Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCCCCCCCc1cccnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCCCC2CCCNC2)CC1

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 starting with 6.59 g of 4-(2,2-diphenylethenyl)piperidine, 6.4 g of 3-(10-chlorodecyl)pyridine, 3.75 g of sodium iodide, 2.65 g of anhydrous sodium carbonate, and 40 mL of dimethylformamide. The mixture was heated at 75° for 18 hours and the solvent was evaporated. The residue was partitioned between 1N sodium hydroxide and ethyl acetate and the organic layer was removed, dried over sodium sulfate, decolorized with charcoal, filtered, and evaporated to give 10.4 g (86%) of product as a colorless oil. Crystallization from hexane provided the pure 3-[10-[4-(2,2-Diphenylethenyl)-1-piperidinyl]decyl]pyridine, mp 63°-65° C. Analysis Calculated for C34H44N2 : C, 84.95; H, 9.23; N, 5.83. Found: C. 85.21; H 9.27; N, 5.84. The fumaric acid salt was obtained from acetone, mp 134°-136° C. Analysis Calculated for C34H44N2.C4H4O4 : C, 76.48; H, 8.11; N, 4.69. Found: C, 76.53; H, 8.17; N, 4.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:24][C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)[CH2:10][CH2:9]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(CN2CCN(c3ccccc3Cl)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
A solution of 8.0 g (0.031 mol) of 1-(2-chloro-phenyl)-piperazine in 300 ml of tetrahydrofuran was treated with 22 ml (0.16 mol) of triethylamine and 11.5 g (0.031 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 5.5 g (55%) of 5-[4-(2-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as beige crystals; m.p. 2:30°-235°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[CH3:17][CH:18]([CH3:30])[C:19]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20]>>[CH3:17][CH:18]([CH3:30])[C:19]([O:21][N:22]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20]
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl [(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (45) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. (1.2 g, 72%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.18-8.34 (2H, m), 8.00-8.14 (2H, m), 3.46 (3H, s), 2.86 (1 H, sept, 7.1 Hz), 1.29 (9H, s), 1.21 (6H, d, 7.0 Hz).
Reaction SMILES: [N-]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([OH:22])=O)=[CH:8][CH:7]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1>>[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([NH:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:9]3[C:4]4[C:5](=[CH:16][C:17]5[C:2]([N:3]=4)=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:6]=[CH:7][CH:8]=3)=[O:22])[CH2:32][CH2:31]2)=[O:22])=[CH:8][CH:7]=1
Reactant: c1c[n-]cn1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=C(O)c1cccc2cc3ccccc3nc12
Product: O=C(NCCCN1CCN(CCCNC(=O)c2cccc3cc4ccccc4nc23)CC1)c1cccc2cc3ccccc3nc12
Yield: 91 %

Procedure:
Similar reaction of acridine-4-carboxylic acid imidazolide with 1,4-bis(3-aminopropyl)piperazine as above, and crystallization of the crude product from CH2Cl2 /EtOAc/iPr2O, gave N1,N4-bis[(acridine-4-carboxamido)propyl]piperazine (36) (91%). 1H NMR [(CD3)2SO] δ 11.39 (t, J=5.2 Hz, 2 H, 2×CONH), 9.33 (s, 2 H, H-9), 8.73 (d, J=7.0 Hz, 2 H, H-3), 8.38 (d, J=8.5 Hz, 2 H, ArH), 8.32-8.20 (m, 4 H, ArH), 7.97 (t, J=7.8 Hz, 2 H, ArH), 7.82-7.63 (m, 4 H, ArH), 3.57 (q, J=6.0 Hz, 4 H, 2×NHCH2), 2.6-2.3 t (m, 12 H, H-piperazine, 2×CH2CH2CH2N), 1.85 (quint, J=6.7 Hz, 4 H, CH2CH2CH2). Crystallization from MeOH/EtOAc/HCl gave the tetrahydrochloride salt, mp 248-253° C. Anal. (C38H38N6O2.4HCl) C, H, N, Cl.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1[C:37](C)=[CH:36]C(C)=[CH:34][C:33]=1C(C1CCCCC1)=O>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:1]([CH:2]1[CH2:36][CH2:37][CH2:32][CH2:33][CH2:34]1)=[O:3])=[O:14])(=[O:21])=[O:22]
Reactant: Cc1cc(C)c(N)c(C(=O)C2CCCCC2)c1
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C2CCCCC2)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that cyclohexyl 2-amino-3,5-dimethylphenyl ketone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([Si:34](OS(C(F)(F)F)(=O)=O)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine a mixture of an oil dispersion of KH (40%, 1 g) in 30 mL anhydrous THF and a suspension of 2-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.2 g, 3 mmol) in 30 mL THF portionwise. Stir for 1 hour at ambient temperature, cooled to 0° C., add triisopropylsilyltrifluoromethanesulfonate (1.85 g, 6 mmol) and stir an additional 1 hour at ambient temperature. Pour the reaction into a rapidly stirring solution of saturated NaHCO3 and extract with 2×50 mL EtOAc. Combine the organic layer, dry over MgSO4 and concentrate to dryness and chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give 2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(C)c(CCNC(C)=O)c(-c3ccccc3)c2c1
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (75 mg, 0.22 mmol) in 2 mL of dichloromethane was added triethylamine (0.076 mL, 0.54 mmol), followed by acetyl chloride (0.017 mL, 0.24 mmol). After 45 minutes, the mixture was partitioned between EtOAc and 10% citric acid solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product as a colorless oil. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H22N2O3 (M+H+): 351.1703. Found 351.1681.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N+:5]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:9]=1[C:10](Cl)=[O:11])([O-:7])=[O:6]>>[OH:2][CH2:1][CH2:3][NH:4][C:10](=[O:11])[C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: NCCO
Reactant: O=C(Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: O=C(NCCO)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
In the method of preparation, one mole of ethanolamine is reacted with each mole of 2,4,6-trinitrobenzoyl chloride to produce N-(2-hydroxyethyl)-2,4,6-trinitrobenzamide which is then nitrated to form the desired N-(2-hydroxyethyl nitrate)-2,4,6-trinitrobenzamide.
Reaction SMILES: [ClH:1].[CH3:2][C@@H:3]([NH:9][CH2:10][CH2:11][P:12]([O:17]CC)(=[O:16])[O:13]CC)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>Cl>[ClH:1].[CH3:2][C@@H:3]([NH:9][CH2:10][CH2:11][P:12]([OH:17])(=[O:13])[OH:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC[C@@H](C)NCCP(=O)(OCC)OCC
Agent: Cl
Product: CCCCC[C@@H](C)NCCP(=O)(O)O

Procedure:
A solution of (R)-diethyl 2-(2-heptylamino)ethanephosphonate hydrochloride (0.19 g, 0.68 mmol) in concentrated HCl (7 mL) was heated at 90° C. for 48 hours. The reaction mixture was then evaporated to dryness and the residue triturated with acetone. The white solid was filtered and air-dried giving an 86% overall yield; m.p.=106-112° C. (no lit. value).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(Br)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4-methyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.08 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][P:13](=[O:52])([O:47]C(C)(C)C)[O:14][CH2:15][C:16]([NH:43]C(=O)C)([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=2)[CH2:27]1)[CH2:17][O:18][Si](C(C)(C)C)(C)C)(C)(C)C>C(Cl)Cl>[NH2:43][C:16]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=2)[CH2:27]1)([CH2:17][OH:18])[CH2:15][O:14][P:13](=[O:12])([OH:47])[OH:52]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(CO[Si](C)(C)C(C)(C)C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(C)=O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(c1)CC(C(N)(CO)COP(=O)(O)O)C2
Reaction time: 3 h

Procedure:
To 1-1 solution of trifluoro acetic acid and CH2Cl2 was added 14 (10 mg, 0.015 mmol). The reaction was left to stir for 3 hours. When reaction complete, product was concentrated and repeatedly co-evaporated with diethyl ether (5×10 mL) to remove TFA. The product could not be purified by column chromatography. Diethyl ether was added to bring the product into solution, followed by the addition of hexanes to precipitate out product 15. The precipitate was then washed with water to remove ionic impurities and then concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CNc1ccc([N+](=O)[O-])nc1
Yield: 80 %

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine was reacted with methylamine to give 5-methylamino-2-nitropyridine in 80% yield; 1H NMR: (DMSOd6) 2.51 (s, 3H), 7.02 (m, 1H), 7.43 (br s, 1H), 7.86 (m, 1H), 8.13 (d, 1H); Mass Spectrum: M−H− 152; which in turn was converted into 5-(N-tert-butoxycarbonyl-N-methylamino)-2-nitropyridine in 51% yield; 1H NMR: (CDCl3) 1.52 (s, 9H), 3.4 (s, 3H), 7.98 (m, 1H), 8.24 (m, 1H), 8.6 (m, 1H); which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-methylamino)pyridine in 100% yield; 1H NMR: (CDCl3) 1.42 (br s, 9H), 3.19 (s, 3H), 4.39 (br s, 2H), 6.46 (d, 1H), 7.3 (m, 1H), 7.94 (m, 1H); Mass Spectrum: M+H+ 224; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-methylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 546.
Reaction SMILES: COC1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[C:14]([NH:21][CH3:22])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(C(C)C)C(C)C)C.ClC(Cl)(O[C:36](=O)[O:37][C:38](Cl)(Cl)Cl)Cl.C1C[O:47][CH2:46]C1>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][C:13]3[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[N:21]([CH3:22])[C:46]2=[O:47])[CH:4]=[C:36]([O:37][CH3:38])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(N2Cc3cnc(SC)nc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-((3,5-dimethoxyphenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (1.1 g, 3.43 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.33 g, 10.30 mmol) in 10 mL of THF was added a solution of triphosgene (357 mg, 1.20 mmol) in 5 mL of THF at 0° C., and stirred for 1 h. The reaction mixture was then warmed to RT and stirred for another 5 h. LCMS showed the reaction was completed. The reaction mixture was quenched by water and extracted with ethyl acetate (3×15 mL). The organic layers were separated, combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (crude 1.1 g, 92%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C16H18N4O3S requires: 346. Found: 347 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:16][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1[nH]nc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Dissolve 5-methyl-3-(trifluoromethyl)pyrazole (1.00 g, 6.66 mmol) in 60% aqueous acetic acid (13 mL). Add sodium acetate (0.819 g, 9.99 mmol) and cool to 0° C. Add bromine (1.17 g, 7.33 mmol) dropwise over 10 min. Stir at 0° C. for 3 hr, then at room temperature for 18 hr. Add ethyl acetate and saturated aqueous sodium sulfite solution. Separate organics and wash one time with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.50 g, 100%). GC-MS: m/z=229 [M+].
Reaction SMILES: [CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:25][C:26](=[O:28])[CH3:27])[CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(C2CCCCC2)c(=O)n1C1CCCCC1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1cnc2c1c(=O)n(C1CCCCC1)c(=O)n2C1CCCCC1

Procedure:
1,3-Di-cyclohexyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclohexyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[C:14]1([CH2:13][N:20]2[C:5]([NH2:6])=[C:4]([C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(-c2nnn(Cc3ccccc3)c2N)c(C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl3, 300 MHz): 7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)N(C)C)c2n(c1=O)CCS2
Yield: 317.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with dimethyl aminosulfonyl chloride (76 mg, 0.528 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.08 g of the product (32% yield).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12](=[O:37])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Li+].C(#N)C.Cl>O>[C:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:12]([CH2:11][NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:38])=[O:2])=[O:37])[CH2:20][CH2:19]1)=[O:36]
Reactant: COC(=O)c1cccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)CNc1cccc(C(=O)O)c1
Yield: 87.6 %

Procedure:
A solution of 3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionyl}methylamino)benzoic acid methyl ester (6.80 g, 13.2 mmol) and lithium hydroxide (1.58 g, 65.9 mmol) in a 1:1 mixture of acetonitrile:water (25.0 mL) was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to pH 5 with aqueous hydrochloric acid (1M) and this mixture was extracted with DCM (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (5.80 g, 87% yield) as an off-white powder.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:33]([NH:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)=[O:34])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Reaction time: 72 h

Procedure:
3-(Indan-5-ylamino)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (Table A, Example A599; 0.08 g, 0.3 mmol) in dichloromethane (10 mL) was was treated with 3-fluorophenyl isocyanate (0.038mg, 0.3 mmol). The mixture was shaken on an orbital shaker for 72 hours. Saturated aqueous sodium bicarbonate (5 mL) was added, shaking continued for 5 minutes and the organic layer transferred directly onto a column of silica gel. Elution with dichloromethane gave the product as a yellow solid.
Reaction SMILES: O=[C:2]([CH3:23])[CH2:3][C:4]1[C:5](=[O:22])[N:6]([CH3:21])[CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[CH:24]([NH:27][CH:2]([CH3:23])[CH2:3][C:4]1[C:5](=[O:22])[N:6]([CH3:21])[CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COc1ccc2c(c1)CCC1CCN(C)C(=O)C(CC(C)=O)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)C(=O)C(CC(C)NC(C)C)=C21

Procedure:
The mixture of 4.7 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, 8.88 ml of isopropylamine, 3.45 ml of 5 N methanolic hydrochloric acid, 1.02 g of sodium cyanoborohydride and 75 ml of methanol is stirred and refluxed overnight. An additional 1.02 g of sodium cyanoborohydride is added and refluxing is continued for another day. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid, the methanol is evaporated and the solution washed with diethyl ether. It is rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide, extracted with diethyl ether, the extract dried and evaporated. The residue is recrystallized from hexane, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 118°-120°.