Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.CO>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[C:18]1[CH:36]=[CH:37][C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1cc(CN2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39.5 %

Procedure:
To a reaction vessel charged with 1-methyl-1H-pyrazole-4-carboxaldehyde (84.5 mg, 0.77 mmol) was added a solution of tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 300 mg, 0.76 mmol) in dichloromethane (7 ml) and N,N-dimethylformamide (0.5 ml). tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate may also be prepared according to the process described in Method 4 below. Acetic acid (50 μl, 0.87 mmol) was added and the reaction mixture allowed to stir at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (250 mg, 1.18 mmol) was then added and reactions allowed to stir for a further 76 hours, before being diluted with methanol and poured directly onto an SCX-2 cartridge (10 g). The cartridge was washed through with methanol (80 ml) before eluting the products with a 2M solution of ammonia in methanol (50 ml). The relevant fractions were evaporated to dryness and the resultant residue redissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (1 ml). This mixture was stirred at ambient temperature for 2 hours before diluting with dichloromethane and pouring onto an SCX-2 cartridge (5 g). The cartridge was washed with methanol (20 ml) then products eluted with a 2M solution of ammonia in methanol (20 ml). The ammoniacal fraction was evaporated to dryness and the resultant residue was purified by flash chromatography on silica, eluting with 10% methanol in dichloromethane, to afford the title compound (117 mg, 40%); NMR Spectrum: (DMSO d6) δ 1.70 (m, 4H), 2.01 (t, 2H), 2.57 (m, 1H), 2.95 (m, 2H), 3.38 (s, 2H), 3.81 (s, 3H), 4.86 (s, 2H), 6.60 (m, 1H), 6.78 (m, 1H), 6.97 (m, 1H), 7.18 (m, 1H), 7.31 (s, 1H), 7.37 (d, 2H), 7.57 (s, 1H), 7.91 (d, 2H), 9.56 (s, 1H); Mass Spectrum: M+H+390.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:15]1[NH:19][C:18]2[S:20][C:21]([Cl:23])=[CH:22][C:17]=2[CH:16]=1)([OH:14])=O.[NH2:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:35][CH2:36][S:37][CH3:38])[C:26]1=[O:39].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:23][C:21]1[S:20][C:18]2[NH:19][C:15]([C:12]([NH:24][CH:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][S:37][CH3:38])[C:26]3=[O:39])=[O:14])=[CH:16][C:17]=2[CH:22]=1
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Reactant: CSCCN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 39.6 %

Procedure:
EDCI (915 mg, 4.77 mmol) was added to a suspension of 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (801 mg, 3.97 mmol), 3-amino-1-[2-(methylthio)ethyl]-3,4-dihydroquinolin-2(1H)-one (Method 16; 1.40 g, 3.97 mmol) and 1-hydroxybenzotriazole (537 mg, 3.97 mmol) in DCM (60 mL) and the reaction stirred for 18 hours. The reaction was evaporated and the residue was partitioned between DCM (100 mL) and water (25 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:EtOAc (9:1)) to afford the title compound (660 mg, 40%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15]C3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(CNC2N=CN=C(O[C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])C=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])[CH:12]=[CH:11][N:10]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of N-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine (Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 ml) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.31 mL, 0.11 mmol) and the mixture stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated first with 3:1 isopropyl ether/EtOAc and then CH2Cl2 to give the title compound (32 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J=12.6 Hz), 7.61 (dd, 3H, J=9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s, 3H), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s, 2H); MS (ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH3:11])[CH:3]=1.F[C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18]2[CH:19]=[N:20][CH:21]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CN
Reactant: O=C(O)c1ccncc1F
Product: COc1cc(Cl)ccc1CNc1cnccc1C(=O)O
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 4-chloro-2-methoxy-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.10 (s, 1H), 8.00 (br s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.24 (d, 1H, J=8.1 Hz), 7.11 (d, 1H, J=1.9 Hz), 6.96 (dd, 1H, J=8.0, 1.9 Hz), 4.47 (s, 2H), 3.87 (s, 3H). [M+H] calc'd for C14H13ClN2O3, 293, 295. Found 293, 295.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of 4-bromophenol (3.30 g, 20.0 mmol), triphenylphoshine (5.25 g, 20.0 mmol) and N-(2-hydroxyethyl)morpholine (2.51 g, 19.1 mmol) in THF (30 mL) was added diisopropyl azodicarboxylate (3.94 mL, 20.0 mmol) over 10 min. The reaction mixture was stirred at room temperature for 2 h, and then hydrochloric acid (50 mL, 1N) was added. The mixture was extracted with diethyl ether (2×50 mL), and then the pH was adjusted to 10 with 2N aq. NaOH. The mixture was then extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford N-(4-bromophenoxyethyl)morpholine (4.54 g, 15.9 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][C:24]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)([CH3:27])[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C.C1COCC1>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:26][CH2:25][C:24]([CH3:27])([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH3:23])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: CC(C)(CN)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCC(C)(C)N3CCOCC3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 156: step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 2-methyl-2-morpholin-4-yl-propylamine (0.023 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (25%–50% EtOAc/Hx) yielded the title compound. 1H-NMR (CDCl3): δ 8.70 (d, 1H, J=2.1 Hz), 8.08 (d, 1H, J=2.1 Hz), 8.02 (s, 1H), 6.82 (t, 1H, J=4.1), 3.90 (s, 3H), 3.76 (t, 4H, J=4.1), 3.37 (d, 2H, J=4.1), 2.64 (s, 3H), 2.57 (t, 4H, J=4.5), 1.59 (s, 3H), 1.13 (s, 6H). ESI-MS (m/z): Calcd. For C20H26BrN3O5S3: 565.54 (M+H); found 564.0, 565.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH:35]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)([CH3:37])[CH3:36].C(N(CC)CC)C.ClCCl.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH:35]([CH3:37])[CH3:36])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CC(C)OCCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3CCOC(C)C)CC2)(c2ccccc2)C1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.52 g, 1.10 mmol), (1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.61 g, 1.09 mmol), and triethylamine (0.65 mL, 4.66 mmol) in acetonitrile (15 mL). Heat to 80° C. After 22 hours, evaporate in vacuo to give a residue. Partition the residue between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated ammonium hydroxide, 95/5/0.05 to give the title compound: Rf=0.29 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide, 90/10/0.1).
Reaction SMILES: [C:1]1([C:7]2[S:8](=[O:21])(=[O:20])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:11](=O)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1([CH3:31])[O:30][C:28](=[O:29])[CH2:27][C:25](=[O:26])[O:24]1>N1CCCCC1>[C:14]1([C:9]2[S:8](=[O:21])(=[O:20])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][C:11](=[C:27]3[C:28](=[O:29])[O:30][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:26])[CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCNCC1
Product: CC1(C)OC(=O)C(=C2C=C(c3ccccc3)S(=O)(=O)C(c3ccccc3)=C2)C(=O)O1
Reaction time: 8 h

Procedure:
A mixture of 1.32 gm (5 mmol) of the Compound of Example 1, 0.80 gm (5.5 mmol) of Meldrum's acid, 10 ml of alcohol and 5 drops of piperidine was refluxed for 1 hour, allowed to stand overnight and the yellow solid titled compound was collected. The solid was recrystallized from alcohol (mp 214°-215° C.).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13](O)([C:25]([F:28])([F:27])[F:26])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C:13]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 9 h
Yield: 98.5 %

Procedure:
1.15 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 2.3 g of toluene, 0.49 g of acetic anhydride, 29 mg of 4-dimethylaminopyridine and 0.38 g of pyridine were fed, and stirred for 9 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 5 ml of toluene, iced water and 0.6 ml of concentrated hydrochloric acid. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 1.09 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[Cl:11][C:12]1[N:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:20]([O:42][CH3:43])=[N:21][N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:13]=1.CC(=CC)C>O.CC(O)(C)C.C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([C:18]([OH:6])=[O:19])[C:15]2[C:20]([O:42][CH3:43])=[N:21][N:22]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:14]=2[CH:13]=1
Reactant: O=P([O-])(O)O
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium chlorite (120 mg, 1.322 mmol) and sodium dihydrogen phosphate (159 mg, 1.322 mmol) were dissolved in water (1.5 ml). A suspension of 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 100 mg, 0.220 mmol) in tBuOH (1.5 ml) and THF (1.5 ml) and 2-methyl-2-butene (233 μl, 2.203 mmol) was then added to the aqueous mixture. The resulting solution was stirred at rt overnight. The reaction contents were concentrated in vacuo, resuspended in water, the solid was filtered, and washed with water. The solids were triturated in MeOH to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid. MS: [M+H]+ m/z 470.
Reaction SMILES: S1C(S)=CC2C=CC=CC1=2.[H-].[Na+].ClC[C:15]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=O.C1C[O:30]CC1>>[NH:17]1[CH2:15][CH2:18][CH2:19][C:20](=[O:30])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]1=2
Reactant: C1CCOC1
Reactant: O=C(CCl)N1CCCc2ccccc21
Agent: Sc1cc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude compound 72 (0.71 g, 4.3 mmol) was dissolved in 40 mL of dry THF under N2, stirred for 30 min at RT and then cooled down to 0° C. NaH (60% in mineral oil, 0.224 g, 5.5 mmol) was added to the ice-cold solution which became a yellowish suspension. The formed suspension was stirred for 40 min at 0° C. and then 2-chloro-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (0.89 g, 4.3 mmol) was added as a solution in 4 mL of dry THF. The reaction mixture was stirred at RT for 16 h. The work-up, the same as for compound 5, gave crude material which was purified by flash chromatography (CH2Cl2/EtOAc) giving 0.56 g of the crude product. Pumping the crude product under high vacuum over P4O10 at 45° C. for 4 h removed the co-crystallized EtOAc to yield the desired product 73 (36%): MS: m/z+ 340.1 [M+H]+; Anal. Calcd (found) for C19H17NOS2: C, 67.22 (67.18); H, 5.05 (5.11); N, 4.13 (4.08); S, 18.89 (18.70).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]4=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]4[CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)OC1(C)C
Reactant: Fc1ccccc1I
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4F)cc3)C2=N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 1.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (18.0 mg) was added to a suspension of 1-fluoro-2-iodobenzene (69.0 mg), 9-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (60.0 mg) and cesium carbonate (152 mg) in toluene (3 mL) and EtOH (3 mL) and the mixture was stirred at 80° C. under nitrogen for 24 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and dissolved in THF (dry) (5 mL) and MeOH (5 mL) and platinum(IV) oxide (6.00 mg) was added and the mixture was stirred at room temperature under hydrogen for 2 days. The insoluble solid was removed by filtration through Celite-pad (eluted with EtOAc). Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and crystallized from THF/IPE to give the title compound (0.80 mg) as colorless crystals.
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:5].C1C=CC(CCN2N=CC3C4N(C(N)=NC2=3)N=C(C2OC=CC=2)N=4)=CC=1.[3H]CCC(N1C(=O)N(C(CC[3H])[3H])C(=O)C2NC(C3CCCC3)=NC1=2)[3H]>>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: Nc1nc2c(cnn2CCc2ccccc2)c2nc(-c3ccco3)nn12
Agent: [3H]CCC([3H])n1c(=O)c2[nH]c(C3CCCC3)nc2n(C([3H])CC[3H])c1=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1.5 h

Procedure:
Perform assays in deep well 96 well plates. Total assay volume is 200 μl. Add 50 μl compound dilution buffer (total ligand binding) or 50 μl CGS 15923 working solution (A2a non-specific binding) or 50 μl NECA working solution (A1 non-specific binding) or 50 μl of drug working solution. Add 50 μl ligand stock ([3H]-SCH 58261 for A2a, [3H]-DPCPX for A1). Add 100 μl of diluted membranes containing the appropriate receptor. Mix. Incubate at room temperature for 90 minutes. Harvest using a Brandel cell harvester onto Packard GF/B filter plates. Add 45 μl Microscint 20 (Packard), and count using the Packard TopCount Microscintillation Counter. Determine IC50 values by fitting the displacement curves using an iterative curve fitting program (Excel). Determine Ki values using the Cheng-Prusoff equation.
Reaction SMILES: [CH2:1]([C:3]([OH:21])([CH2:19][CH3:20])[C@H:4]([NH:11][C:12](=[O:18])OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCCCCC>[CH2:19]([C:3]1([CH2:1][CH3:2])[O:21][C:12](=[O:18])[NH:11][C@H:4]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:20]
Reactant: CCC(O)(CC)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)N[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of (R)-tert-butyl (2-ethyl-2-hydroxy-1-phenylbutyl)carbamate (1.2 g, mmol) in dry THF (5 mL) in a 25 mL round bottom flas was cooled to 0° C. To the solution was added potassium t-butoxide (1.46 g, 13.04 mmol) in one portion, and the mixture was allowed to slowly warm to room temperature and stirred for 2 hours. After completion of reaction (monitored by TLC, TLC eluent: 30% EtOAc in hexane), the solvent was removed under reduced pressure, the reaction was quenched in saturated NH4Cl solution. The product was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to afford 0.6 g (66.6%) of (S)-5,5-diethyl-4-phenyloxazolidin-2-one colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.38-7.33 (m, 3H), 7.28-7.25 (m, 2H), 5.63 (s, 1H), 4.71 (s, 1H), 1.80-1-2 (m, 2H), 1.38-1.28 (m, 1H), 1.06 (t, J=7.2 Hz, 3H), 0.72 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:9]=[O:10].[OH-].[K+].Cl.NO>O>[OH:10][CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: C=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Reaction time: 68 h
Yield: 14.5 %

Procedure:
A 2-L, three-necked flask equipped with a mechanical stirrer, thermometer, condenser, and nitrogen-inlet bubbler was charged with uracil (185.0 g, 1650 mmol) (Aldrich), paraformaldehyde (61.50 g, 2050 mmol as formaldehyde) (Aldrich), and a solution of potassium hydroxide (86.9%, 59.95 g, 928.5 mmol) (Aldrich) in water (1.445 L). The mixture was stirred at 50–52° C. for 68 hours. TLC analysis indicated complete reaction. After concentration at 60° C./14 mm Hg to a volume of ca. 500 mL, the residue was diluted with acetone (500 mL). The resulting precipitate was collected by filtration, washed with acetone, and dried by suction, then at 50° C./25 mm Hg to give crude 5-(hydroxymethyl)-1,3-dihydropyrimidine-2,4-dione (250 g) as a white solid. The combined mother liquor and washes were concentrated to a volume of ca. 100 mL and a solution of hydroxylamine hydrochloride (27.52 g, 396.0 mmol, Aldrich) in water (100 mL) was added. The resulting precipitate was collected by filtration, washed with acetone, and dried by suction to give second crop of crude 5-(hydroxymethyl)-1,3-dihydropyrimidine-2,4-dione (34 g) as a white solid. The two lots were combined (244 g, 4% overweight) and used directly in the next step.