Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][S-:32].[Na+]>CO>[OH:25][C:24]1[C:4]2[O:3][C:2]([S:32][CH3:31])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2c(SC)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
To a suspension of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (22 mg, 0.046 mmol) in methanol (1 ml) in a screw cap vial was added sodium thiomethoxide (16 mg, 0.23 mmol) and the resulting orange solution was shaken for 20 minutes during which time the reaction became homogeneous. The crude reaction mixture was concentrated onto silica and chromatographed (silica gel, eluent=2:1 hexanes:ethyl acetate) to give the product as a resin (10 mg, 54%) that could be crystallised by standing in hexanes in the freezer overnight; 1H NMR (CDCl3) δ 7.08 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 5.73 (br s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.84 (s, 6H), 2.66 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:24][C:22]1[N:23]=[C:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][NH:8]3)=[CH:12][CH:13]=2)[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Nc3nc(Br)cn4ccnc34)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cn2ccnc2c(Nc2ccc3cc[nH]c3c2)n1

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-indole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate; the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indol-6-yl)-amine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:10]=[CH:11][CH:12]=1.[C:14](OCC)(=[O:16])C>>[O:13]1[C:3]2[C:4]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[CH2:10][CH2:11][CH2:12][C:2]=2[NH:1][C:14]1=[O:16]
Reactant: Nc1cccc2cnccc2c1=O
Reactant: CCOC(C)=O
Product: O=c1[nH]c2c(o1)-c1ccncc1CCC2
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
N,N'-carbonyldiimidazole (4.86 g, 0.030 mole) was added portionwise to a stirred, aqueous solution of 6-aminocyclohepta[1,2-c]pyridin-5-one (4.20g, 0.0169 mole) maintained at 2° C. After stirring for 30 minutes, ethyl acetate (~300 ml) was added and the mixture stirred until it reached room temperature. The organic phase was extracted with water (150 ml), washed with brine, and dried (MgSO4). The light brown solid isolated after solvent removal was heated (180° C.) for 35 minutes, cooled to room temperature, then quenched with water (200 ml). The aqueous mixture was stirred for about 12 hours and the brown residue collected by filtration, after washing with ethyl acetate (50 ml), then methylene chloride (50 ml), was recrystallized from aqueous ethanol (50%, ~50 ml) to give 0.29 g of the desired product, m.p. >285° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=2)[C:9]1=[O:34].[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[K]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:39]3[C:35](=[O:45])[C:36]4=[CH:44][CH:43]=[CH:42][CH:41]=[C:37]4[C:38]3=[O:40])[CH:23]=2)[C:9]1=[O:34]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(S(C)(=O)=O)nc32)c1
Agent: [K]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A solution of 250 mg (0.44 mmol) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(methanesulfonyloxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of dimethylformamide was treated with 111 mg (0.6 mmol) of potassium phthalimide and the mixture heated at 90° C. for 1 hour then cooled and evaporated. The residue was partitioned between 30 ml of dichloromethane and 30 ml of water. The organic phase was collected, dried over magnesium sulfate, filtered and evaporated to afford 270 mg (99%) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =618].
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: O=C1NCCc2ccsc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccsc2C1=O
Yield: 50.6 %

Procedure:
Using analogous reaction conditions as described in example 1, 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (I-5d: 130 mg, 0.849 mmol) was reacted with 3-iodo-4-methyl-pyridine (185 mg, 0.849 mmol), 1,4-dioxane (5 mL), copper iodide (16 mg, 0.0849 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.04 mL, 0.254 mmol) and potassium phosphate (538 mg, 2.54 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 105 mg of the product (51.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Sc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 91.6 %

Procedure:
Using the method of Example 3, Step A, 3-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(3-chlorophenylthio)pyridine (1.48 g, 92% yield) as an oil. 1H NMR (CDCl3) δ 8.16 (d, 1H), 7.56 (s, 1H), 7.39-7.49 (m, 3H), 6.94 (s, 1H), 6.88 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N[CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([CH3:25])[CH:13]=1)CCC>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([CH3:25])[CH:13]=1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: COCCN
Product: CCOC(=O)COc1ccc(CNCCOC)cc1C

Procedure:
Prepared using 2-methoxyethylamine (1.4 mL, 16.2 mmol) and the synthetic procedure described for Intermediate 7. Purification of the crude product by SCX SPE (5×10 g) loading and washing with EtOH and then eluting product with 5% NH3 in EtOH, and removal of the solvent in vacuo yielded the title compound as a brown oil (1.8 g).
Reaction SMILES: [Na].[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[CH:14][N:15]=2)[CH:12]=1)(OCC)=O.[CH:16]1([N:21]2[C:25]([NH2:26])=[C:24]([C:27]([NH2:29])=[O:28])[C:23]([CH2:30][CH3:31])=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([N:21]2[C:25]3=[N:26][C:2]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([CH:13]=[CH:14][N:15]=5)[CH:12]=4)=[N:29][C:27](=[O:28])[C:24]3=[C:23]([CH2:30][CH3:31])[NH:22]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)c1ccc2nccn2c1
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4nccn4c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 60 h
Yield: 61.1 %

Procedure:
Sodium metal (0.21 g, 9.2 mmol) was dissolved in ethanol (25 ml) and 6-carboethoxyimidazo[1,2-a]pyridine (1.75 g, 9.2 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.02 g, 4.6 mmol) were added. The reaction mixture was heated to reflux for 24 hours, cooled to room temperature and stirred for 60 hours. The solvent was removed in vacuo, the residue was dissolved in water (100 ml) and the solution was neutralized by the addition of concentrated HCl. A precipitate was obtained which was collected by filtration through a glass frit. The solid was recrystallized from ethanol and washed with ether to afford 0.98 g (62%) of 1-cyclopentyl-3-ethyl-6-(6-imidazo[1,2-a]pyridinyl)-pyrazolo[3,4-d]pyrimidin-4-one as white crystals, m.p. >300° C. when dried for 18 hours at 120° C. in high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:35]1[C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:38][C@@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72]([C@@H:74]([NH:78][C:79](=[O:82])[O:80][CH3:81])[CH:75]([CH3:77])[CH3:76])=[O:73])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)[N:49]=2)[NH:36]1>CN(C=O)C>[CH3:7][C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:8]([N:36]1[C@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:51]=[CH:52][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72](=[O:73])[C@@H:74]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH:75]([CH3:77])[CH3:76])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:54][CH:55]=3)[N:49]=2)[CH2:38][C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:35]1)=[O:10]
Reactant: COC(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](C)C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)OCCCO2
Reaction time: 0.05 h
Yield: 29 %

Procedure:
To a stirred solution of N-[(methyloxy)carbonyl]-L-alanine (22.5 mg, 0.153 mmol, prepared according to the procedure provided in WO2003055474) in DMF (2 mL) were added TEA (15.5 mg, 0.153 mmol) and HATU (58.2 mg, 0.153 mmol). After ˜3 min stirring, methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Example 19) (100 mg, 0.153 mmol) was introduced. After stirred for additional 2 hrs at rt, the reaction mixture was directly loaded to RP HPLC, eluting with 5 to 80% acetonitrile/water (0.2% NH3H2O (conc.)), to give methyl ((1S)-1-methyl-2-{(3S)-3-[4-(4′-{2-[(2S)-1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl}-2-oxoethyl)carbamate (Example 5) as solid (36 mg, yield: 29%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.04-11.11 (m, 2H) 7.37-8.02 (m, 8H) 7.18-7.36 (m, 2H) 5.60 (br. s., 2H) 5.17-5.40 (m, 2H) 3.17-4.73 (m, 14H) 2.79-3.19 (m, 1H) 2.45-2.81 (m, 1H) 2.29-2.45 (m, 1H) 1.49-2.29 (m, 8H) 1.22-1.47 (m, 3H) 0.73-1.16 (m, 6H). HRMS: (M+H)+ calcd: 783.3830; found: 783.3832.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C@:5]([CH2:14][OH:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.[CH3:29][C:30]([CH3:43])([O:32][C:33]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34])[CH3:31].Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:3]2[C:4](=[O:16])[C@@:5]([CH2:14][O:15][C:37](=[O:38])[C@@H:36]([NH:35][C:33]([O:32][C:30]([CH3:29])([CH3:43])[CH3:31])=[O:34])[CH:40]([CH3:42])[CH3:41])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:6]([CH3:7])[C:2]2=[O:1])=[CH:18][C:19]=1[C:25]([F:28])([F:26])[F:27])#[N:22]
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(CO)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@@]1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
A solution of 0.45 g of (S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 0.33 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid, 0.185 g of 4-dimethylamino pyridine and 0.45 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 70 mL of dichloromethane is stirred for 1 hour then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired compound.
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.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[N:43][CH:42]=1)=[O:40]>>[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:39]([C:41]2[CH:46]=[CH:45][N:44]=[N:43][CH:42]=2)=[O:40])[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)c1ccnnc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccnnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyridazine-4-carboxamide
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[C:11](=[O:13])=[O:12].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(F)cccc1Br
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(Br)ccc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 56.0 mL, 89.6 mmol) to a stirred solution of diisopropylamine (13.7 mL, 96.9 mmol) in tetrahydrofuran (150 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then cooled again to −78° C. A solution of 1-bromo-3-fluoro-2-methoxybenzene (15.28 g, 74.5 mmol) in tetrahydrofuran (40 mL) is added dropwise to the previous solution over a period of 30 min. to give an amber solution. After stirring this solution at −78° C. for 1.5 h, dry ice (˜125 g) is added, and the resulting mixture is allowed to warm slowly (˜1 h) to room temperature with stirring as it degasses. The reaction mixture is acidified to pH ˜1 by addition of a 5% aqueous solution of hydrochloric acid (˜500 mL), and the product is extracted with diethyl ether (6×100 mL). The combined organic extracts are washed with brine (100 mL), and the product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL). The combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL) and acidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL). The product is extracted with diethyl ether (3×200 mL), and the combined organic extracts are washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 12 as an off-white solid. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. mp 168-170° C. 1H NMR (CD3OD): δ 3.92 (d, JH-F=1.0 Hz, 3H, OCH3), 7.44 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, H-5), 7.55 (dd, JH-H=8.5 Hz, JH-F=7.0 Hz, 1H, H-6). 19F{1H} NMR (CD3OD): δ −127.0 (s). 13C{1H} NMR (CD3OD): 662.1 (d, JC-F=4.5 Hz, OCH3), 121.5 (d, JC-F=8.5 Hz, C-1), 123.6 (d, JC-F=2.0 Hz, C-4), 128.0 (s, C-6), 129.0 (d, JC-F=4.5 Hz, C-5), 147.7 (d, JC-F=13.5 Hz, C-3), 157.1 (d, JC-F=263.5 Hz, C-2), 166.3 (d, JC-F=3.0 Hz, CO2H). HRMS m/z calcd for C8H679BrFNaO3 270.9382 ([M+Na]+). Found 270.9377.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>CCO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To a solution of ethyl (1RS,3RS)-1,3-di-(3,4-methylenedioxyphenyl)indane-2-carboxylate (75 mg, 0.17 mmol) in EtOH (20 ml) was added NaOH (0.10 g, 2.5 mmol). The resulting mixture was allowed to stir at room temperature for 3 d, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. The mixture was then heated at reflux for 36 h, allowed to cool and was concentrated under reduced pressure. To the residue was added concentrated HCl, and the solid which formed was collected by filtration and dried. The solid was triturated with boiling hexanes to afford the title compound as a white solid (50 mg, 73%); m.p. 182°-185° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([NH:28][NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 0.29 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.10 g of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.30 g of 4-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)cn1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 6-methyl-pyridin-3-ylamine with 4-tert-butyl-benzene-sulfonyl chloride
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH2:64][NH2:65])[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:65][CH2:64][C:58]2[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:56]([O:55][CH3:54])[CH:57]=2)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(I)c2n1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 322.6 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (5 g, 15.72 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (10.43 g, 23.58 mmol) in anhydrous DMF (250 mL) at room temperature under a nitrogen atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.23 mL, 28.3 mmol) and the reaction mixture was stirred for 2.5 hours. (3,4-Dimethoxyphenyl)methanamine (20 mL, 94 mmol) was added and the mixture was warmed to 40° C. for 3 hours. The reaction mixture was evaporated in-vacuo and the resulting oil partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated in-vacuo to yield as a semi-crystalline yellow oil (23.7 g). The residue was absorbed onto Florosil, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 4 column volumes. Appropriate fractions containing only the desired material by LC-MS analysis were combined and evaporated in-vacuo to yield the title compound as a pale yellow foam (4.58 g).