Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.ClC1C=CC(C(F)(F)F)=CC=1B(O)O.[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:43]=1B(O)O)([O-:41])=[O:40]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:43]4[CH:44]=[C:45]([C:48]([F:51])([F:50])[F:49])[CH:46]=[CH:47][C:42]=4[N+:39]([O-:41])=[O:40])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1B(O)O
Agent: OB(O)c1cc(C(F)(F)F)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 23 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-(trifluoromethyl)phenylboronic acid (2-nitro-5-trifluoromethylphenylboronic acid, pinacol ester (available from Combi-Blocks Inc.; 117 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-nitro-5′-trifluoromethyl-biphenyl-2-carboxylic acid (31 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ 13.48 (s, 1H), 8.55 (d, J=1.7 Hz, 1H), 8.51 (s, 1H), 8.29-8.37 (m, 2H), 8.24 (d, J=8.3 Hz, 1H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 8.03 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2c(Cl)cccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2c(Cl)cccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 41.3 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-chloro-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.695 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.31 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the hydrochloride salt to afford the title compound (0.220 g); mp 175°-185° C.; MS: m/z=549(M+1); NMR(CD3OD): 1.92 (m,4), 2.13 (m,2), 2.54 (m,2), 3.29 (s,3), 3.66 (m,3), 4.37 (m,1), 6.76 (dd,1, J=8.3, 21), 6.96 (d,1, J=21), 7.29 (d,1, J=8), 7.5 (d,1, J=8), 7.65 (t,1, J=7.8), 7.83 (d,1, J=7.5). Analysis for C29H31Cl3N4O2.2.5 H2O.1.0 HCl: Calculated: C, 53.14; H, 5.69, N, 8.55; Found: C, 53.13; H, 5.67; N, 9.51.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.FC(F)(F)C(O)=O.[N+:30]([O-])([OH:32])=[O:31]>ClCCl>[N+:30]([C:5]1[S:4][C:3]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:2]([CH3:1])[CH:6]=1)([O-:32])=[O:31]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sccc3C)c(C)nn12
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cc(C)nc2c(-c3sc([N+](=O)[O-])cc3C)c(C)nn12
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Dissolve 3-(3-methyl-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.419 g, 1.33 mmol) in dichloromethane (2.5 mL), stir under an inert atmosphere, chill in an ice bath to 0° C. and add trifluoroacetic acid (5 mL). Add concentrated (70%) nitric acid (0.132 g, 1.47 mmol) to the reaction dropwise. The solution changes color from yellow to dark green. Stir 1 h under an inert atmosphere while in an ice bath and confirm the reaction is complete using TLC. Dilute the reaction with dichloromethane (80 mL) and quench with saturated sodium bicarbonate. Separate and extract the aqueous basic phase with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (30% ethyl acetate/hexane) to 0% hexane/100% (30% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (0.363 g, 76%). 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 6.51 (s, 1H), 3.62-3.58 (m, 1H), 2.56 (s, 3H), 2.48 (s, 3H), 2.18 (s, 3H), 1.88-1.70 (m, 4H), 0.88 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.O>[F:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 4-propyl phenylboronic acid (T16; 200.0 g), 1-bromo-3-fluorobenzene (T8; 177.8 g), potassium carbonate (281.9 g), Pd(Ph3P)2Cl2 (7.2 g), toluene (600 ml), and Solmix A-11 (600 ml) were put and heated under reflux for 2 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (2,000 ml) and toluene (1,000 ml), and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The solution was further purified by recrystallization from Solmix A-11 and then dried, whereby 175.5 g of 3-fluoro-4′-propylbiphenyl (T17) was obtained. The yield based on the compound (T8) was 80.3%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:31]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:32][CH:33]([OH:39])[CH2:34][NH:35][C:36](=[O:38])[OH:37])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)=[CH:14][CH:13]=4)=[C:9]([C:26](=[O:29])[NH:27][CH3:28])[C:8]=3[CH:30]=2)[CH2:3][CH2:2]1.[CH:44]1[CH:45]=[CH:46][NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:55]C([O-])=O.[Na+]>C(Cl)Cl>[C:45]([O:38][C:36](=[O:37])[NH:35][CH2:34][C:33](=[O:39])[CH2:32][N:31]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:30][C:8]2[C:9]([C:26](=[O:29])[NH:27][CH3:28])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)[S:40]([CH3:43])(=[O:41])=[O:42])([CH3:44])([CH3:46])[CH3:55]
Reactant: CC(=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)oc2cc(N(CC(O)CNC(=O)O)S(C)(=O)=O)c(C3CC3)cc12
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)oc2cc(N(CC(=O)CNC(=O)OC(C)(C)C)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 8 h
Yield: 45.6 %

Procedure:
step 2—A solution of 36 (0.178 g, 0.267 mmol), PCC (0.114 g, 0.680 mmol), NaOAc (214 mg) and DCM (8 mL) was added stirred overnight. The solvent was evaporated and the crude product purified on a SiO2 column eluting with an EtOAc/hexane gradient (0 to 50% EtOAc) to afford 0.081 g of [3-({5-cyclopropyl-2-[4-(4-fluoro-phenoxy)-phenyl]-3-methylcarbamoyl-benzofuran-6-yl}-methanesulfonyl-amino)-2-oxo-propyl]-carbamic acid tert-butyl ester (38).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.7 %

Procedure:
To a solution of 2-(3-methoxyphenyl)acetonitrile (2 g; 13.59 mmol) in 13 mL of dry DCM) cooled at 0° C. under nitrogen atmosphere, a 1M solution of BBr3 in DCM (28.54 mmol; 28.54 mL) is slowly added dropwise. The mixture is stirred at room temperature for 20 hours. The reaction mixture is then poured into ice, water is added and the organic phase is extracted three times with DCM, washed with brine and dried over anhydrous Na2SO4. After evaporation, the crude mixture is chromatographed on silica gel using PE/EtAc (80/20) as an eluant, yielding 1.28 g (71%) of 2-(3-hydroxyphenyl)acetonitrile.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]([CH:17]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH:8]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:33]=[N:34][C:44]([CH3:43])=[N:45][CH:37]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)C2)cnn1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO)Oc3ccc(Cl)cn3)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of [(3RS,4SR)-3-[(RS)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone 0.024 g (0.038 mmol) dissolved in THF (4 mL) was added 0.05 mL of TBAF (1.0M in THF). The reaction mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 18 mg (93%) of the title compound as a light yellow oil. ES-MS m/e: 509.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[C:8]([NH2:11])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:1][N:2]1[C:9]2[N:10]=[C:12]([CH3:13])[NH:11][C:8]=2[C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5,6-diaminouracil (2.5 g) in acetic anhydride (25 ml) was heated at reflux for 2 hours and then concentrated. The residue was dissolved in 10% sodium hydroxide solution (50 ml) and heated at reflux for 2 hours. After cooling to room temperature the solution was acidified to pH 4 with concentrated hydrochloric acid. The product was filtered, washed with water (15 ml), with acetone (15 ml) and then dried under vacuum. Yield 1.8 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29](SC)[C:24]=4[N:23]=[C:22]3[CH2:32][O:33][CH3:34])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].Cl[C:37]1C=CC=C(C(OO)=O)C=1.[S:47]([O-:51])([O-])(=[O:49])=S.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([S:47]([CH3:37])(=[O:51])=[O:49])[C:24]=4[N:23]=[C:22]3[CH2:32][O:33][CH3:34])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCc1nc2c(SC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCc1nc2c(S(C)(=O)=O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
(E)-2-(3-fluoro-8-{[2-(methoxymethyl)-4-(methylthio)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propionitrile (120 mg, 0.25 mmol) obtained in Reference Example 2M was dissolved in methylene chloride (1.2 mL), m-chloroperbenzoic acid (227 mg, 0.989 mmol) was added at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction was discontinued with aqueous sodium thiosulfate solution, the mixture was extracted with chloroform, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=10/1 v/v) to give (E)-2-(3-fluoro-8-{[2-(methoxymethyl)-4-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propionitrile (79 mg, 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:24]([O:28][C:29](=[O:41])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH2:39][NH2:40])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl.O>[C:24]([O:28][C:29](=[O:41])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH2:39][NH:40][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1cnccn1
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (0.570 g, 4.60 mmol) in CH2Cl2 (50 mL) was added EDC (0.960 g, 5.01 mmol) and HOBt (0.620 g, 4.60 mmol) at room temperature. The mixture was stirred for 10 min, and 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (1.05 g, 4.18 mmol) was added. The reaction mixture was stirred for 18 h at room temperature, treated with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/hexanes, 1:1 to 1:0) to obtain the title compound (1.05 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 2.52 (t, 2H, J=7.6 Hz), 2.91 (t, 2H, J=7.6 Hz), 4.66 (d, 2H, J=6.4 Hz), 6.73 (dd, 1H, J=2.9, 7.8 Hz), 6.83 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=8.3 Hz), 8.17 (br s, 1H), 8.49 (dd, 1H, J=1.5, 2.4 Hz), 8.73 (d, 1H, J=2.4 Hz), 9.41 (d, 1H, J=1.5 Hz). MS (ES) m/z 356.1 ([M−H]−).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: CSc1nc(-c2cccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 400 mg) with p-nitro-phenyl chloroformate (207 mg) was performed according to the methods described in example 1g. Evaporation of the solvent under reduced pressure yielded the crude title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([F:28])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (80 mg, 88%), MS (ISP) m/z=363.4 [(M+H)+], mp 242.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].S(Cl)(Cl)=O.[NH2:17][C:18]1[C:19]([Cl:26])=[N:20][CH:21]=[N:22][C:23]=1[O:24][CH3:25]>C1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[C:19]([Cl:26])=[N:20][CH:21]=[N:22][C:23]=2[O:24][CH3:25])=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Reactant: COc1ncnc(Cl)c1N
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ncnc(Cl)c1NC(=O)c1ccc(Cl)c(C#N)c1
Temperature: 25 °C
Reaction time: 115 h
Yield: 75.4 %

Procedure:
To a suspension of the above-mentioned 4-chloro-3-cyanobenzoic acid (1.20 g, 6.61 mmol) in dry benzene (10 mL) was added thionyl chloride (0.58 mL, 7.95 mmol). The mixture was heated under refluxing for 4 hours, and then placed under reduced pressure to distill the solvent off. To the residue was added dry dichloromethane (5 mL), and the mixture was placed under reduced pressure to distill the dry benzene and the remaining thionyl chloride off. The residue was dissolved in dry dichloromethane (45 mL). The resulting solution was dropwise added under ice-cooling to a solution of 5-amino-4-chloro-6-methoxypyrimidine (2.11 g, 13.2 mmol) in dry dichloromethane (45 mL) for 5 minutes. The mixture was stirred at room temperature for 115 hours. The precipitated crystalline product was collected by filtration, washed with dichloromethane (5 mL×2), and placed under reduced pressure to distill the solvent off. The residue was repeatedly purified by silica gel column chromatography (methanol/chloroform), to obtain 1.61 g (yield 75%) of the titled compound as a pale brown crystalline product.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[C:17](O)([C:19]([F:22])([F:21])[F:20])=[O:18]>C(N(CC)CC)C>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:17](=[O:18])[C:19]([F:22])([F:21])[F:20]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C(F)(F)F
Yield: 20 %

Procedure:
To a solution of 10-methoxyharmalan (40 mg) in triethylamine (1 ml) is added TFA (2.2 eq). After reaction for 15 min. at 0° C., the mixture is hydrolysed and extracted with CH2Cl2. The crude product is then chromatographed on a preparative plate (eluent: CH2Cl2). 1-Methylene-2-trifluoroacetyl-6-methoxy-1,2,3,4-tetra-hydro-β-carboline is recovered (yield: 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[OH2:23].[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC1CCc2c(-c3ccc(N)cc3)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4C)cc1
Product: O

Procedure:
A mixture of 0.7 g (2.1 mmole) of 8-(4-aminophenyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 ml of acetic acid and 2.5 ml of acetic anhydride was heated at its reflux temperature until solid was observed to precipitate. The mixture was diluted with 10 ml of water, stirred and cooled. The product was separated by filtration to provide 8-(4-acetamidophenyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 168°-170° C. Analysis: Calculated for C22H20N2O4.0.75H2O: %C, 67.8; %H, 5.6; %N, 7.2; Found: %C, 67.9; %H, 5.3; %N, 7.4. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[F:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:23]2[CH2:24][CH2:25][CH:20]([F:19])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: FC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCC(F)CC1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 4-fluoropiperidine hydrochloride (0.25 g, 1.8 mmol). The reaction was heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.44 g, 99%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.79 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, 2.0 Hz), 6.97 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 4.97-4.79 (m, 1H), 3.26-3.17 (m, 2H), 3.06-2.99 (m, 2H), 2.14-1.97 (m, 4H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2, 225.2 (M-Cl+2H), found 225.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][N:31]1[C:35]([C:36]2[CH:41]=[CH:40][N:39]3[C:42]([C:45](OC)=[O:46])=[CH:43][N:44]=[C:38]3[CH:37]=2)=[CH:34][CH:33]=[N:32]1>C1COCC1.CO.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:45]([C:42]2[N:39]3[CH:40]=[CH:41][C:36]([C:35]4[N:31]([CH3:30])[N:32]=[CH:33][CH:34]=4)=[CH:37][C:38]3=[N:44][CH:43]=2)=[O:46])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: COC(=O)c1cnc2cc(-c3ccnn3C)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6ccnn6C)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (46.7 mg, 0.185 mmol) in anhydrous THF (2 ml) was added under a nitrogen atmosphere at ambient temperature lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.38 mL). The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (47.4 mg, 0.185 mmol) in anhydrous THF (2 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the dried product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as eluent to afford 45.7 mg of pure, desired product as a yellow-brown solid. MS (ES+APCI) m/z=477 (M+H) detected.