Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15](I)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:15]([N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1NCCN1c1ccccc1
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCN(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
To a 0° C. suspension of 5.00 g (30.8 mmol) 1-phenylimidazolidin-2-one in 50 mL of dimethylformamide was added 1.48 g (37.0 mmol, 1.2 equiv) of sodium hydride (60% oil dispersion). After 45 minutes, 6.7 mL (8.88 g, 37.0 mmol, 1.2 equiv) of octyl iodide was added. The mixture was allowed to stir overnight with gradual warming to room temperature. TLC analysis indicated the presence of starting material. An additional 830 mg portion of sodium hydride was added. After 5 hours, TLC analysis again indicated the presence of starting material, so 0.5 g more sodium hydride and 6 mL of octyl iodide were added. After 2 hours, the reaction was complete as judged by TLC analysis. The mixture was concentrated in vacuo, and partitioned between 200 mL of ethyl acetate and 50 mL of water. The organic phase was washed sequentially with three 50-mL portions of water and one portion of brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 10-25% ethyl acetate/hexane) provided 3.97 g (47%) of 3-octyl-1-phenylimidazolidin-2-one. A 3.93 g portion of this material was added over 45 min to 6 mL of chlorosulfonic acid in a salt/ice bath. Stirring was continued at -5° C. until gas evolution ceased (~3 hours). The reaction mixture was poured into 50 mL of ice and extracted with 3 150-mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (25% ethyl acetate/hexane) provided 2.49 g of the title compound: 1H NMR (500 MHz, CDCl3) δ7.94 (d, 2H), 7.76 (d, 2H), 3.87 (dd, 2H), 3.55 (dd, 2H), 3.31 (t, 2H), 1.56 (m, 2H), 1.36-1.21 (m, 10H), 0.85 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][NH:25][N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1.Cl.[Cl:28][C:29]1[C:30]([CH2:38]Cl)=[N:31][CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:38][C:30]4[C:29]([Cl:28])=[C:34]([O:35][CH3:36])[C:33]([CH3:37])=[CH:32][N:31]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Reactant: COc1c(C)cnc(CCl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3Cl)nc3c-2c1CSN=C3N
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
Dimethylformamide (1 ml) was added to 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (28 mg), 3-chloro-2-(chloromethyl)-4-methoxy-5-methylpyridine hydrochloride (36 mg), and potassium carbonate (69 mg). The resulting mixture was stirred at 60° C. for 2.5 hours. Thereafter, the insoluble matter was removed by filtration, and the solvent was then distilled away in a nitrogen stream. The resulting residue was dissolved in dimethyl sulfoxide (1 ml), and it was then purified by preparatory reverse-phase HPLC. The solvent was distilled away under reduced pressure, so as to obtain the title compound (27.0 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])=[CH:9][CH:8]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OC[C@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Temperature: 150 °C
Reaction time: 0.03 h
Yield: 53.5 %

Procedure:
3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (10.2 g) was dissolved in 108 mL NMP-diglyme (1:9) under nitrogen and heated to 150° C. internal temperature. A suspension of sodium hydride (1130 mg of 60% NaH in mineral oil) in 10 mL NMP-diglyme (1:9) was added all at once via syringe while stirring. After 2 minutes, the reaction was removed from heating and cooled, then poured onto saturated ammonium chloride and EtOAc. The layers were separated and the organic layer washed 3 times with 1 N HCl and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM-hexanes 1:1 to DCM). The residue was crystallized from refluxing MeOH/DCM (about 3:1), to give 5.2 g of desired product. 1H NMR (400 MHz, CDCl3): 7.53 (d, 1H), 7.45 (d, 1H), 7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.22 (d, 1H) 7.18 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:17]1[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][N:24]=2)[N:22]=1.O>CN(C)C=O>[CH2:3]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]2[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)[N:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc(O)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1ccc(Oc2nc(-c3ccncn3)cc(=O)n2C)cc1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 202 mg, 5.05 mmol) in N,N-dimethylformamide (1.0 ml) was added 4-hexylphenol (899 mg, 5.04 mmol) at room temperature, and stirred for one hour. 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (935 mg, 4.20 mmol) was added to the solution. The mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=50/50) to afford 2-(4-hexylphenoxy)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (1.14 g, 3.13 mmol, 75%).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1/[CH:37]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCOCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrole-2-carbaldehyde (166 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:12][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=1)[C:2]([NH2:1])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (Example 1, step (i), 2.41 g) was stirred in dichloromethane (125 mL) and to the suspension was added trifluoroacetic acid (8 mL). The mixture was stirred for 2 h and then concentrated to ˜12 mL in vacuo. The residue was stirred for 2 days, dissolved in ethyl acetate/dichloromethane and washed with water containing an excess of sodium bicarbonate. The organic layer was dried and evaporated to the sub-titled compound (1.52 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[C:10]2[CH2:18][CH2:17][CH2:16][C:15]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]=[CH:12][C:11]2=3)[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][CH2:16][C:15]3[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:13]=[CH:12][C:11]2=3)[CH2:4][CH2:3]1
Reactant: CC1CCN(CC=C2CCCc3c2cnn3-c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(CCC2CCCc3c2cnn3-c2ccccc2)CC1
Reaction time: 18 h
Yield: 39.6 %

Procedure:
Pd-C (100 mg, 20%) is added to a solution of a mixture of E/Z isomers of 4,5,6,7-tetrahydro-4-(2-(4-methylpiperidin-1-yl)ethylidene)-1-phenyl-1H-indazole (324 mg, 1.01 mmol) in 75 mL of EtOH, and the resulting solution is stirred in a nitrogen atmosphere (45 psi) in a Parr hydrogenator for 18 hours. The reaction mixture is purged with nitrogen, filtered through Celite and the solvent is evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography giving 4,5,6,7-tetrahydro-4-(2-(4-methylpiperidin-1-yl)ethyl)-1-phenyl-1H-indazole (130 mg, 0.40 mmol, 40%, oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=S)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1.[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=[CH:24]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=[N:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: NCCCn1ccnc1
Reactant: COc1cccc(CN2C(=S)c3cccc4cccc2c34)c1
Solvent: CCO
Product: COc1cccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)c1
Yield: 80.1 %

Procedure:
A mixture of 2.5 g of 1-[(3-methoxyphenyl)methyl]benz[cd]indole-2(1H)-thione (Ck), 1.1 g of 1H-imidazole-1-propanamine, 200 ml ethyl alcohol, and 2.6 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp. 95°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(CC)CC.[CH2:17]=[O:18].Cl>CC#N>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:17]=[O:18]
Reactant: C=O
Reactant: Oc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available 3,5-difluorophenol (3.000 g; 23.10 mmol), anh. magnesium chloride MgCl2 (6.587 g; 69.20 mmol), and NEt3 (8.04 ml; 57.70 mmol) in anh. MeCN (100 ml) was stirred at rt, under nitrogen, for 20 min. Paraformaldehyde (3.459 g; 115.00 mmol) was then added, and the resulting mixture was heated to 80° C., under nitrogen, for 1.5 h. After cooling to rt, aq. 1N HCl (80 ml) was added, and the aq. layer was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2,4-difluoro-6-hydroxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>[Pd]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.7 mmol) was reacted with (4-chlorophenyl)magnesium bromide (6.7 mL, IM in diethyl ether, 6.7 mmol, 4 equiv) according to General Procedure 3. The resulting endo-olefin (methyl 4-(4-chlorophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound. 49.2 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.84 (br. s, 1H), 7.23-7.27 (m, 2H), 7.10-7.16 (m, 2H), 6.62 (d, J=1.61 Hz, 1H), 4.20 (t, J=7.22 Hz, 1H), 3.83 (s, 3H), 2.72-2.99 (m, 3H), 2.20-2.31 (m, J=12.81, 8.65, 6.47, 6.47 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)([O:16][CH3:24])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(Br)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
Sodium hydride (76 mg, 1.90 mmol) was added portionwise to a solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (519 mg, 1.46 mmol) in anhydrous THF (10 mL) at 0° C. After 1 h, methyl iodide (136 μL, 2.19 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched by the addition of water (10 mL), the organic layer was separated and the aqueous layer back-extracted with DCM (3×10 mL). The combined organic phase was concentrated in vacuo to afford the title compound (607 mg, quantitative). 1H NMR (CDCl3, 400 MHz): 7.49 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 3.97 (d, J=13.0 Hz, 2H), 3.15 (t, J=13.0 Hz, 2H), 2.97 (s, 3H), 1.97 (d, J=13.5 Hz, 2H), 1.83-1.74 (m, 2H), 1.47 (s, 9H). LCMS (Method B): RT=4.61 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][OH:12])[NH:2]1.C=O.[Na].[C:16](=O)([O-])[O-].[K+].[K+]>C(O)=O>[CH3:16][N:2]1[CH:3]([CH2:11][OH:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: OCC1Cc2ccccc2CN1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Agent: [Na]
Solvent: O=CO
Product: CN1Cc2ccccc2CC1CO
Temperature: 140 °C

Procedure:
In a sealed tube, a mixture of 1.80 g of 1,2,3,4-tetrahydro-3-isoquinolinemethanol, 1.69 g of 90% formic acid and 1.04 g of 35% formalin was heated at 140° C. for 16 hours. The reaction solution was cooled and then made alkaline by addition of 10% aqueous sodium solution. Subsequently, potassium carbonate was added to the solution and a precipitated oil was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to remove the solvent. There was obtained 1.95 g of 2-methyl-1,2,3,4-tetrahydro-3-isoquinolinemethanol.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21]C1C=CC(B(O)O)=CC=1>>[F:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(F)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (100 mg, 0.54 mmol) and 4-fluorobenzeneboronic acid (79 mg, 0.57 mmol) were coupled to yield 2-(4-fluorophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 107 mg (99%), as a pale-yellow solid. 1H NMR (300 MHz, d6-DMSO) δ3.04 (m, 2H), 3.38 (m, 2H), 7.22 (app t, 1H, J=7.7 Hz), 7.39 (m, 2H), 7.56 (dd, 1H, J=8.0, 0.9 Hz), 7.64 (m, 3H), 8.05 (br t, 1H), 11.57 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H14FN2O: 281.1090, Found: 281.1093; Anal. (C17H13FN2O.0.6 H2O) C, H,N.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Reaction time: 2 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (3.0g., 0.012 mol) and 1,1'-carbonyldiimidazole (2.0 g., 0.012 mol) in tetrahydrofuran (180 ml) and dimethylformamide (3.5 ml) is refluxed under nitrogen for 5 hours. The solution is cooled in an ice-bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice-bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off and washed with tetrahydrofuran. The precipitate is treated with hot 0.5 mol aqueous sodium bicarbonate solution, filtered, washed with water, washed with acetone and sucked dry to give the product (2.0 g.), mp 334° C. (dec).
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].[NH:29]([C:31]1[C:32]([O:37][CH3:38])=[N:33][CH:34]=[CH:35][CH:36]=1)[NH2:30]>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:30][N:29]([C:31]4[C:32]([O:37][CH3:38])=[N:33][CH:34]=[CH:35][CH:36]=4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: COc1ncccc1NN
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and 3-hydrazinyl-2-methoxypyridine (Step 71.1). The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) followed by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 12-17% in 6 min_total 11 min) and triturated in Et2O. tR: 0.99 min (LC-MS 2); ESI-MS: 500 [M+H]+ (LC-MS 2); Rf=0.33 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 3H) 2.45 (s, 3H) 2.62 (s, 3H) 3.92 (s, 3H) 6.59 (s, 1H) 7.21 (dd, J=7.6, 5.01 Hz, 1H) 7.34 (s, 1H) 7.37-7.48 (m, 4H) 8.00 (dd, J=7.6, 1.71 Hz, 1H) 8.33 (dd, J=4.9, 1.6 Hz, 1H) 8.47 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][CH2:18]O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl.CCOCC>[CH2:1]([N:8]([CH2:17][CH2:18][Br:46])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN(CCBr)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of Compound 4 (2.94 g, 11.1 mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. was added PPh3 (3.49 g, 13.3 mmol). NBS (2.37 g, 13.3 mmol) was added portionwise into the reaction mixture over 1 h. The resulting mixture was stirred at 0° C. for 30 minute after which the ice bath was removed, and the reaction mixture was stirred for 3 h. The resulting mixture was evaporated into an orange solid. The residue was dissolved in ether (100 mL). The solution was filtered, and the filtrate was evaporated and washed with ether again (3 times). The resulting clear filtrate was evaporated to give a white solid. The residue was then dissolved in ether (100 mL) and was passed through a short silica gel column to eliminate as much of the leftover PPh3 as possible. The resulting pure fractions (according to TLC analysis) were collected and dried overnight. The residue was on column chromatography eluted with 5% EtOAc in hexanes to provide Compound 5 (1.83 g, 50.4%) was collected at the ratio ethyl acetate to hexane as 1:11. 1H NMR (CDCl3) δ 1.47 (s, 9H), 3.10 to 3.18 (m, 2H), 3.31 (s, 2H), 3.30 to 3.40 (m, 2H), 3.88 (s, 2H), 7.20 to 7.38 (m, 5H); 13C NMR (CDCl3) δ 28.12, 30.47, 55.14, 55.85, 57.99, 80.96, 127.17, 128.26, 128.69, 138.74, 170.48. HRMS (Positive ion FAB) Calcd for C15H23N4O2Br [M+H]+ m/z 328.0929. Found: [M+Na]+ m/z 328.0912.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](O)=[O:10]>>[CH:9]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=CO
Reactant: Nc1cccc(O)c1
Product: O=CNc1cccc(O)c1
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A mixture of 100 g m-aminophenol and 150 g formic acid was refluxed for 1.5 h and then evaporated to dryness under reduced pressure (90°-95° C., 10-15 mm Hg). Solid material was dried at 100° C., 10 mm Hg, for 1.5 h. 117 g of the title compound were isolated, melting point 112° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
Cyano-phenyl-acetic acid tert-butyl ester (4.52 g) was mixed with Raney nickel (5 mL, 50% water) in MeOH (100 mL) and stirred under hydrogen balloon at rt overnight. The mixture was then filtered through Celite and concentrated to give crude product (4.36 g). 1H NMR in CDCl3, δ in ppm: 7.4-7.2 (m, 5H), 3.54 (m, 1H), 3.3-2.9 (br, 2H), 1.41 (s, 9H).
Reaction SMILES: ClC1C=CC(C2CC(=[S:16])C3C(=CC=C(Cl)C=3)O2)=CC=1.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH:25]2[CH2:34][C:33](=O)[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=3)O2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=3)[S:16]2)=[CH:23][CH:22]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(Cl)cc21
Reactant: S=C1CC(c2ccc(Cl)cc2)Oc2ccc(Cl)cc21
Product: Clc1ccc(C2CCc3cc(Cl)ccc3S2)cc1

Procedure:
4',6-dichlorothioflavanone, (m.pt. 125°-127°), was prepared from 4',6-dichloroflavanone by a method exactly analogous to that used in Example 1(c).