Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH3:28])[N:20]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[N:20]=3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cn1nc(CCl)c2ccccc21
Product: Cn1nc(CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21

Procedure:
180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 145.39 mg (0.78 mmol) of 3-chloromethyl-1-methyl-1H-indazole were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 250 mg of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl-isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12f and 4-bromoanisole
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]=O.O>C(O)C>[CH:1]1([N:7]2[C:8]3[C:9]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:10]=4[N:11]=[CH:12][C:13]=3[CH:14]([CH3:15])[O:16][CH2:28]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=O
Reactant: CC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Solvent: CCO
Solvent: O
Product: CC1OCN(C2CCCCC2)c2c1cnc1c2ccn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol (9 mg, 0.02 mmol) and aqueous formaldehyde (35 wt %, 0.3 mL, 4 mmol) in ethanol (1 mL) were stirred at 75° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting pale yellow oil (9 mg) containing the title compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([SH:8])[CH:7]=1.[C:10](=S)=[S:11].C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:10]([SH:11])[S:8][C:6]=2[CH:7]=1
Reactant: Nc1ccc(Cl)cc1S
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
4-Chloroaniline (14.3g, .112mol) was dissolved in 30 mL of glacial acetic acid and added slowly to S2Cl2 (75 mL) cooled in a CH2OH--ice bath. The reaction was stirred for 15 hours at room temperature. It was then increased to 50° C. for 4 hours and then to 78° C. for 3 hours. The reaction was cooled and 100 mL of dry benzene added. The mixture was stirred for 30 minutes and filtered. The product was washed two times with 25 mL of benzene. The green/yellow substance was added to 250 mL of crushed ice and 150mL of H2O and stirred 3 hours. The purple product was filtered and added with vigorou stirring to cooled 5% NaOH. The reaction was stirred to one hour, filtered and the pH adjusted to 7 with dilute acetic acid. The product precipitated and was isolated by vacuum filtration to yield 10.7g of 5-chloro-2-aminobenzenethiol (59.8% yield): m.p. 70° -72° C.; NMR(DMSO-d6) δ7.3-6.7(m, 3H); 5.7-4.7(s, 3H); mass spectrum, m/e 159(M calcd. 159.6) 5-Chloro-2-aminobenzenethiol(15g, 0.095mol) was dissolved in 5% NaOH and 17mL of carbon disulfide were added. The reaction was stirred 15 hours at room temperature and heated at reflux for 3 hours. The pH of the reaction was adjusted to 6 with dilute acetic acid and filtered to yield 16.9g of 6-chloro-2-mercaptobenzothiazole (89.4% yield): m.p. 243° -246° C. (decomposes); NMR(DMSO-d6) δ11.5(s, lH); 8.0-7.2(m, 3H)
Reaction SMILES: [Cl:1]Cl.[C:3]([NH2:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[Cl:1][NH:11][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Reactant: NC(=O)c1ccccc1
Solvent: O
Product: O=C(NCl)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A stream of gaseous chlorine in introduced at a speed of about 33 g/h into a suspension of 111 g of 99.5% pure benzamide (0.91 mol) in 700 ml of water maintained at a temperature of 15°-20° C. After 2 h and 15 min 75 g of chlorine (1.05 mol), controlled by weighing, have been absorbed. The mass is stirred for another 15 min at a temperature of 20° C., then the chlorinated product obtained is filtered off and is washed with water until the hydrochloric acid has disappeared. 140 g of N-chlorobenzamide (yield 98.9%) containing 21.87% of active chlorine, corresponding to a titer of 96%, are obtained.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C:27]1=[O:35])=O)(C)(C)C>O>[NH2:25][C@H:26]1[C@@H:29]([CH3:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C:27]1=[O:35]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: C[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O

Procedure:
Following the procedure of example 2D, but substituting (3S-cis)-3-[(t-butoxycarbonyl)-amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt for (3S-trans)-3-[(t-butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt yields the title compound, melting point 200° C., dec., [α]D21 =-61.8°[c=5.1, water].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (72.6 mg, 0.224 mmol) in tetrahydrofuran (4.0 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (46.3 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (68 mg, 0.672 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, washed with ethyl acetate/hexane to give the title compound (64 mg, 64%) as a brown powder.
Reaction SMILES: [CH2:1](OCC)C.FB(F)F.[CH:10]1[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[NH:13][S:12](=[O:25])(=[O:24])[N:11]=1.C[Li]>C1COCC1>[CH3:1][CH:10]1[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[NH:13][S:12](=[O:25])(=[O:24])[NH:11]1
Reactant: CCOCC
Reactant: O=S1(=O)N=Cc2ccc3cccnc3c2N1
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1NS(=O)(=O)Nc2c1ccc1cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Ethoxyethane—trifluoroborane (1:1; 32.3 μl, 0.26 mmol) was added dropwise to a solution of 4H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 406 (60 mg, 0.26 mmol) in dry THF (3 ml) under an atmosphere of N2. The mixture was stirred at room temperature for 1 h and then cooled to −78° C. Methyllithium (1.6M in Et2O; 1.61 ml, 2.57 mmol) was added dropwise and the mixture was stirred −78° C. for 1 h. The reaction was quenched with sat NH4Cl (2 ml) at -78° C. and the mixture was warmed to room temperature. The mixture was extracted with EtOAc and the residue was purified by preparative HPLC (acidic conditions 1) to give the title compound (18 mg, 28%).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=2)[NH:25]1)[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH:24]1[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:37])[CH:30]=2)[NH:25]1)[CH3:11]
Reactant: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of 60% sodium hydride (356 mg, 8.9 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (1 g, 8.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A47. A solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.27 mmol) and 1,1′-carbonyldiimidazole (412 mg, 2.54 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B47. Solution B47 was added to Solution A47 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (100 mg, 15%) as a white solid: MS (ESI) M+1=498.1.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:31]1[N:36]([CH3:37])[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=1>O1CCCC1>[CH3:37][N:36]1[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=[C:31]1[N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[CH2:18]1
Reactant: CN1CCN(c2ccc(C3CCCNC3)cc2)CC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C3CCCN(c4nc(-c5ccncc5)cc(=O)n4C)C3)cc2)CC1
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine trihydrochloride salt (0.4 g, 1.08 mmol) and triethylamine (0.6 g, 5.93 mmol) in tetrahydrofuran (10 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.22 g, 0.99 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 3-methyl-2-(3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidin-1-yl)-6-(piridin-4-yl)-3H-pyrimidin-4-one (0.31 g, 0.70 mmol; 71%) as white crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)O1.[NH2:19][C:20]1[C:29]2[C:24](=[C:25](Br)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]>>[NH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]
Reactant: CCc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Product: CCc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 4-amino-8-bromo-7-ethylcinnoline-3-carboxamide. ESI-MS m/z [M+H]+ 333.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([C:21]([NH:20][CH3:19])=[O:22])[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: CNC(=O)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CNC(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperidine-4-carboxylic acid methylamide (Example 25) using General Procedure B-3 yielded 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-methylpiperidine-4-carboxamide.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+]>O>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:15][CH2:14][CH2:13][Br:12])[CH:2]=[CH2:3]
Reactant: BrCCCBr
Reactant: C=CCc1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cc(F)ccc1OCCCBr

Procedure:
To a stirred and refluxing mixture of 162 parts of 2-allyl-4-fluorophenol, 363 parts of 1,3-dibromopropane in 700 parts of water is added dropwise a solution of 56 parts of sodium hydroxide in 175 parts of water. Upon completion, the whole is stirred and refluxed for 8 hours. After cooling, the aqueous layer is separated and extracted with chloroform. The extract is dried over magnesium sulfate, filtered and evaporated. The oily residue is distilled twice, yielding 142 parts of 3-allyl-4-(3-bromopropoxy)fluorobenzene; bp. 160° -170° C. at 14 mm. pressure.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([OH:18])=[O:17].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([O:18][CH2:1][CH3:2])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 16.09 g (78 mmol) of 1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride was added a suspension of 15.4 g (71 mmol) of 4-carboxybenzyl bromide in 100 ml methylene chloride and then 4.9 g (106.5 mmol) of absolute ethanol and 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml of methylene chloride was added to the reaction mixture and mixture heated at reflux for 2 hours. The mixture was allowed to cool to room temperature and the resultant white precipitate removed by filtration. The filtrate was washed with water, dried (MgSO4) and then concentrated in-vacuo to give the title compound as a colorless oil which crystallized on standing. PMR (CDCl3); δ 1.39 (3H, t, J~7.2 Hz), 4.38 (2H, q, J~7.2 Hz), 4.50 (2H, s), 7.45 (2H, d, J~7.7 Hz), 8.03 (2H, d, J~7.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([CH2:23][C:24]#[N:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#CCC(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (2 ml) was added to a stirred solution of benzoylacetonitrile (0.145 g) in ethanol (8 ml) and the resulting solution heated under reflux for 6 hours. Glacial acetic acid (1 ml) was added and the resulting mixture heated under reflux for a further 6 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g), using dichloromethane as eluant, followed by reverse phase HPLC on C18 silica, using acetonitrile:methanol:water (50:10:40) as eluant, to afford the title compound as a white solid, m.p. 141.5-142.5° C. δ(CDCl3): 3.60 (br.s,2H), 6.08 (s,1H), 7.30-7.45 (m,3H), 7.80 (s,2H), 7.80-7.85 (m,2H). MS (thermospray): M/Z [M+H] 372.1; C16H10Cl2F3N2 +H requires 372.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH3:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:13][CH3:12])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=CCCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNCCCc1ccc(Cl)cc1

Procedure:
Intermediate 21 (0.35 g), methylamine (2.07 ml, 2M solution in tetrahydrofuran) were stirred together in tetrahydrofuran (15 ml) for 5 min, before sodium triacetoxyborohydride (1.32 g) was added. The reaction was stirred for 18 h, before water (10 ml) was added, and the tetrahydrofuran was removed in vacuo. The resulting slurry was washed with ethyl acetate (3×50 ml), and then basified to pH 11 using sodium hydroxide (2M). The aqueous was then re-extracted with ethyl acetate (3 ×50 ml). These combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate (1 g), and the solvent removed in vacuo to yield the title compound as a colourless oil (0.13 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:25][CH2:26]Br>O>[CH3:12][O:11][C:8]1[C:9]2[O:10][CH2:25][CH2:26][O:1][C:2]=2[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc2c1OCCO2
Temperature: 100 °C
Yield: 42.9 %

Procedure:
In a vial was placed 0.5 g (3.0 mmol) of 3,4-dihydroxy-5-methoxybenzaldehyde, 414 mg (3.0 mmol) of K2CO3, and 3 mL of anhydrous DMF. To this mixture was added, 0.56 g (3.0 mmol) of 1,2-dibromoethane dropwise. The vial was sealed and heated to 100° C. overnight. Water was added to the reaction and the mixture was extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the crude product. The material was purified by silica gel chromatography using 50% ethyl acetate/hexane as the eluent to afford 0.25 g (43%) of the pure aldehyde 10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[N:6]=1)=[O:4].[F:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2B(O)O)=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:25]2[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]2[CH:37]=[CH:38][C:18]([F:17])=[CH:19][CH:20]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Reactant: COC(=O)c1cccc(C2=C(Br)CCC2)n1
Product: COC(=O)c1cccc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)n1

Procedure:
Prepared by general procedure 3 but using 6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl) -benzoic acid ethyl ester and 2-(4-fluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH:16]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.OS([O-])=O.[Na+].CCOC(C)=O>C(Cl)Cl>[O:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:14]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1=O
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
To a solution of ethyl (2RS,3SR)-3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindane-2-carboxylate (130 mg, 0.32 mmol) in CH2Cl2 (3 ml) under an argon atmosphere was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol). The resulting mixture was stirred for 2.5 h. Aqueous NaHSO3 and EtOAc were added, and the mixture was stirred for 5 min. The aqueous phase was separated and extracted with EtOAc, and the combined organic extracts were washed successively with aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel to afford the title compound (110 mg, 85%).