[C:15]([CH3:22])=[CH2:14])=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: C=C(C)C(=O)OCC[NH3+]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)n1ccnc1
Temperature: 17 °C
Reaction time: 3 h

Procedure:
25.4 g (0.17 mole, >97% FLUKA) CDI were suspended in about 150 ml THF (tetrahydro furane) at room temperature. Upon partial dissolution the suspension was cooled down to about 17° C. After about 30 min stirring 25.9 g (0.16 mole) 2-(2-Methyl-acryloyloxy)-ethyl-ammonium chloride were added to the mixture under cooling on ice in several portion during about 1 h keeping the reaction mixture at about 23° C. A yellow suspension was obtained. After about 3 h of stirring at about 23° C. the suspension was filtrated. The filter cake was washed with THF. To the clear yellow filtrate about 300 mg phenothiazine were added. Solvent was evaporated. A clear orange viscous resin was obtained (containing traces of residual solvent). Yield was quantitative, 1H NMR indicates the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C(OCC)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:18]=[O:19])=[N:7][C:6]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1nc2cc(F)ccc2s1
Temperature: -50 °C

Procedure:
To a stirred solution of 36 g of 5-fluorobenzothiazole in 100 ml of diethyl ether cooled to -70° C. was added dropwise over a 5 minute period 9.4 ml of a 2.5M solution of n-butyl lithium in hexane. The reaction mixture was allowed to warm to -50° C. for one hour and was then cooled to -78° C. Dry dimethylformamide (2.8 ml) was added dropwise and the reaction mixture allowed to warm to room temperature over a period of two hours. The reaction was diluted with 300 ml of diethyl ether and washed with 1N hydrochloric acid (1×40 ml), water (1×40 ml), a saturated sodium bicarbonate solution (1×40 ml) and dried over magnesium sulfate. The solvent was removed and the residual product flash chromatographed on silica (50% ethyl acetate--hexane; v:v) to give 24.7 g of the titled product, m.p. 105°-107° C.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].N>>[S:8]1[C:7]2[CH2:6][C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[NH:1][C:2](=[O:3])[C:11]=2[CH:10]=[CH:9]1
Reactant: O=C=Nc1ccccc1Cc1cccs1
Agent: N
Product: O=C1Nc2ccccc2Cc2sccc21

Procedure:
10.5 g of 2-(2-isocyanato-benzyl)-thiophene (B.P. 108°/0.05 mm of Hg) are heated to 110° with 105 g of polyphosphoric acid for 1 hour while stirring. The reaction mixture is subsequently rendered alkaline with a concentrated ammonia solution while cooling internally and externally with ice and the resulting precipitate is filtered off. This is washed with water, dried and crystallized from acetone while treating with charcoal. 4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one is obtained in the form of grains having a M.P. of 225°-236° (between 150° and 200° conversion into bright needles).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>CN(C=O)C>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13]([C:15]4[S:16][C:17]([CH3:20])=[CH:18][CH:19]=4)=[O:14])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:26][CH2:25]1)(=[O:29])[CH3:28]
Reactant: COc1ccc(N2CCNCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26 mmol) were suspended in DMF (2 ml) and treated with acetyl chloride (22 μl, 0.30 mmol) and pyridine (27 μl, 0.34 mmol) and the mixture stirred for 5 h at ambient temperature. Workup and purification as described in the general procedure C afforded the product as a white solid (55%), MS: m/e=431 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4].C(#[N:20])C>[OH-].[NH4+].O>[NH2:20][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4]
Reactant: O=C(CCl)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Reactant: CC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NCC(=O)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 192 h

Procedure:
2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide (300 mg; 1.182 mmol) was suspended in ammonium hydroxide (7 ml) and stirred slowly in a vial at 4 C for 8 days (30%). The reaction mixture was transferred into a flask and hot water (25 ml) was added to the reaction mixture, filtered, and the filtrate was collected. The initial pH (12) of the filtrate was adjusted to 5.38 by slow addition of acetic acid to obtain the intermediate. The beige colored solid was filtered, rinse with water (10 ml), washed with methanol (50 mL), and finally with ether (50 ml), and then dried under reduced pressure. The residue was suspended in hydrazine (30% in water, 22 ml) and heated to dissolve the precipitates. The contents were allowed to cool to RT, pH was adjusted to 4.8, and precipitates were obtained upon cooling. The resultant precipitates were filtered, washed with water, methanol (cold), ether, and then dried under reduced pressure to obtain 2. 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (d, 1H), 7.85 (t, 1H), 7.60 (d, 1H), 3.33 (s, 2H), 2.16 (s, 3H, Methyl for Acetic Acid); ESMS: Calcd for C10H10N4O3: 234.0, Found, 235.0; HPLC: Purity was further analyzed on a C-18 column (Vydac) employing a mobile phase eluent gradient of 10-90% acetonitrile in water containing 0.1% TFA over 30 minutes with a flow rate of 1 mL/min, Rt=13.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:27]([F:30])([F:29])[F:28])=[CH:10]\[C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[S:33])C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:33])([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-thietan-3-yl-benzamide (500 mg) was added thioacetic acid (6 eq.) and triethylamine (4 μL). The solution was stirred under argon at room temperature for 41 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:1]([O:26][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)[CH2:16][O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(O)COCCN2CCOCC2)c1
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN1CCOCC1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.65 ml of pyridine and 0.99 ml of acetic anhydride were added to 1 g of 1-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethanol. The mixture was stirred for 3 hours at room temperature. The reaction mixture was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 20 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 1 g of oily 1-acetoxy-1-(3-methylphenyl)-2-[2-(morpholin-4-yl)ethoxy]ethane (compound No. 178).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se-:9][Se-:10].[Mg+2].Cl>O>[CH2:1]([Se:9][Se:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Se-][Se-]
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: c1ccc(C[Se][Se]Cc2ccccc2)cc1

Procedure:
About 12.6 grams (0.1 moles) benzylchloride is now added by dropwise addition over a period of 15 minutes to the magnesium diselenide reagent. In about 5 to 10 minutes after the mixture of these materials, the reddish brown color of the solution appears discharged. This solution is diluted further by the addition of 200 milliliters water and the addition of 10 milliliters concentrated hydrochloric acid. Upon cooling of this solution, the solids contained within the flask are collected by filtration and recrystallized from ethanol. Yield: 14 grams of yellow crystals (m. p. 94° C.). Infrared spectral analysis of this material confirms that it is dibenzyl diselenide.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:4][C:3]3=[O:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1c(=O)[nH]c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(=O)[nH]c2ccccc2c1=O

Procedure:
3-Amino-1H-quinazoline-2,4-dione and 1-adamantaneacetyl chloride were reacted as describe in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.58-1.68 (m, 12H), 1.92-1.98 (m, 3H), 1.98-2.07 (m, 2H), 7.21-7.27 (m, 2H), 7.68-7.74 (m, 1H), 7.93-7.96 (m, 1H), 10.34 (s, 1H), 11.51 (s, 1H) ppm; MS (DCI/NH3) m/z 354 (M+H)+; Elemental Analysis: Calculated for 1.58-1.68 (m, 12H), 1.92-1.98 (m, 3H), 1.98-2.07 (m, 2H), 7.21-7.27 (m, 2H), 7.68-7.74 (m, 1H), 7.93-7.96 (m, 1H), 10.34 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: C([O:8][C:9]([CH:11]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:12]([NH:14][C:15]1[C:16](=[O:41])[N:17]([CH2:27][C:28]([NH:30][CH:31]([CH:38]([CH3:40])[CH3:39])[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:13])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:9]([CH:11]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:12]([NH:14][C:15]1[C:16](=[O:41])[N:17]([CH2:27][C:28]([NH:30][CH:31]([CH:38]([CH3:39])[CH3:40])[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)=[O:13])([OH:10])=[O:8]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)C(C(=O)O)c2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To 2-[3-(2-Benzyloxycarbonylphenylacetylamino)-2-oxo-6-phenyl-1,2-dihydo-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.6 g) in methanol (50 mL) was added 10% (w/w) palladium on carbon (0.2 g), and the mixture was shaken under a hydrogen atmosphere (3.4 bar) for 3 h. The catalyst was filtered and the solvent evaporated to give a solid which was chromatographed, eluting with methanol:dichloromethane (gradient, 2:98 to 10:90), to give the title compound (0.5 g); TLC: Rf =0.25, methanol:dichloromethane (10:90); MS: m/z=588(M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.2 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.65 g, 5 mmol) and 5% palladium carbon (0.8 g) in ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.11 g, 94.2%) as crystals.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)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>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)c1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: c1ccc2ncc(-c3cccc4c5c([nH]c34)C3CCN(CC3)C5)cc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of the product of Example 1B (150 mg, 0.52 mmol), 3-quinolineboronic acid (102 mg, 0.59 mmol; Aldrich), dichlorobis(triphenylphosphine)palladium (II) (18 mg, 0.026 mmol; Aldrich) and 1.0 M sodium carbonate (1.3 mL) in 2-propanol (3.8 mL) was purged with nitrogen and then stirred at 80° C. for 1 hour in a sealed tube. The reaction mixture was cooled and partitioned between CHCl3 (2×30 mL) and 1.0 M sodium carbonate (50 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.98-2.16 (m, 4 H), 3.02-3.14 (m, 3 H), 3.25 (ddd, J=14.1, 8.8, 5.5 Hz, 2 H), 4.28 (s, 2 H), 7.12-7.22 (m, 2 H), 7.39 (dd, J=7.3, 1.5 Hz, 1 H), 7.66 (ddd, J=8.1, 7.0, 1.1 Hz, 1 H), 7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1 H), 8.03 (dd, J=8.2, 0.9 Hz, 1 H), 8.09 (d, J=8.5 Hz, 1 H), 8.57 (d, J=2.1 Hz, 1 H), 9.09 (d, J=2.1 Hz, 1 H); MS (ESI+) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1F)=[O:4].[N-:26]=[N+]=[N-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1[NH2:26])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc3ccc4c(OC)cccc4c3nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N)ccc2nc3ccc4c(OC)cccc4c3nc12
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 10-fluoro-4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.5) (466 mg) and sodium azide (900 mg) in N,N-dimethylformamide (10 mL) was heated at 90° C. for 18 hours. The reaction mixture was then cooled, diluted with water, and then sodium hydroxide solution was added resulting in a brown precipitate. This was collected by filtration and washed with water and ether to yield the desired title compound as a yellow solid (242 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1)(C)(C)C.[CH3:31][C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:18])([F:20])[F:19])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:38]([C:35]3[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][N:36]=3)=[O:39])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: Cc1cnc(C(=O)O)cn1
Product: Cc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methylpyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3+MeOD) δ ppm 2.68 (s, 3 H), 2.84 (dd, J=13.6, 3.8 Hz, 1 H), 3.15 (dd, J=13.9, 3.0 Hz, 1 H), 3.30-3.42 (m, 1 H), 3.88 (d, J=10.4 Hz, 1 H), 4.61 (d, J=8.6 Hz, 1 H), 4.68 (quin, J=7.2 Hz, 1 H), 7.13-7.25 (m, 1 H), 8.05 (ddd, J=11.6, 6.8, 2.8 Hz, 1H), 8.46 (s, 1 H), 9.30 (d, J=1.3 Hz, 1 H)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([NH:40][NH2:41])=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:24][CH2:25][CH2:26][CH2:27]6)(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:27]>C(Cl)Cl>[ClH:27].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([NH:8][NH2:9])=[CH:11][CH:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NNc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Title compound 50A, N-(4-Pyrrol-1-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.32 g, 1.0 eq, 1.2 mmol) was suspended in a mixture of 4M HCl in Dioxane (4.9 ml, 17.0 eq, 19.7 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 24 hr solvent was then removed in vacuo to yield the title compound as an off-white solid (0.25 g, 1.12 mmol, 95%). LCMS: [M+H]+=157/174, rt=0.98 min, 98% purity.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 81 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (93 mg, 81%) which was obtained as a white solid. MS: m/e=384.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline from Example 6A (87 mg, 0.37 mmol) were reacted to the title compound to give 158 mg of a crude product (72% purity, 67% yield), which was used in the next step without further purification.