Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[S:3]([CH:6]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH2:7][CH:8](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:32]1([C:38]2[CH:43]=[CH:42]C=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39]=2[OH:50])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[F:27][C:26]([F:28])([F:29])[S:23]([CH:6]([S:3]([C:2]([F:31])([F:30])[F:1])(=[O:5])=[O:4])[CH2:7][C:8]1[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:39]([OH:50])[C:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:43][CH:42]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: CC#N
Product: O=S(=O)(C(Cc1ccc(-c2ccccc2)c(O)c1-c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reaction time: 9 h
Yield: 97 %

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (157.3 mg, 0.28 mmol) was added to an acetonitrile (0.25 ml) solution of 2,6-diphenylphenol (61.9 mg, 0.25 mmol) at room temperature. After 9 hours of stirring, it was purified by Kugelrohr distillation (120° C./3 mmHg) thereby obtaining 4-(2,2-bis(trifluoromethylsulfonyl)ethyl-2,6-diphenylphenol [1n] with a yield of 97% (130.7 mg, 0.24 mmol).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[C:37]([F:40])([F:39])[F:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[C:37]([F:38])([F:40])[F:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: OC(c1ccccc1Cl)C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F

Procedure:
In a similar manner as described for example B31, 1.53 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.0 g of 1-(2-chlorophenyl)-2,2,2-trifluoroethanol, 2.43 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.68 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#N)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC1C(CN)=NC=C(C)C=1[O:20]C>>[CH3:1][C:2]1[C:3]([CH2:11][OH:20])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)cnc(CN)c1C
Reactant: COc1c(C)cnc(C#N)c1C
Product: COc1c(C)cnc(CO)c1C

Procedure:
A process for the preparation of compounds of formula I ##STR1## in which X is the radical OH or Cl, by the catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine, subsequent reaction of the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and, if desired, chlorination to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine, and the novel intermediate 3,5-dimethyl-4-methoxy-2-aminomethylpyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 65 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.), methyl bromoacetate (2 eq.) in DMF was heated for 24 hours at 65° C. and then was cooled to room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the desired ester as a brown oil. MS (ES) C27H29FN4O5 requires 508. Found: 509 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][OH:13])=[N:10][CH:11]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:15])=[O:13])=[N:10][CH:11]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1ccc(OCCCCl)cn1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OCCCCl)cn1

Procedure:
The mixture of 30.0 g of 5-(3-chloropropoxy)-2-pyridine methanol and 1,200 ml of water is stirred vigorously at 5°. To this mixture is added 31.0 g of potassium permanganate in several portions during which time the temperature of the mixture rises to 25° and then the mixture is stirred at 25° for 30 minutes. Then the mixture is filtered, the precipitated manganese dioxide washed with several portions of water, the washing is combined with the filtrate and the resulting aqueous solution is adjusted to pH 5. Then the aqueous solution is evaporated to a small volume and the concentrate is extracted several times with ethyl acetate. After the extracts are combined, the combined ethyl acetate solution is washed and dried. The solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2-pyridinecarboxylic acid melting at 120°-121°.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O)(C)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: Fc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 90 %

Procedure:
1-Thiomorpholino-3-piperazino-5-fluoro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-fluoro-isoquinoline by heating for 30 hours with piperazine in diphenyl ether at 200°C. M.p. 213°-215°C (from isopropanol); yield: 90% of theory.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1([O:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][OH:15]>C(Cl)Cl>[Cl:4][CH:13]1[CH2:12][CH2:11][CH2:10][C:9](=[N:14][OH:15])[C:8]1([O:7][CH3:6])[O:16][CH3:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC1(OC)CCCCC1=NO
Solvent: ClCCl
Product: COC1(OC)C(=NO)CCCC1Cl

Procedure:
A solution of 1.66 parts sulfuryl chloride dissolved in 8 parts dry methylene chloride was added under a dry nitrogen atmosphere over a 15-minute period to a stirred solution of 1.73 parts 2,2-dimethoxycyclohexanone oxime dissolved in about 8 parts dry methylene chloride. After the addition was completed, the contents were stirred for an additional hour and then treated by the procedure in Example 1 to yield 1.5 parts of 3-chloro-2,2-dimethoxycyclohexanone oxime.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[C-:16]#[N:17].[K+]>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:6][N:5]=[C:4]([CH3:15])[C:3]=2[CH2:2][C:16]#[N:17])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CC#N
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (10.74 mmol) in DMF (30 mL) was added potassium cyanide (0.729 g, 10.74 mmol), and the reaction was stirred at 65° C. overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=O>CO>[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1/[CH:45]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1
Reactant: O=Cc1ccccc1Br
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: Brc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
To a solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (3.0 g, 6.3 mmol) in methanol (18 mL), DBU (1.4 mL, 9.5 mmol) was added dropwise and 2-bromobenzaldehyde (0.81 mL, 7.0 mmol) was further added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was washed with methanol (15 mL) and dried under reduced pressure to obtain (E)-3-[2-(2-bromophenyl)vinyl]-1H-indazole (0.22 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[CH:12]=[C:11]([N:22]3[CH2:25][CH2:24][CH2:23]3)[N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>N1C=CC=CC=1>[CH3:21][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:12]=[C:11]([N:22]3[CH2:23][CH2:24][CH2:25]3)[N:10]=[C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=4)=[CH:3][CH:4]=3)[N:14]=2)[NH:20][N:19]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)Nc2ccc(Sc3nc(Nc4cc(C)n[nH]4)cc(N4CCC4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
2-(4-Aminophenylthio)-6-(azetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.57 mmol) was taken up in pyridine (2 mL) and m-toluoyl chloride (0.187 mL, 1.42 mmol) was added dropwise at room temperature. After 15 minutes the reaction mixture was concentrated in vacuo and the residue taken up in methanol (3 mL). Sodium methoxide (25% w/w solution in MeOH, 1 mL) was added and the resulting cloudy solution stirred at room temperature for 15 minutes. The reaction mixture was purified directly by chromatography (silica, 5-100% EtOAc-petrol gradient elution) to give the title compound (89 mg, 33%) as a white solid. 1H NMR: (400 MHz, DMSO) 1.99 (3H, brs), 2.31 (2H, qn), 2.42 (3H, s), 3.88 (4H, t), 5.39 (1H, brs), 5.67 (1H, vbrs), 7.43-7.46 (2H, m), 7.54 (2H, d), 7.73-7.76 (2H, m), 7.91 (2H, d), 9.23 (1H, brs), 10.42 (1H, s), 11.67 (1H, brs). ES+472.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26](O)=[O:27])[CH:19]=[CH:18]2.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26]([O:1][N:2]1[C:3](=[O:12])[C:4]3[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=3[C:6]1=[O:7])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)ON3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of N-hydroxyphthalimide (7.1 g, 43.4 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 10 g, 43.4 mmol) and N,N-dimethylaminopyridine (DMAP, 5.3 g, 43.4 mmol) in CH2Cl2 (70 mL) and DMF (30 mL) at 0° C. was treated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (8.3 g, 43.4 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under vacuum. The residue was then dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to give the title compound (7.6 g, 47% yield) as a white solid. Mp 110-112° C. 1H NMR (300 MHz, d6-DMSO) δ 7.80-8.06 (m, 7H), 7.50 (dd, J=1.7 and 8.5 Hz, 1H), 7.32-7.37 (m, 1H), 7.20 (dd, J=2.5 and 9.0 Hz, 1H), 4.50 (q, j=7.1 Hz, 1H), 3.89 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 171.2, 161.8, 157.5, 153.0, 135.5, 133.6, 133.5, 129.3, 128.4, 128.2, 127.3, 126.1, 126.0, 124.0, 119.0, 105.8, 55.2, 41.8, 18.6. Mass spectrum (API-TIS) m/z 376 (MH+), 393 (MNH4+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:19].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[ClH:19].[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Agent: Cl
Product: CC(=O)Oc1ccc(SC2CCCc3cccnc32)cc1
Yield: 49 %

Procedure:
A mixture of 4.0 g (15.6 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 40 ml of acetic anhydride was heated under reflux for 2 hours. A reagent was then removed under reduced pressure and the residue was subjected to flash chromatography (Kieselgel 60; 5% ethyl acetate in dichloromethane). The thick yellow oil thus obtained was treated with ethereal hydrogen chloride to yield 3.4 g (49%) of 8-(4-acetoxyphenylthio)-5,6,7,8-tetrahydroquinoline hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1.[NH4+:18].[OH-]>C1COCC1.CO>[NH2:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide (500 mg) in THF/MeOH (1:1, 15 ml) was added NH4OH (4.5 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between EtOAc/H2O and the aq phase was extracted by EtOAc (3×). The organic phase was then combined, washed with brine, dried over Na2SO4 and concentrated to give 4-(aminomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:24][N:23]([CH3:25])[CH2:22][C@@H:21]2[OH:26])=[C:15]([N+:27]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:49](OC2C=CC=CC=2)=[N:50][C:51]#[N:52])=CC=1>C(O)(C)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[CH:33]=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[C@@H:21]([OH:26])[CH2:22][N:23]([CH3:25])[CH2:24]3)/[C:49](=[N:50]/[C:51]#[N:52])/[NH:27][C:15]=2[CH:14]=1
Reactant: CN1C[C@H](Nc2ccc(/C=C3\c4ccccc4COc4cc(F)ccc43)cc2[N+](=O)[O-])[C@@H](O)C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of (3S,4S)-4-(4-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-2-nitrophenylamino)-1-methylpyrrolidin-3-ol (3.10 mmol, 1.43 g) in isopropanol (85 mL) and triethylamine (9.3 mmol, 1.30 mL) add 5% Pt/C (420 mg) and hydrogenate at 50 psi for 1.5 h. Filter through a plug of diatomaceous earth and wash with isopropanol (50 mL). Add diphenyl cyanocarbonimidate (3.1 mmol, 0.74 g) and stir at room temperature overnight, then heat to reflux for 3 h. Remove the solvent and purify the residue by column chromatography eluting with a gradient from 0% to 20% methanol in methylene chloride to give the title compound as a light brown solid (955 mg, 57%). [α]D23+13.8 (c 0.17, CH3OH); ESI MS m/z 482 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH2:29][C:28]#[CH:27])[N:12]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and propargylbromide were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 300.1, found 300.2
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:25][N:26]([CH:30]1[CH2:36][CH2:35][CH2:34][NH:33][C:32]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:31]1=2)[C:27](=[O:29])[CH3:28]>ClCCl>[C:1]([N:33]1[CH2:34][CH2:35][CH2:36][CH:30]([N:26]([CH2:25][C:24]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:22]([C:21]([F:20])([F:49])[F:50])[CH:23]=2)[C:27](=[O:29])[CH3:28])[C:31]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Reaction time: 15 h
Yield: 71.7 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by dimethylaminopyridine (cat.) and pyridine (0.3 mmol) to a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.05 g, 0.11 mmol) in dichloromethane (1 ml). After stirring for 14-16 h dilute with dichloromethane (2 mL) and wash with 5% HCl (2 mL), water (2 mL) and brine (2 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This afford the title compound (0.04 g, 89%) as a colorless solid: MS (ES+): 507 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([N:9]([CH3:15])[CH3:10])(=[O:7])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(N)=CC(=O)CS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 1.9 ml of methyl iodide in 50 ml of dimethylformamide was treated with 6 g of finely ground dry potassium carbonate and the mixture was thereupon stirred intensively at room temperature under argon for 6 hours. The organic salts were then filtered off, rinsed with methylene chloride and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water and methylene chloride, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The solid product was recrystallized from isopropanol, whereby there were obtained 2.5 g of 4-amino-N,N-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 137°-140°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=1>>[CH3:27][N:25]1[CH:26]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[C:23]([CH3:28])=[N:24]1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: Cc1nn(C)cc1N
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Nc1cn(C)nc1C

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 4-amino-1,3-dimethylpyrazole to give N-(1,3-dimethylpyrazol-4-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (CDCl3) 2.06 (s, 3H), 3.62 (s, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 5.07 (s, 2H), 6.58 (m, 1H), 6.61 (d, 1H), 7.17 (d, 1H), 7.38 (m, 6H), 7.79 (s, 1H); Mass Spectrum: M+H+ 366; which material was hydrogenated to give N-(1,3-dimethylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 2.09 (s, 3H), 3.44 (s, 2H), 3.68 (s, 3H), 3.7 (s, 3H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 7.76 (d, 1H), 9.23 (br s, 1H), 9.3 (br s, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:11]=1)[C:7]#[N:8].[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:35])[CH2:33]Br)=[C:27]([Cl:36])[CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C>[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:35])[CH2:33][O:19][C:17]2[CH:18]=[C:13]([O:12][C:10]3[CH:9]=[C:6]([C:7]#[N:8])[CH:5]=[C:4]([Cl:3])[CH:11]=3)[CH:14]=[C:15]([Cl:20])[CH:16]=2)=[C:27]([Cl:36])[CH:26]=1)(=[O:24])=[O:23]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(Cl)c2)c1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Nc3ccc(S(N)(=O)=O)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid sodium hydride (18 mg, 0.458 mmol) was added in portions to a DMF solution of 128 mg (0.458 mmol) of 3-chloro-5-(3-chloro-5-hydroxyphenoxy)benzonitrile (B-4). This was stirred for 30 minutes at room temperature and then 75 mg (0.229 mmol) of solid N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (A-3) was added. The reaction was then stirred at 50° C. for 14 hours until an LC/MS analysis indicated that the reaction was complete. The product was purified by a reverse phase hplc column on a Gilson unit. Clean fractions were combined and concentrated in vacuo to give the desired product 2-1 as an amorphous solid. HRMS: measured 525.9788; theoretical 525.9793. 1H NMR (DMSO-d6): 4.91 (s, 2H), 6.80 (m, 1H), 6.89 (m, 1H), 7.03 (m, 1H), 7.48 (s, 2H), 7.54 (m, 1H), 7.60 (m, 1H), 7.77 (d, 1H), 7.85 (s, 1H), 7.91 (s, 1H), 8.02 (d, 1H), 9.87 (s, 1H).
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[CH:17]=[CH:16][N:15]=[CH:14][C:12]=3[NH:13][C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Agent: Cl
Product: O=C(c1ccc(Cl)cc1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 68 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with p-chlorobenzoyl chloride as described in Example 2 to obtain 1-(p-chlorobenzoyl)-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 68%; m.p.: 215° C.