Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmols), tert-butyl(1S)-1-(3-hydroxyphenyl)ethylcarbamate (13.4 g, 56.5 mmols), potassium carbonate (9.4 g, 68 mmols) and N,N-dimethylformamide (150 ml) was stirred at 100° C. for 1 hour. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography, and the resulting crystal was re-crystallized from hexane/ethyl acetate to give a crystal of tert-butyl(1S)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.7 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]([NH2:51])=[O:50])N=1>C(Cl)Cl>[C:49]([CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[N:17]1)(=[O:50])[NH2:51]
Reactant: NC(=O)Cn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(N)=O)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, the crude 2-(3-amino-pyrazol-1-yl)-acetamide (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-(1-Carbamoylmethyl-1H-pyrazol-3-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (38 mg, 28%) as a white solid: ESI-LRMS m/e calcd for C20H25ClN4O4S [M+] 452.13, found 453.2 [M+H+]; 1H NMR (400 MHz, CD3OD) δ ppm 1.11-1.27 (m, 2H, CH2), 1.46-1.92 (m, 8H, 4×CH2), 2.07-2.27 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.85 (dd, J=8.6, 6.4 Hz, 1H, CH), 4.73 (s, 2H, NCH2), 6.55 (d, J=2.4 Hz, 1H, Ar), 7.53 (d, J=2.4 Hz, 1H, Ar), 7.59 (dd, Jo=8.2, Jm=1.5 Hz. 1H, Ar), 7.71 (d, Jm=1.5 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25](O)=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:25](=[O:26])[C@H:18]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:10]([C@H:11]([CH2:13][CH3:14])[CH3:12])[NH:9][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.1 g of t-butoxycarbonylisoleucylhistidine hydrochloride and 6.3 g of prolylserine methyl ester hydrochloride are dissolved in 100 ml of dimethylformamide. The solution is cooled to 0° C. To the solution is added 3.4 g of 1-hydroxybenzotriazole, 2.8 ml of N-methylmorpholine and 7.6 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for two hours at 0° C. and then is allowed to stand at 4° C. for sixteen hours. Dicyclohexylurea is filtered from the reaction mixture and is washed with acetone. 300 ml of ethyl acetate is added to the solution. The solution is extracted three times with 300 ml saturated potassium bicarbonate and two times with 300 ml of brine. The product is extracted into 300 ml of 2 M potassium bisulfate. The acidic solution is neutralized with potassium carbonate. The slightly basic aqueous solution is extracted three times with 300 ml of methylene chloride. The methylene chloride solution, which contains the product, is dried over sodium sulfate, filtered and stripped of solvent under vacuum. The residue is dissolved in 100 ml of ethyl acetate. The solution is added to 1 liter of cold rapidly stirring Skellysolve B. The white precipitate was filtered and dried under vacuum at 55° C. to afford the product t-butoxycarbonylisoleucylhistidylprolylserine methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)=[CH:6][CH:7]=2)=[CH:37][CH:36]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc(/C=C/[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d above (1 g), 4-methoxyphenyl boronic acid (0.61 g), tetrakistriphenylphosphine palladium (0) (0.232 g), and potassium carbonate (0.832 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (20 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 50% ethyl acetate in hexane as eluant to afford the title compound (0.62 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:23]1([CH2:22][C:13]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: N#CC1CCCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(Cc2ccccc2)CCCCCC1
Yield: 55.8 %

Procedure:
Obtained by operating as in example 27b, from 195 mmoles of lithiated diisopropylamine (25.6 g (252.9 mmoles) of diisopropylamine treated with 122 ml (195 mmoles) of n-butyllithium 1.6M in hexane) in 300 ml of dry tetrahydrofuran, 24 g (195 mmoles) of commercial cycloheptanecarbonitrile and 24.6 g (195 mmoles) of benzyl chloride. After distillation, there is obtained 23.2 g (yield=55.8%) of a yellow viscous liquid. b.p.16 =190°-7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:5]=1[OH:8]
Reactant: COCOc1cc(O)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCOc1cc(O)c(Br)cc1F
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4-Fluoro-3-methoxymethoxy-phenol from example A1 (6.89 g; 40.0 mmol) is dissolved in dry di-chloromethane (160.0 mL). The stirred solution is cooled to −15° C. N-bromosuccinimide (7.12 g; 40.0 mmol) is added in small portions over one hour. After complete addition the reaction mixture is stirred for another 30 min at −15° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N+:23]#[C-:24])[CH:17]=1>>[N+:23]([CH2:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)#[C-:24]
Reactant: [C-]#[N+]Cc1cccc(Br)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: [C-]#[N+]Cc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 1-bromo-3-(isocyanomethyl)benzene (117 mg, 0.60 mmol) according to the general procedure IC to give 109 mg (71%) of a pale yellow oily product after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.27 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.51-7.44 (m, 4H), 7.36 (t, J=7.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.19 (d, J=8.3 Hz, 2H), 3.73 (s, 2H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.2, 131.8, 131.2, 131.0, 130.2, 129.2, 128.4, 127.6, 124.5, 120.8, 117.5, 90.3, 88.1, 51.7, 35.4, 30.8, 23.4; ESI-MS m/z 326.1 (M+Na+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:21])([CH3:20])[N:4]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)=O.CC(C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:7]2[O:6][C:5]([CH3:21])([CH3:20])[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]2[CH2:2][F:1])=[CH:13][CH:12]=1)#[CH:15]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a THF (20 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-((trimethylsilyl)ethynyl)phenyl)oxazolidine-3-carboxylate (1.65 g, 4.1 mmol) that had been cooled to −78° C. (dry ice/acetone) is added tetra-n-butyl-ammonium fluoride (5 ml of 1M solution in tetrahydrofuran, 5 mmol). The reaction is stirred at −78° C. for 1 hour. The reaction mixture is quenched (while at −78° C.) by the addition of of saturated aqueous ammonium chloride solution (2 ml). The reaction mixture is warmed to room temperature and diluted with ethyl acetate (50 ml). The organic phase is washed with water (3×25 ml), dried over sodium sulfate and the volatiles removed by evaporation to give the title product (1.35 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:11](=[O:22])[CH2:12][CH2:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O>C(O)C>[CH3:21][C:14]12[CH2:13][CH2:12][C:11](=[O:22])[N:7]3[C:15]1=[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=13)[CH2:17][CH2:18][CH2:19]2
Reactant: NNc1ccccc1
Reactant: COC(=O)CCC1(C)CCCCC1=O
Solvent: CCO
Product: CC12CCCc3c1n(c1ccccc31)C(=O)CC2

Procedure:
A mixture of phenylhydrazine (1.08 g), 1-methyl-2-oxocyclohexanepropionic acid methyl ester (1.98 g), described in Example 6, and ethanol is heated at reflux for 3 hr. The mixture is evaporated to dryness keeping the temperature of the mixture at about 40° C. The residue is heated with 200 ml of 10% aqueous sulfuric acid at reflux temperature for 1 hr. The mixture is cooled and extracted with ether. The extract is washed with 10% sodium hydroxide and brine, and then evaporated. The residue is subjected to chromatography on silica gel. Elution with benzene gives 1,2,3,3a,4,5-hexahydro-3a-methyl-6H-pyrido[3,2,1-jk]carbazol-6-one (6, R1 = CH3, R2 and R3 = H, m = 3 and n = 2) mp 93°-95° C. Further elution with 5% ethyl acetate in hexane as the eluant gives the title compound, nmr (CDCl3) δ 1.27 (s, 3H), 3.6 (s, 3H), 7.0-7.6 (m, 4H), 7.9 (b, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15]>CN(C)C=O.O>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2)[CH:6]=[CH:7][NH:8]1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2cc[nH]c(=O)c2c1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
To a suspension of 7-bromoisoquinolin-1(2H)-one (70 g, 0.31 mol) in N,N-dimethylformamide (1 L) was added copper cyanide (56 g, 0.63 mol). The reaction was heated to 180° C. for 2 hours. The reaction was cooled to room temperature and was diluted with water (1 L). The solution was extracted with ethyl acetate (3×). The organics were dried over sodium sulfate, filtered, and concentrated to give crude 1-oxo-1,2-dihydroisoquinoline-7-carbonitrile (37 g). This crude material was taken up in ethanol (500 mL) and 1 N aqueous sodium hydroxide (400 mL) was added. The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to ˜2 with 1 N aqueous hydrochloric acid. The solids were collected by filtration, rinsed with water, and dried under vacuum to give the title compound (35 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.15 (br. s., 1H), 11.49 (s, 1H), 8.75 (s, 1H), 8.17-8.14 (m, 1H), 7.75 (d, 1H), 7.34-7.29 (m, 1H), 6.62 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C(N(CC)CC)C.[SH2:23]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[S:23])[NH2:2]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(N)=S)cc1
Reaction time: 72 h

Procedure:
First, 2.00 g of 2-cyano-4′-methyl-1,1′-biphenyl was dissolved in a mixture of 15, ml of methanol and 4.18 g of triethylamine, and hydrogen sulfide gas was bubbled thereinto at room temperature to the point of saturation. After keeping at room temperature for 3 days, the solution was kept at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate containing 1% hydrochloric acid. The organic layer was concentrated to give 2.18 g of 2-thiocarbamoyl-4′-methyl-1,1′-biphenyl. Yield, 92%; m.p., 111-115° C.; m/z, 227
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH:35]=[C:36](OS(C(F)(F)F)(=O)=O)[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>COCCOC.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>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH:35]=[C:36]([C:14]1[CH:13]=[CH:12][C:11]([N:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]3)=[CH:16][CH:15]=1)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1(C)OB(c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
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: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)CC1CC2
Yield: 37.8 %

Procedure:
1-Methanesulfonyl-4-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)phenyl]-piperazine (1.8 g, 4.9 mmol) and 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]-oct-2-ene-8-carboxylic acid tert-butyl ester (3.8 g, 5.9 mmol) are placed in 35 ml of DME and 6.14 ml of a 2N aqueous solution of K2CO3. After degassing with nitrogen, tetrakis(triphenylphosphine)palladium (1.136 g, 0.98 mmol) is added. The reaction medium is refluxed for 6 h. After hydrolysis and addition of ethyl acetate, the reaction medium is filtered on Celite®. The aqueous phase is then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaHCO3 and than with water. After drying over MgSO4 and concentration to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane ranging from 0% to 20%. 0.83 g of 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][C:11]([O-])=O.[Na+].ClCC=O>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[CH:11]=[CH:10][NH:8][C:6]=2[N:7]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: CC(=O)[O-]
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a mixture of 2,4-diamino-6-hydroxypyrimidine (20.0 g, 159 mmol) and NaOAc (26.0 g, 317 mmol) in H2O (300 mL) at 65° C. was added a solution of chloroacetaldehyde (22.0 mL, 50% in H2O, 173 mmol) in H2O (22 mL) dropwise for 90 min. The mixture was stirred at 65° C. for an additional 2 h and cooled to room temperature. The reaction mixture was concentrated in vacuo to one third of its original volume and stored at 4° C. for 16 h. The light pink precipitates were filtered, washed with an ice cold H2O (5 mL), and dried under high vacuum for 16 h. The precipitates were placed in Soxhlet extractor and refluxed with methanol (200 mL) for 24 h. The methanol was concentrated to give 13.3 g (56%) of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of Compound 58 (5 g, 25 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 7.3 g (96%) of white solids. 1H NMR (DMSO-d6): δ 5.45 (s, 2H), 7.14–7.17 (m, 3H), 7.44 (m, 2H), 7.64 (dd, J=1.7, 8.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.C(Cl)(=O)C>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:3](=[O:5])[CH3:2])[CH2:29][CH2:28]2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CC(=O)Cl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and acetyl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone. MS (M+H)+, 388.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:28]
Reactant: CI
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 5.00 g (0.012 mol) of 5-bromo-2-(4-methoxy-benzenesulfonylamino)-3-methyl-benzoic acid methyl ester (U.S. Pat. No. 5,776,961) in 40 mL of DMF was added 0.604 g (0.015 mol) of 60% sodium hydride. The resulting mixture was stirred at room temperature foe 0.5 h and then 1.2 ml (0.018 mol) of iodomethane was added. The reaction was then stirred for 15 h and then diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether and the resulting white solid was collected by filtration and dried in vacuo to provide 4.45 g (86%) of the N-methyl sulfonamide. Electrospray Mass Spec 429.8 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]([CH:17]=[O:18])[NH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[F:22]C1C=C(C2NC=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1.CN1C2=CNC(C3C=C(C=CC=3)C#N)=C2C(=O)N(C)C1=O>>[F:22][C:13]1[CH:12]=[C:11]([C:10]2[NH:9][C:8]([CH:17]=[O:18])=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Agent: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C=O)c2n(C)c1=O

Procedure:
The title compound was prepared in a similar manner to 1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Na), starting from 5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (prepared in a similar manner to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) using the appropriate halo compound in step 3 and omitting Step 1.