Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:4][CH:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[N:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Br)s1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 111.2 %

Procedure:
A solution of the product of Example 202A (300 mg, 0.8274 mmol) in anhydrous N,N-dimethylformamide (8 mL) was treated with 4-mercaptophenol (104.4 mg, 0.8274 mmol) and cesium carbonate (539 mg, 1.655 mmol) at room temperature, then heated at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in water (50 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was extracted with ethyl acetate (100 mL), and the organic extract washed with water (2×25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give the product as a golden-brown solid (416 mg, 111%).
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3]1([C:10]([Cl:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:10]([F:11])([F:12])[C:3]1([C:2]([Cl:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:17](=[O:16])[NH2:18])[CH2:5][O:4]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A sample of 15 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.055 mols) is dissolved in 75 ml methylene chloride and 7.16 grams of sodium cyanate (0.11 mols) is added. Trifluoroacetic acid, 12.6 grams (0.11 mols) is added dropwise with stirring at 23°-33° C. The temperature is then raised to 40° C. and stirring continued for 18 hours. The product is filtered and the filtrate washed with water until neutral. Vacuum stripping gives a quantitative yield of crude products which solidified partly. Filtration and recrystallization from a mixture of benzene-hexane and once from cyclohexane yields 2,2-bis(chlorodifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 56°-57° C.)
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C:10]1[CH:14]=[C:13]([C:15]#[C:16][C:17]([CH3:20])([CH3:19])[CH3:18])[S:12][C:11]=1[C:21]([OH:23])=[O:22])(C)(C)C.CCN(CC)CC.F.F.F>C1COCC1>[CH3:19][C:17]([CH3:18])([CH3:20])[C:16]#[C:15][C:13]1[S:12][C:11]([C:21]([OH:23])=[O:22])=[C:10]([N:9]([CH2:8][CH2:7][OH:6])[C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])[CH:14]=1
Reactant: CC(C)(C)C#Cc1cc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H]2CC[C@H](C)CC2)c(C(=O)O)s1
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(N(CCO)C(=O)[C@H]2CC[C@H](C)CC2)c(C(=O)O)s1
Reaction time: 1 h

Procedure:
3-[[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (273 mg) in THF (4 mL) was treated with triethylaminetrihydrofluoride (0.5 mL). After 1 hour, volatiles were removed under vacuum and the residue was purified by silica gel chromatography (0-10% Methanol:DCM) to provide 83 mg of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(2-hydroxy-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[N:50][CH:51]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:45][C:46]4[CH:51]=[N:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)=[N:3][CH:4]=[C:5]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:37][CH:36]=4)[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (503 mg, 0.820 mmol) and 5-amino-2-methoxypyridine (112 mg, 0.905 mmol) were dissolved in THF (8.0 mL) and the flask was cooled in an ice water bath while the reaction was stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran (2.5 mL, 2.500 mmol) was added via syringe, and the reaction was stirred for 40 min. Then, the reaction was treated with ice water (0.60 mL) and the reaction was diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH). The pure fractions were set aside, while the impure ones were collected, concentrated, and purified on another silica gel filter (30 mL fritted filter with about 1 inch of silica gel; DCM to 100:1 DCM/MeOH). The fractions with product were combined with the pure fractions from the first column and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (412 mg). 1H NMR (CDCl3, 400 MHz) δ 11.58 (s, 1H), 8.61 (d, J=2.35 Hz, 1H), 8.26 (d, J=2.54 Hz, 1H), 8.13 (d, J=2.35 Hz, 1H), 7.87 (dd, J=8.90 Hz, 2.64 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.61 Hz, 2H), 7.15 (d, J=8.61 Hz, 2H), 6.87 (d, J=8.61 Hz, 2H), 6.82 (d, J=8.41 Hz, 2H), 6.70 (d, J=8.80 Hz, 1H), 4.85 (s, 2H), 4.77 (s, 2H), 4.00 (s, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H). m/z (ESI, +ve ion) 718 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.N#N.[N:15]1C=CC=C[CH:16]=1.Cl>CN1CCCC1=O.[Cl-].[Na+].O.O>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:16]#[N:15])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2ccc(Br)cc2c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 2,7-dibromonaphthalene (189) (20.0 g, 0.07 mol) in 1-methyl-2-pyrrolidinone (60 mL) was purged with N2 for 10 min. CUCN (7.52 g, 0.09 mol) and pyridine (0.5 mL) were added and the mixture was heated at 180° C. under N2 for 1.5 h. After cooling to 80° C., FeCl3 (40 g), water (200 mL) and conc. HCl (50 mL) were added and the mixture was stirred for 1 h at 80° C. The mixture was cooled, brine was added, and the mixture was extracted with CH2Cl2 (×3). The organic extracts were washed with aqueous HCl (2N, x2), water, 10% aqueous NaOH, brine, and dried. Chromatography eluting with CH2Cl2/petroleum ether (1:1, then 4:1) gave 7-bromo-2-naphthonitrile (190) (6.40 g, 39%) as a cream powder. A sample was recrystallised (petroleum ether) to give colorless needles: mp 126-128° C.; 1H NMR (CDCl3) δ 8.13 (s, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.8, 1.9 Hz, 1H), 7.62 (dd, J=8.4, 1.5 Hz, 1H; 13C NMR δ 133.2, 133.0, 132.4, 130.6, 130.3, 129.6, 129.2, 126.8, 121.9, 118.7, 110.6. Anal. (C11H6BrN) C, H, N, Br.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=[O:7].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC=CC=1>C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[O:19][CH2:18][CH2:17][O:7]1
Reactant: COc1ccc(Cl)cc1C(=O)CCCCCl
Reactant: OCCO
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C1(CCCCCl)OCCO1
Yield: 95.4 %

Procedure:
A mixture of 5-chloro-1-(5-chloro-2-methoxyphenyl)-1-pentanone (2 g, 7.66 mmol), prepared as in Example 7, ethylene glycol (1.25 g, 20 mmol), 2-napthalenesulfonic acid (50 mg, 0.24 mmol) and toluene (approximately 80 mL) was heated 4-5 hours at reflux (removing water with a Dean-Stark trap) and then additional ethylene glycol (1 g, 16 mmol) was added. The mixture was heated approximately 16 hours at reflux and then washed with saturated sodium bicarbonate, water (3×) and brine (1×), dried (K2 CO3), filtered and concentrated to give 5-chloro-1-(5-chloro-2-methoxyphenyl)-1,1-ethylenedioxypentane (2.23 g, 7.31 mmol) as an oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=1.O>CN(C=O)C.C(OCC)(=O)C>[O:18]=[C:10]1[NH:11][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[N:9]1[CH:6]1[CH2:5][CH2:4][N:3]([C:29]2[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.40 g (18.6 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 11 mL (63.93 mmol) DIPEA were added to 3.40 g (18.2 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 80 mL DMF. After 3 h stirring at RT the solvent was eliminated i.vac. The residue was combined with 70 mL water and stirred for 10 min. 5 mL ethyl acetate were added and the mixture was stirred vigorously. The precipitated solid was suction filtered and dried at 40° C. in the circulating air dryer.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23].CC(C)([O-])C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2[NH:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(Nc2nc3ccc(F)cc3c3c(Cl)nccc23)c1
Temperature: 25 °C

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthytidine (Example 1, Step 5) (500 mg, 1.87 mmol) and methyl 3-amino-4-methylbenzoate (340 mg, 2.06 mmol) in THF (9.3 mL) was added sodium tert-butoxide (396 mg, 4.12 mmol). The reaction stirred at room temperature for ten minutes and was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-30% EtOAc/heptane) afforded the title compound.
Reaction SMILES: O[C:2]1[CH2:3][CH2:4][C:5](O)=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)[C:7]2=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.O>C(O)CCCC.ClCCl.C1COCC1>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=4)[C:7](=[O:20])[C:6]=3[C:5]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)C1=C(O)CCC(O)=C1C2=O
Reactant: Cc1ccc(N)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Nc2ccc(Nc3ccc(C)cc3)c3c2C(=O)c2ccc(C(=O)O)cc2C3=O)cc1
Temperature: 110 °C
Yield: 72.2 %

Procedure:
1,4-Dihydroxy-2,3-dihydro-6-carboxy-anthraquinone (300 mg) Boric acid (300 mg) and p-Toluidine (1.8 g) is mixed in n-pentanol (5 mL) and heated to 110° C. for 4 hours, the mixture is co-evaporated with 2×50 ml of water. The residue is redissolved in dichloromethane/THF (1/1) 200 ml washed with water (3×100 mL) dried (Na2SO4), filtered and concentrated. The residue is purified on a silicagel column (CH2Cl2/MeOH/NEt3; 90/9/1) resulting in 350 mg of pure material. MALDI-MS: m/z 463.2 (M+H)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>C1COCC1>[F:41][C:40]([F:43])([F:42])[CH2:39][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=c1[nH]c(-c2ccc(N3CCNCC3)cc2)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(N3CCN(CC(F)(F)F)CC3)cc2)nc2ccccc12
Yield: 93.5 %

Procedure:
To a mixture of 2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.325 g, 1.06 mmol) in THF (50 mL) was added Hünig's base (0.192 g, 1.48 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.295 g, 1.3 mmol). The reaction mixture was heated at reflux for 15 hours, concentrated, and purified by flash chromatography on silica gel, eluting with 100% CH2Cl2 to 100% ethyl acetate, to afford the title compound as an off-white solid (0.385 g, 94%). 1H NMR (300 MHz, DMSO-d6): δ 12.27 (br s, 1H), 8.10-8.14 (m, 3H), 7.76-7.82 (m, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.42-7.47 (m, 1H), 7.05 (d, J=9.1 Hz, 2H), 3.21-3.34 (m, 6H), 2.73-2.78 (m, 4H). APCI MS m/z 389 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Ph3PCH3Br (57 g) in THF (240 mL) at 0° C. was dropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowed to warm to room temperature and stirred for 1 h. After recooling to 0° C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with water, concentrated, and extracted with methylene chloride. The combined organic layer was dried over magnesium sulfate, concentrated under vacuum. The crude product was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to give the title compound as an oil (18 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:33]([C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:34]([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:34]([O:33][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=3[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2,3-dichlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (644 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 nL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:3 ethyl acetate/hexane) to give the title compound as a colorless syrup (930 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2 H), 1.47 (s, 9 H), 1.75 (m, 2 H), 1.90 (m, 1 H), 2.25 (s, 3 H), 2.73 (t, 2 H, J=2.0 Hz), 3.68 (d, 2 H, J=3.2 Hz), 4.13 (m, 2 H), 6.47 (d, 1 H, J=1.1 Hz), 6.53 (d, 1 H, J=0.4 Hz), 6.59 (s, 1 H), 7.34 (t, 1 H, J=8.2 Hz), 7.75 (m, 1 H), and 7.92 (m, 1 H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:19]#[N:20])=[N:16][C:17]=1[CH3:18].[CH3:21]N(C)P(=O)(N(C)C)N(C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:12]1[CH:13]=[CH:14][C:15]([C:19]#[N:20])=[N:16][C:17]=1[CH3:18])[CH3:21]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1ccc(C#N)nc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc(C#N)nc1C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (41 mL, 0.5M in toluene, 20.4 mmol) was added to a solution of 2-cyano-5,6-dimethylpyridine from Example 1, Step 2 (2.45 g, 18.5 mmol) and hexamethylphosphoric triamide (9.7 mL, 55.6 mmol) in dry THF (30 mL) at -78° C. After stirring 30 minutes, MeI (5.77 mL, 92.7 mmol) was added and the reaction mixture stirred 45 minutes at -78° C. Saturated aq. NH4Cl was added, the mixture was extracted with EtOAc (3×), the organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (from 15:15:70 to 20:20:60 of Et2O: CH2Cl2 : hexanes) to give 1.2 g (44%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-fluoroaniline (47 μl, 0.486 mmol) similar to Example 11 and isolated as a light brown solid (74 mg, 54%). 1H NMR (CDCl3): 8.83 (d, J=4.8 Hz, 1H), 8.47 (d, J=9 Hz, 1H), 7.88 (m, 1H), 7.44-7.30 (m, 4H), 7.18-7.14 (m, 1H), 6.92-6.86 (m, 1H), 6.80 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.[NH2:14][CH:15]1[C:20](=[O:21])[N:19]2[CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][CH:18]2[N:17]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])(=[O:40])=[O:39])[CH2:16]1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:22]2[N:19]3[C:20](=[O:21])[CH:15]([NH:14][C:11]([C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:13])[CH2:16][N:17]([S:38]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=4[Cl:48])(=[O:40])=[O:39])[CH:18]3[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[C:23]2=[O:29])=[CH:32][CH:33]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnc4ccccc4c3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 29e using 3-quinolinecarboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=713.10 (calculated, monoisotopic); measured value (M+H)+:714
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([N:28]([CH3:30])[CH3:29])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:29][N:28]([CH3:30])[C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:18]=1
Reactant: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(O)cc2)cc1

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl) -N,N-dimethyl-1H-pyrazol-3-amine obtained by Example 15 (0.83 g) and 10% Pd-C 50% wet (160 mg) in acetic acid (8 ml) was hydrogenated under H2 1 atm at room temperature for 10 hrs.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH:26]=O)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[N:28]1[N:29]=[C:30]([NH2:33])[NH:31][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH2:26][NH:33][C:30]3[NH:31][CH:32]=[N:28][N:29]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: Nc1nnc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(c1cccc2cc(C3=NCC(CCNc4nnc[nH]4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (200 mg) and 4H-1,2,4-triazol-3-amine (80 mg) in acetic acid (3 mL) was added sodium triacetoxyborohydride (200 mg) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (120 mg, yield 50%) as white crystals from a fraction eluted with ethyl acetate. melting point 195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:17]([NH:19][CH2:20][CH2:21]O)=[S:18])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC>[S:18]1[CH2:21][CH2:20][N:19]=[C:17]1[NH:16][CH:10]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccs2)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccs2)c1
Temperature: 90 °C
Yield: 0.1 %

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-1-thiophen-2-yl-ethyl]-3-(2-hydroxy-ethyl)-thiourea (0.30 g) from example 6 and diisopropyethylamine (0.16 g) in propionitrile (10 ml) was added cyanomethyl-trimethyl-phosphonium iodide (0.27 g, prepared according to Tetrahedron 2001, 57, 5451-54). The reaction mixture was heated up to 90° C. for 72 h. Extraction with ethyl acetate, washing with potassium carbonate solution and water followed by drying and evaporation of the solvent yielded 0.27 mg (95%) of the title compound as brownish oil.