Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[C:29]([C:34]([O:36]C)=[O:35])[N:30]=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[C:29]([C:34]([OH:36])=[O:35])[N:30]=[CH:31]4)=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OCc1noc(C(C)C)c1COc1ccc(-c2ccc3cc(C(=O)O)ncc3c2)cc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (44 mg, 0.082 mmol) in 2:1 tetrahydrofuran:methanol (3 mL) was added 0.123 mL of 1 N sodium hydroxide. The solution was heated in a microwave reactor at 100° C. for 500 seconds. Then 1N hydrochloric acid (0.123 mL, 0.123 mmol) was added and the solution was concentrated. The residue was taken up with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combine organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was dried under vacuum overnight and then suspended in ethyl acetate and washed three times with water. The solvent was evaporated to afford 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (32 mg, 75%). 1H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.24-8.19 (m, 2H), 7.86 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H), 7.00-6.91 (m, 3H), 5.09 (s, 2H), 4.90 (s, 2H), 3.41 (septet, J=7 Hz, 1H), 2.14 (s, 6H), 1.27 (d, J=7 Hz, 6H). HRMS (ESI) C32H30N2O5 calculated: 523.2228 (M+H)+, found: 523.2230 (M+H)+.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[N:21][OH:22])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[O:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1cccc(Oc2ccccc2)c1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2cccc(Oc3ccccc3)c2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (3-phenoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.573 mmol) described in Manufacturing Example 64-1-3 and 3-ethynyl-pyridin-2-ylamine (30.0 mg, 0.254 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (106 μL, 0.762 mmol) at room temperature, which was stirred for 2 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2), the mixture was further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (6.6 mg, 43%) as a trifluoracetic acid salt.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.NN>C(O)C.[Pd]>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)N1CCC(c2ccc(N)cc2)CC1

Procedure:
To a solution of 1-isopropyl-4-(4-nitro-phenyl)-piperidine (2.405 g, 9.698 mmol), prepared according to Example 5, in ethanol (100 mL) under nitrogen is added Pd/C 10% (515.9 mg, 0.485 mmol), followed by dropwise addition of hydrazine hydrate (2.427 g, 48.49 mmol). The mixture is refluxed overnight until completion of the reaction. After filtration through a celite plug, the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([OH:41])([CH3:40])[CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]([C:26]2[CH:31]=[C:30]([C:32]([NH:34][CH:35]4[CH2:37][CH2:36]4)=[O:33])[CH:29]=[CH:28][C:27]=2[CH3:38])[C:19]3=[O:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[CH:35]1([NH:34][C:32](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([CH3:38])=[C:26]([N:20]3[C:19](=[O:39])[C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][C:13]([OH:41])([CH3:40])[CH2:12][N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)[CH:17]=4)[N:22]=[CH:21]3)[CH:31]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(O)COc2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)(O)CN3CCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of the crude 3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (0.2 g) in anhydrous DMF (10 ml) was added potassium carbonate (0.1 g) followed by pyrrolidine (0.15 g) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated and purification by preparative HPLC provided the title compound as a gum (50 mg); NMR Spectrum: (CDCl3) 0.60 (m, 2H), 0.90 (m, 2H), 1.20 (m, 1H), 1.40 (s, 3H), 1.80 (m, 4H), 2.20 (s, 3H), 2.75 (m, 6H), 4.20 (m, 2H), 6.40 (s, 1H), 7.50 (m, 2H), 7.70 (m, 3F[), 7.80 (d, 1H), 7.90 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].[NH:51]1[CH:55]=[N:54][CH:53]=[N:52]1>ClCCl>[N:51]1([CH2:2][C:3]2[CH:8]=[CH:7][N:6]3[C:9]([C:12]4[CH:13]=[C:14]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:15]=[CH:16][CH:17]=4)=[CH:10][N:11]=[C:5]3[N:4]=2)[CH:55]=[N:54][CH:53]=[N:52]1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3nc(CO)ccn23)c1
Reactant: c1nc[nH]n1
Agent: BrC(Br)(Br)Br
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(Cn4cncn4)ccn23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
To a solution of 3′-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile (0.1 g, 0.31 mmol) in dichloromethane (5 ml) was added carbon tetrabromide (153 mg, 0.46 mmol) and triphenylphosphine (121 mg, 0.46 mmol). This mixture was stirred at ambient temperature for 6 h after which time 1,2,4-triazole sodium salt (84 mg, 0.93 mmol) was added and the reaction stirred at ambient temperature for a further 18 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography eluting with dichloromethane on a gradient of methanol (0-10%). Further purification by high performance liquid chromatography gave 3′-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (15.3 mg): δH (400 MHz, DMSO) 5.76 (2H, s), 7.32 (1H, d, J 7), 7.52-7.84 (8H, m), 8.16 (2H, d, J 5), 8.73 (1H, s), 9.22 (1H, s); m/z (ES+) 378 (M++H).
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C(F)(F)F)[CH:5]=[CH:4][C:3]=1C1C=CC=C2C=1C=CC=[C:17]2[CH2:22][OH:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:43]([O:47]C(NC(NC(OC(C)(C)C)=O)=N)=O)(C)(C)[CH3:44].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.O>[CH3:44][CH2:43][O:47][C:22]([CH3:17])=[O:23].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C(F)(F)F)ccc1-c1cccc2c(CO)cccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 251.9 %

Procedure:
(5-(2-Methyl-4-(trifluoromethyl)phenyl)naphthalen-1-yl)methanol (67 mg), PPh3 (83 mg, 1.5 eq.), and 1,3-bis(t-butoxycarbonyl)guanidine (110 mg, 2 eq.) in 3 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.06 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H2O were added, and the solution was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a clear oil (93 mg, 79% yield). 1H NMR (400 MHz) (CDCl3) δ 9.55 (bs, 2H), 8.10 (d, J=8 Hz, 1H), 7.62-7.57 (m, 3H), 7.41-7.22 (m, 5H), 5.84-5.74 (m, 2H), 2.06 (s, 3H), 1.48 (s, 9H), 1.17 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ163.80, 160.97, 155.04, 138.98, 137.77, 135.08, 131.60, 130.85, 130.69, 126.61, 126.20, 125.71, 125.37, 124.60, 122.88, 122.45, 122.23, 84.03, 78.99, 45.23, 28.26, 27.57, 19.93.
Reaction SMILES: Cl.C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=2[C:14]#N)[CH2:7][CH2:6]1)(=O)C.[OH-:19].[Na+].[OH2:21]>>[N+:16]([C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([C:14]([OH:21])=[O:19])[CH:11]=1)[NH:5][CH2:6][CH2:7]2)([O-:18])=[O:17]
Reactant: [OH-]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])cc(C#N)c21
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1NCC2
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
Into concentrated hydrochloric acid (63.6 ml) was dissolved N-acetyl-7-cyano-5-nitroindoline (5.3 g), which was then subjected to stirring at 140° C. for 45 minutes. The reaction mixture was cooled to 0° C. to give deposited crystal, which was then collected by filtration. The obtained crude crystal was suspended into water (50 ml), and was rendered basic by adding 50% sodium hydroxide, and the insoluble matter was collected by filtration. After adding concentrated hydrochloric acid to the filtrate, the deposited crystal was collected by filtration and dried to give the intended compound 3.7 g (77.1%) as yellow powder. M.P.: 294°-297° C. (decomp.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:18][C:19]([F:27])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:18][CH:19]([F:27])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC(F)F)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated with ether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (d, J=2.76 Hz, 1 H), 8.68 (dd, J=9.03, 2.76 Hz, 1 H), 7.98 (s, 0.5 H), 7.62 (s, 0.5 H), 7.34 (d, J=9.03 Hz, 1 H).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:3][CH2:2]1.[CH3:22][CH:23]([C:27]([OH:29])=O)[C:24]([OH:26])=O.C(OC(=O)C)(=O)C>>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:27]([OH:29])=[C:23]([CH3:22])[C:24](=[O:26])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:2][CH2:3]1
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a 2:1 mixture (34.6 g) of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H-pyrimidine-2,4,-dione 53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g) was added acetic anhydride (173 ml), and the mixture was stirred at 100° C. for 2 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Acetone (104 ml) was added to the residue, and the mixture was stirred with heating under reflux for 30 min. After allowing to cool to room temperature, the precipitated crystals were collected by filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48, 21%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC.[F-].[K+]>O1CCOCC1.C(OCC)(=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>[C:44]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=[O:46])[CH3:45]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C(C)=O)cc1
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of ethyl 4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (122.0 mg, 0.20 mmol) prepared in Example 153, tributyl(1-ethoxyvinyl)tin (94.0 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.0 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was heated to reflux under argon atmosphere for 16 hours. After cooling, the reaction solution was diluted with ethyl acetate, and poured into aqueous potassium fluoride solution. The mixture was stirred for 6 hours. The insoluble was filtered off, and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water. Then, thereto was added 2 mol/L hydrochloric acid, and the mixture was stirred for 3 days. Then, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to give ethyl 4-({(4-acetylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (53.4 mg, 47%) as a white powder.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=O)[CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(OC2CC2)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(OC2CC2)c1

Procedure:
3-cyclopropoxybenzaldehyde (7.51 g, 46.3 mmol) was dissolved in pyridine (195 mL) then malonic acid (19.3 g, 185 mmol) and piperidine (6.86 mL, 69.5 mmol) were added. The reaction was stirred at reflux for 2 hr then concentrated. The residue was poured on to ice cold 6N HCl and decanted to collect the solution. The solution was diluted with DCM and extracted with DCM. The extract and the solid from the water layer were combined and basified with 2N NaOH. The basic solution was washed with DCM, acidified and filtered to give 3-(3-cyclopropoxy-phenyl)-acrylic acid as white solid: 1H NMR (CDCl3, 300 MHz) δ 7.77 (d, 1H), 7.36-7.09 (m, 4H), 6.44 (d, 1H), 3.77 (m, 1H), 0.81 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17](O)=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[CH2:17][Cl:26])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
From 6.0 g. of 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 175 ml. of methylene chloride, 2.4 ml. of triethylamine, 2.2 ml. of trimethylsilyl chloride and 2.5 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:23])=[C:21]([Cl:22])[C:16]=4[C:15](=[O:24])[N:14]4[CH2:25][CH2:26][C@H:13]4[C:12]=23)[O:5][N:4]=1.[CH2:27](Br)[CH:28]=[CH2:29].C(N(C(C)C)[CH:34]([CH3:36])[CH3:35])C>C(Cl)Cl>[CH2:27]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:23])=[C:21]([Cl:22])[C:16]=4[C:15](=[O:24])[N:14]4[CH2:25][CH2:26][C@H:13]4[C:12]=23)[O:5][N:4]=1)[CH2:36][CH:34]=[CH2:35])[CH:28]=[CH2:29]
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)n1
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)n1
Yield: 37.3 %

Procedure:
11.7 g (31.2 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 100 ml of methylene chloride, 6.04 g (50 mmol) of allyl bromide and 7.75 g (60 mmol) of N-ethyldiisopropylamine were stirred at room temperature overnight. The solution was concentrated and the residue was purified by chromatography on 500 g of silica gel while eluting with ethyl acetate. After recrystallization from methanol there were obtained 5.3 g (47%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 139°-140°, which was converted into the hydrochloride of m.p. 127°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc([N+](=O)[O-])c2)cnn1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.0 g, 24.52), Fe powder (3.84 g, 68 mmol) and ammonium chloride (3.84, 71.78 mmol) in ethanol (135 ml) and water (64 ml) was heated at reflux under nitrogen atmosphere. After 1 h, the reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g) as a solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccccc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-phenyl-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-phenyl-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20]#[C:21][CH3:22].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:21]([CH3:22])=[C:20]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC#CCBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=C=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.61 g; 2.2 mmol), 1-bromo-2-butyne (1.7 mL; 18.8 mmol) and indium (2.49 g; 21.7 mmol) were suspended in THF (10 mL) and 0.045 M HCl (20 mL) and stirred vigorously overnight. The reaction mixture was diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4. The resulting crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClC(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1)[C:29](=[O:31])[CH3:30])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Solvent: ClC(Cl)Cl
Product: CCN(CCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21)C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
7.8 Parts of N-ethyl-2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-3-ethanamine were taken up in 75 parts of trichloromethane. 1.51 Parts of acetic acid anhydride were added (exothermic reaction). The reaction mixture was stirred for 18 hours at room temperature. The whole was filtered over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in methylbenzene and the whole was evaporated again, yielding 8.5 parts (100%) of N-ethyl-N-[2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]ethyl]acetamide as a residue (compound 176).