Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccc(C)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccc(C)cc1)Sc1ccc(Cl)cc1

Procedure:
The reaction of 4.07(0.0193 mol) g of 1-chloro-1-[(4-methylphenyl-)hydrazono]-2-propanone, 3.43 g of 4-chlorothiophenol and 3.36 ml of triethylamine in 40 ml of ethanol as in Example 11 yielded 5.55 g of 1-[(4-chlorophenyl)thio]-1-[(4-methylphenyl)hydrazono]-2-propanone, mp 133°-135.5° C.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH3:17].O>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([CH3:17])[CH:12]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: Cl[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1ccccc1
Yield: 89 %

Procedure:
1.03 mol of a phenylmagnesium chloride solution (26% by weight in THF) are added dropwise in the course of 60 minutes to a boiling solution of 1.0 mol of 2-bromo-5-chlorotoluene and 0.2 g of Pd(dppf) Cl2 *CH2Cl2 in 200 ml of THF. After stirring under reflux for eight hours (conversion >97%), the mixture is hydrolyzed with water. After purification by distillation, 4-chloro-2-methylbiphenyl is obtained as a colorless liquid in a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=O)[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[S:18])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2Nc2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1Nc2ccc(Cl)cc2Nc2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.88 g. of 6-chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The reaction mixture is concentrated to dryness and the residue is stirred with 20 ml. of 1N sodium carbonate solution (pH 7-7.2) for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give an orange solid, m.p. 235°-237° C. (dec.).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([C:19](F)(F)F)=[CH2:18])[CH:14]=[C:13]([Cl:23])[CH:12]=1.C(=O)([O-])O.[Na+]>C(OC(=O)C)C>[CH2:2]([O:3][C:4]([C:6]1[CH2:18][C:17]([C:15]2[CH:14]=[C:13]([Cl:23])[CH:12]=[C:11]([Cl:10])[CH:16]=2)([CH3:19])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC(C)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
A solution of ethyl chlorooximidoacetate (9.0 g, 59.1 mmol) in ethylacetate (30 ml) was added at ambient temperature with a syringe pump over a period of 40 h to a suspension of 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (prepared according to WO 2005/085216) (9.5 g, 39.4 mmol) and sodium hydrogen carbonate (15.9 g, 189 mmol) in ethylacetate (85 ml). The reaction mixture was diluted with ethylacetate and washed with water. The organic phase was separated dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica (cyclohexane/ethylacetate; 4/1) to give 8.9 of a yellow oil. 1H-NMR (CDCl3, 400 MHz): 7.45 (m, 3H), 4.49 (q, 2H), 3.96 (d, 1H), 3.59 (d, 1H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([CH2:29][CH2:30][CH2:31]Cl)[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([CH2:29][CH2:30][CH2:31][N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OCCC1CCNCC1
Reactant: CCCCCCCOc1ccc2c(c1)N(CCCCl)c1cccc(S(=O)(=O)N(C)C)c1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(=O)(=O)N(C)C)c1S2
Temperature: 130 °C
Yield: 73.2 %

Procedure:
A mixture of 2-heptyloxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine (24.3 g.), 4-hydroxyethylpiperidine (7.1 g.) and sodium bicarbonate (16.1 g.) in dimethylformamide (180 cc.) is heated at about 130°C. for 8 hours with stirring. After cooling, the reaction mixture is evaporated to dryness under reduced pressure (15 mm.Hg) with heating to 65°C. The residue is taken up in distilled water (300 cc.) and then extracted with methylene chloride (total 560 cc.). The combined organic extracts are acidified by addition of a solution of methanesulphonic acid (57.6 cc.) in water (250 cc.). The organic phase is washed with an 8% aqueous solution of sodium hydroxide (total 300 cc.) and then with distilled water (total 1 litre), and is finally dried over sodium sulphate. On evaporation of the solvent under reduced pressure (15 mm. Hg) at 40°C., crude 2-heptyloxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (21.1 g.), in the form of a brown viscous oil, is obtained.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.C(O)(C)C.C(=O)=O.[CH2:19]([O:26][C:27]([O:29][CH:30]1[CH2:39][CH2:38][C:37]2[N:36]=[CH:35][C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:33](O)[C:32]=2[CH2:31]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([O:26][C:27]([O:29][CH:30]1[CH2:39][CH2:38][C:37]2[N:36]=[CH:35][C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:33]([Cl:4])[C:32]=2[CH2:31]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(OC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.82 g) is added to 100 mL of DMF dropwise under stirring and cooling (isopropanol-dry ice) maintaining the temperature below -20°. Stirring is continued for 30 minutes at the same temperature. To the mixture, 2.66 g of ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in one portion, and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The reaction mixture is evaported to dryness and the residue is taken up in CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated to leave an oil which is purified by flash chromatography on a silica gel column obtaining ethyl 6-benzyloxycarbonyloxy-4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:92]1[CH:97]=[C:96]([CH:98]=O)[CH:95]=[N:94][CH:93]=1.C(OC(C)C)(C)C.CCCCCC>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:98]\[C:96]4[CH:95]=[N:94][CH:93]=[N:92][CH:97]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: O=Cc1cncnc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: COc1ccc(COC(=O)C2=C(/C=C\c3cncnc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
p-Methoxybenzyl 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (4 g) and 5-pyrimidinaldehyde (0.8 g) were stirred for 12 hours in dichloromethane (40 ml). The reaction mixture was concentrated to about 15 ml and then subjected to chromatography on a silica gel column. Relevant fractions were combined and concentrated, whereby an oily matter was obtained. It was added dropwise to a mixed solvent of isopropyl ether (20 ml) and n-hexane (80 ml). The resulting precipitate was collected by filtration, whereby the title compound (1.5 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:43])[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[O:43]=[C:38]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:3]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.508 mmol) was dissolved in DCM (5 mL) and pyridine (0.0820 mL, 1.02 mmol) was added, followed by the addition of methyl 2-chloro-2-oxoacetate (0.0620 g, 0.508 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of water (10 mL) and the mixture extracted with CH2Cl2 (4×10 mL). The combined organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2-oxo-2-((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)acetate (0.180 g, 70.2%). The residue was taken for the next step without further purification. LCMS Condition B-80: retention time 2.32 min, [M+1]=480.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3H), 4.93 (d, J=4.7 Hz, 2H), 6.83 (d, J=2.8 Hz, 1H), 7.25-7.39 (m, 2H), 7.44-7.63 (m, 6H), 7.79 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 8.36-8.41 (m, 1H), 8.95-9.05 (m, 2H), 9.19 (d, J=1.8 Hz, 1H), 11.20 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5](O)=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5]([Cl:19])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(Br)c2sc3ccc(Cl)cc3c12
Product: Clc1ccc2sc3c(Br)cnc(Cl)c3c2c1

Procedure:
A suspension of 4-bromo-8-chloro[1]benzothieno[3,2-c]pyridine-1-ol in POCl3 (1 M) was placed in a microwave reactor at 240° C. (normal absorption) for 10 min. The reaction mixture was carefully extracted with EtOAc/NaHCO3, dried over Na2SO4, filtered and evaporated to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:17]=[C:18]([NH:19][C:2]3[N:7]=[C:6]([NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[C:16]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:17]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2cccc(-c3ccccc3)c2)nc1Nc1cccc(-c2ccccc2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-phenylaniline were reacted to yield N2,N4-bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.02 (d, 1H, J=5.1 Hz), 7.82 (t, 1H, J=1.5 Hz), 7.67 (t, 1H, J=1.8 Hz), 7.58 (dd, 1H, J=1.2 and 7.2 Hz), 7.42-7.24 (m, 15H); LCMS: ret. time: 32.06 min.; purity: 94%; MS (m/e): 433 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].CC(C)([O-])C.[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CS(C)=O.CO>[CH:37]1([CH2:36][O:19][C:17]2[CH:16]=[CH:15][C:14]([C:20]([F:23])([F:21])[F:22])=[C:13]([CH2:12][N:9]3[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=4[F:28])=[N:8]3)[CH:18]=2)[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1ccn(Cc2cc(OCC3CC3)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[5-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 42)(75 mg, 0.189 mmol) in DMSO (1 ml) was added potassium t-butoxide (23 mg, 0.205 mmol, Aldrich). The solution was stirred at ambient temperature for 5 min. To the solution was added (bromomethyl)cyclopropane (0.023 ml, 0.245 mmol, Alfa Aesar) and the mixture stirred overnight at ambient temperature under nitrogen. The solution was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (36 mg); LCMS: (System 4) MH+=452, tRET=3.18 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:5]2/[C:6](=[O:11])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)/[CH:24]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
To a solution of 5-fluorooxindole (7.5 g, 49 mmol) in THF (80 mL) at 0° C., was added 1 M LHMDS in THF (100 mL, 100 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (6.4 g, 33 mmol) in THF (20 mL) was added to the reaction mixture. The reaction was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature over 5 hours. To the reaction mixture was added aqueous 2 M HCl (100 mL). The resulting mixture was stirred at 60-65° C. for 1 hour, cooled to room temperature, poured into water (3000 mL) and stirred at room temperature for 2 hours. The precipitates separated and were collected, washed with water, and dried in vacuo to provide 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (8.7 g, yield 80%), which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].NN>C(O)CO>[CH2:1]([C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: O=C(O)c1ccc(Cc2ccccc2)s1
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
5-Benzoylthiophene-2-carboxylic acid (1.2 g.) was combined with potassium hydroxide (4 g.), hydrazine (3 ml.) and ethylene glycol (8 ml.) and heated in a 140° C. oil bath. A thick, foamy slurry formed which was diluted with 10 ml. additional ethylene glycol. The bath temperature was increased to 180° C., and the reaction held at this temperature for 45 minutes. The reaction was cooled, filtered and the filtrate diluted with 75 ml. of water. The mixture was cooled in an ice bath, acidified with conc. hydrochloric acid, and product (658 mg.) recovered by filtration. Recrystallization from methanol/water gave purified 5-benzylthiophene-2-carboxylic acid (480 mg., 123°-125° C., m/e 218).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:31]3[CH:30]=[C:29]([C:28](=[O:45])[NH:27][CH:24]4[CH2:26][CH2:25]4)[CH:34]=[CH:33][C:32]=3[CH3:35])[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of the product of step i) (0.37 g), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.29 g) [prepared as described in US2005020590] and potassium carbonate (0.27 g) in degassed N,N-dimethylformamide (8 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.115 g) and the mixture heated at 80° C. under nitrogen for 24 hours. The reaction mixture was concentrated to dryness and the crude product purified (SiO2, 2% methanol in dichloromethane as eluent) to give the sub-title compound (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([N:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1)[C:22]#[CH:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:23]#[C:22][CH2:21][N:24]3[CH2:25][CH2:26][S:27](=[O:31])(=[O:30])[CH2:28][CH2:29]3)=[CH:14][C:6]1=2
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: O=S1(=O)CCN(CC#Cc2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Yield: 34 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (108 mg) was coupled with 4-prop-2-ynyl-thiomorpholine 1,1-dioxide as in General Procedure 5 to give the title compound as an off-white solid (34% yield). M.p.>200° C., LCMS: m/z=467.33 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.11 (8H, s), 3.40 (2H, t, J=4.8 Hz), 3.56 (2H, s), 3.61 (2H, t, J=4.7 Hz), 4.41 (2H, s), 6.42 (1H, dt, J=1.5 Hz), 7.22 (2H, m), 7.35 (1H, d, J=8.3 Hz), 7.58 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:3]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1ccn(-c2ccc(C(=O)O)cc2)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccc(C(=O)Cl)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a suspension of 4-(3-methylpyrazol-1-yl)benzoic acid (1.84 g) in dichloromethane (25 ml) was added oxalyl chloride (1.16 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. Dichloromethane was added, the solution filtered, and the solvent evaporated under reduced pressure to yield 4-(3-methylpyrazol-1-yl)benzoyl chloride as a yellow oil (1.76 g), which was utilized without further purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:18](OC)=[O:19])=[N:16][CH:17]=1.[OH-].[Na+]>O1CCCC1.C(OCC)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([CH2:18][OH:19])=[N:16][CH:17]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cnc(Cl)cn1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
Diisobutylaluminum hydride (4.29 mL, 4.29 mmol) was added dropwise over 5 min to a solution of methyl 5-chloropyrazine-2-carboxylate (185 mg, 1.07 mmol) in tetrahydrofuran (10 mL) at −70° C. under an atmosphere of nitrogen. The reaction mixture was stirred at −70° C. for 5 min and then allowed to reach ambient temperature and stirred over night. The reaction mixture was cooled on ice and approximately 2 mL of 1 M sodium hydroxide was added dropwise while stirring. The reaction mixture was diluted with diethyl ether and stirred for 45 min at ambient temperature and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using a gradient of ethyl acetate in heptane to yield 43 mg (28%) of the title product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (d, 1 H), 8.52-8.55 (m, 1 H), 5.71 (t, 1 H), 4.64 (d, 2 H);
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (14.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution was added 60% sodium hydride (142 mg) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1-bromo-3-methyl-2-butene (0.83 ml), and the mixture was stirred at 60° C. for 60 hours. After cooled to room temperature, the mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl/acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.71 g).