Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([OH:7])=O.C(Cl)CCl.[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:13][N:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)=[O:7]
Reactant: Nc1ccc2cnccc2c1
Reactant: CN(C)CC(C(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN(C)CC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% MeOH/CH2Cl2) gave pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide. The pure compound was taken up in CH2Cl2 and HCl was added. The solvents were evaporated to give pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([CH2:38][C:39](Cl)=[O:40])=[C:33]([F:42])[CH:32]=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:39](=[O:40])[CH2:38][C:34]2[C:33]([F:42])=[CH:32][C:31]([Br:30])=[CH:36][C:35]=2[F:37])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Reactant: O=C(Cl)Cc1c(F)cc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1c(F)cc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[Li]N1C(C)(C)CCCC1(C)C.CON(C)[C:50]([C:52]1[CH:57]=[N:56][CH:55]=[CH:54][N:53]=1)=[O:51].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:50]([C:52]2[CH:57]=[N:56][CH:55]=[CH:54][N:53]=2)=[O:51])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1cnccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Cl-]
Agent: [Li]N1C(C)(C)CCCC1(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cnccn3)c(F)c2Cl)C[C@H](C)O1
Reaction time: 1 h

Procedure:
A solution of butyllithium, 2.5M in hexanes (1.718 mL, 4.30 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.802 mL, 4.73 mmol) in 15 ml THF at −78° C. The flask was removed from the −78° C. bath, and stirred at ca 0° C. for 10 minutes, then recooled to −78° C. to give a pale yellow solution of LiTMP. A solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42, 1.1 g, 2.15 mmol) 20 ml THF was cannulated into the LiTMP solution to give a yellow solution which was stirred at −78 for about 1 hour; then N-methoxy-N-methylpyrazine-2-carboxamide (1.077 g, 6.44 mmol) was added. The mixture was stirred at −78° C. After 5 hours the reaction was worked up by adding saturated NH4Cl to the −78° C. solution and extracting with EtOAc (3×). After drying over MgSO4, concentration of the mixture gave material that was purified on SiO2 using 0-10% acetone/hexanes to recover 891 mg (67%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[ClH:1].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1
Product: Cl

Procedure:
Using alkylation method A, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (200 mg, 0.45 mmol) and acetone (0.33 mL, 4.5 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine) and conversion to the HCl salt by general method B, 120 mg (55%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=3)[CH2:11][N:10](P(=O)(OCC)OCC)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=3)[CH2:9][NH:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)N1CC(c2cccc(Br)c2)(c2cccc(Br)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cccc(C2(c3cccc(Br)c3)CNC2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a solution of diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate (960 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) under N2 was added TFA (5 mL). The mixture was stirred at 20° C. for 3 h, then concentrated by rotary evaporation. The residue was dissolved in dichloromethane (20 mL) and washed with aq. NaHCO3 (30 mL). The organic layer was dried and concentrated to afford 595 mg of the title compound (1.6 mmol, 85%) as a yellow oil which was used directly to next step without purification. LC/MS: [M+1]=368.
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19]>CO>[C:17]([OH:26])(=[O:25])[CH:18]([CH:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COC(=O)C1CCN1[C@@H](C)c1ccccc1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate (0.27 g, the ratio: 2S isomer/2R isomer=52/48) and L-tartaric acid (0.15 g) were dissolved in methanol (6 ml) at room temperature. Then, the mixture was concentrated to give tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate, which was recrystallized from a mixed solvent of methyl tert-butyl ether (6 ml) and methanol (2 ml) to give crystals of tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (0.12 g, colorless crystals, yield: 28%). 1H-NMR (DMSO), δ: 7.29 (m, 5 H); 4.39 (s, 2 H); 3.79 (t, J=8.3 Hz, 1 H); 3.70 (s, 3 H); 3.47 (q, J=6.3 Hz, 1 H); 3.00 (q, J=5.9 Hz, 1 H); 2.77 (q, J=7.6 Hz, 1 H); 2.18 (m, 2 H); 1.15 (d, J=6.3 Hz, 3 H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C(N(CC)CC)C.[CH3:20][C:21]([C:23]1[C:28]([NH2:29])=[CH:27][C:26]2[O:30][CH2:31][O:32][C:25]=2[CH:24]=1)=[O:22]>C1(C)C=CC=CC=1>[C:21]([C:23]1[C:28]([NH:29][C:6]([C:4]2[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[O:1][CH:5]=2)=[O:7])=[CH:27][C:26]2[O:30][CH2:31][O:32][C:25]=2[CH:24]=1)(=[O:22])[CH3:20]
Reactant: O=C(Cl)c1coc2ccccc12
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(cc1NC(=O)c1coc3ccccc13)OCO2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Into solutions of 154 (5.0 mmol) in 200 mL of dry toluene were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (5 mmol). The mixtures were stirred at 20±2° C. for 24 h and then evaporated. The residues were washed with acetone and EtOH and then recrystallized from acetone or EtOH to form 155. Obtained as a pale-yellow solid; mp 144-145° C.; ESI-MS (Positive mode): m/z 324 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ 2.63 (3H, s), 6.19 (2H, s), 7.41-7.50 (21-1, m), 7.68 (1H, s), 7.75 (1H, dd, J=1.6, 6.8 Hz), 8.15 (1H, dd, J=2.0, 8.8 Hz), 8.27 (1H, s), 8.71 (1H, s), 12.63 (1H, s); IR (KBr): 1635, 1677 (C═O) cm−1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
Combine 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (0.304 g, 1.07 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.339 g, 2.14 mmol), and diisopropylethyl amine (0.19 mL, 1.07 mmol) in a mixture of toluene (3 mL) and dimethylsulfoxide (1 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (s)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.110 g, 0.283 mmol, 26%) as a yellow oil. Mass spectrum (APCI): m/z=389.1 (M+1).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:2]([Cl:1])=[O:4])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25° C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70° C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][C:12](=[O:14])[CH3:13].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[C:12]([O:11][C:4]1[C:3]([O:2][CH3:1])=[C:8]([I:15])[CH:7]=[CH:6][C:5]=1[O:9][CH3:10])(=[O:14])[CH3:13]
Reactant: II
Reactant: COc1cccc(OC)c1OC(C)=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To an ice-cooled suspension of acetic acid 2,6-dimethoxy-phenyl ester (1.0 g, 5.1 mmol) and silver triflouroacetate (5.1 mmol) in CHCl3 (16 ml) was added iodine (1.3 g, 5.1 mmol) and the reaction stirred for 1 hour. The crude mixture was filtered through celite to remove the precipitated silver iodide and the filtrate was washed with 10% Na2S2O3(aq). An emulsion was formed and the mixture was again passed through celite and the filtrate washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the product as a tan solid (1.57 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.9 Hz, 1H), 6.54 (d, J=8.9 Hz, 1H), 3.80 (s, 6H), 2.33 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[CH2:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: BrCCCc1ccccc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(CCCc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Bromo-3-phenylpropane (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[CH3:12][N:13]1[C:17](Br)=[C:16]([N+:19]([O-:21])=[O:20])[N:15]=[C:14]1[CH3:22]>[OH-].[Na+].C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:17]2[N:13]([CH3:12])[C:14]([CH3:22])=[N:15][C:16]=2[N+:19]([O-:21])=[O:20])[N:6]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: Cc1nc([N+](=O)[O-])c(Br)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)nc(Sc2c([N+](=O)[O-])nc(C)n2C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (3.0 g) was dissolved in an aqueous solution of sodium hydroxide (0.7 g in 100 ml water). 1,2-Dimethyl-5-bromo-4-nitro-1H-imidazole (3.9 g) dissolved in ethanol (50 ml) was added dropwise, and the mixture was stirred at room temperature 10 for 6 hours. The precipitated product was filtered, washed with water, dried and recrystallised from acetonitrile to give 3.1 g of the desired product, mp 228°-30° C.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][C:11]([C:12]#[N:13])([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17]
Reactant: N#CCc1cccc2ccccc12
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1cccc2ccccc12
Yield: 59 %

Procedure:
A mixture of 20.9 g. (0.125 mole) of the known compound (1-naphthyl)acetonitrile and 58 ml. of methyl acrylate in 60 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 19 ml. of 40% methanolic Triton B in 28 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at refux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.5 mm. to give 24.96 g. (59% yield) of dimethyl-4-cyano-4-(1-naphthyl)pimelate, having a boiling point of 209° to 219°C. The NMR spectrum of the compound confirms its expected structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=[C:2]2[CH:11]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(N)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1
Reaction time: 8 h

Procedure:
To 75 ml. of acetone was added 3.5 g. (0.20 mole) of 2-amino-4-methoxyquinoline, 4.3 g. (0.22 mole) of ethyl bromopyruvate and 3.0 g. (0.20 mole) potassium carbonate. The resulting mixture was heated at reflux for 5.5 hours and the resulting dark slurry allowed to stand at room temperature overnight. The solvent was removed by evaporation in vacuo and 200 ml. of water added to the residue to afford a gummy precipitate. This was extracted twice with 200 ml. portions of ethyl acetate, the extracts dried over anhydrous sodium sulfate, decolorized with active carbon (Darco), filtered and the solvent removed in vacuo to afford 3.5 g. of crude product. Filtration of the aqueous phase from the extraction step afforded another 1.0 g. of crude material. The combined crops were recrystallized from 100 ml. of 1:1 (by volume) isopropanol-water to afford 900 mg. of the title compound, M.P. 175°-176.5° C.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]#[CH:36]>CN(C=O)C.[Cu](I)I>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]#[C:36][C:12]1[CH:13]=[CH:14][C:9]([S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: C#CCCOCCCCCCBr
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCCC1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(C#CCCOCCCCCCBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A stirred solution of 4-bromophenyl cyclopentyl sulfone (EP683172 A1) (0.5 g) and N,N-diisopropylethylamine (3.33 ml) in DMF (15 ml) was treated with dichlorobis(triphenylphosphine) palladium (II) (50 mg) and copper iodide (13.68 mg). The solution was heated to 70° under nitrogen and a solution of 4-[(6-bromohexyl)oxy]but-1-yne (DE 3513885 A1) and N,N-diisopropylethylamine (1.66 ml) in DMF (5 ml) was added dropwise. The mixture was stirred at 70° for 19 h. The reaction mixture was cooled to room temperature, poured onto water and extracted 3 times with EtOAc. The extracts were dried (MgSO4) and evaporated in vacuo. The residual oil was purified on a silica SPE bond elut cartridge (100 g), using a gradient of 0% to 30% diethyl ether in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (280 mg). LCMS RT=3.93 min
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](Cl)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].[CH3:36]CN(C(C)C)C(C)C>CC(O)C.CS(C)=O>[C:31]([O:30][C:29]([NH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:4]1[N:3]=[C:2]([Cl:1])[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]([CH3:36])[C:6]=2[C:5]=1[F:19])=[O:35])([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC1c2c(F)c(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Cl)c2C(=O)N1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
To a flask containing a mixture of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1 g, 2.98 mmol) in 2-propanol (7 mL) was added tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (767 mg, 3.58 mmol) dissolved in DMSO (1.2 mL) followed by DIPEA (0.677 mL, 3.88 mmol). The flask was equipped with a condenser and nitrogen blanket and was lowered into a 90° C. oil bath, where the reaction mixture was allowed to stir for 16 h. The mixture was subsequently purified via preparative HPLC to give the title compound as a white solid (490 mg, 32%). [M+H] calc'd for C19H26ClFN4O3, 413. found, 413.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)CCC>[ClH:1].[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Solvent: CCCCO
Product: Cl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Temperature: 95 °C

Procedure:
A nitrogen-flushed, suitably equipped 22 L 4-neck round bottom flask is charged with 1392 g (8.78 mol, 1.0 eq.) of 5-chloro-2-nitropyridine (A2d), 1512 g (17.56 mol, 2.0 eq.) of piperazine (A2c) and 11,340 g (14,000 mL) of n-butanol. The resulting suspension is stirred and heated to 95° C. This temperature is maintained for at least 24 h or until the remaining starting material, A2d, is ≧2% (area normalization) as determined by HPLC analysis. The resulting slurry is cooled to 25° C. over 1 h. The solids are filtered through a polypropylene filter pad. The filter cake is washed twice with a total of 2267 g (2×1300 mL) of isopropyl acetate. The solids are dried at 60° C. for 16 h, to afford 1769 g (82.3%, uncorrected) of A2b as a yellow, crystalline solid, mp>230° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([Cl:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([Cl:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(Cl)sc1N
Reactant: N#Cc1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-5-chloro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine.