Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[CH:9]=[C:8]3[NH:11][C:12](=O)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:12]1[NH:11][C:8]2=[CH:9][C:10]3[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[CH:6]=[C:7]2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(=O)[nH]c3cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(Cl)nc3cc21
Temperature: 25 °C

Procedure:
7,7-Dimethyl-5-pentyl-5,7-dihydro-1H,3H-imidazo[4,5-f]indole-2,6-dione (3.80 g) is suspended in phosphoryl chloride (39 ml) and heated under reflux for 5 h. After re-cooling to RT the dark reaction mixture is poured into ice-water (1 l) and heavily stirred. The aqueous phase is made alkaline and extracted with CH2Cl2. The combined organic layer is washed with brine, dried over MgSO4 and evaporated to give F1 (2.85 g) as a dark oil.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(Cl)c6)c5)c4c3)cn2)CC1
Yield: 26 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) propan-2-ol (124 mg, 0.181 mmol) was hydrolyzed with lithium hydroxide (38 mg, 0.908 mmol) in THF/methanol/water (2/2/1 mL) to yield 30 mg (26.0% yield). 1H NMR (CD3OD, 300 MHz): δ 8.54-8.53 (d, 1H), 8.45-8.41 (d, 1H), 8.41-8.40 (d, 1H), 8.21 (s, 1H), 8.07-8.03 (dd, 1H), 7.957-7.955 (d, 1H), 7.68 (s, 1H), 7.34-7.30 (m, 3H), 7.24-7.21 (dt, 1H), 7.11-7.08 (d, 1H), 5.42 (s, 2H), 4.30-4.20 (m, 1H), 3.26-3.08 (m, 2H), 1.27-1.25 (d, 3H). MS: m/z=528.4 (M+1), HPLC: 97.22% in method A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:18])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:18][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(Oc2ccccc2)c1CBr
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 2-methyl-3-phenoxy-benzoic acid ethyl ester (5.23 g, 0.02 mol), N-bromosuccinimide (3.82 g, 0.02 mol) and benzoyl peroxide (247.5 mg, 1.1 mmol) in carbon tetrachloride (80 mL) was refluxed for 4 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (7.08 g): 1H NMR (CDCl3, 200 MHz): δ=7.66 (m, 1H), 7.24 (m, 3H), 7.03 (m, 1H), 6.98 (m, 3H), 5.09 (s, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:12]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][S:10][C:9]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([O:16][C:14](=[O:15])[NH:13][C:12]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:10][CH:11]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1csc(Br)c1NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1csc(-c2ccccc2)c1NC(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
In a flame-dried round-bottom flask, tetrakis(triphenylphosphine) palladium (59 mg, 0.051 mmol) was added to a degassed solution of compound 58 (400 mg, 1.02 mmol) in DME (5 mL). Phenylboronic acid (186 mg, 1.53 mmol), water (2.5 mL), and Na2CO3 (324 mg, 3.06 mmol) were successively added, degassing and purging with nitrogen between each addition. The mixture was refluxed under nitrogen atmosphere for 3 h and partitioned between Et2O and water. The organic layer was dried over MgSO4 and concentrated in vacuum. The title compound 59 (398 mg, 100% yield) was obtained as a brown oil. 1H NMR: (CDCl3) δ(ppm): 7.51-7.31 (m, 6H), 1.54 (s, 18H). m/z: 413.5 (M+Na+). This procedure is essentially as described in Brugier et al., Tetrahedron, 56: 2985-2993 (2000), which is incorporated by reference in its entirety.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:46][CH2:47]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C34H43N6O4SCl2 [(M+H)+] 701.2438, observed 701.2439.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1.O.[CH3:25][N:26]([CH:28]=[O:29])C>>[CH:19]1([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:26]3[CH2:25][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:28]3=[O:29])=[CH:6][CH:7]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
At 0° C., 611.3 mg (15.3 mmol, 60%) of sodium hydride were added to 2.035 g (15.3 mmol) of 1-oxoindoline in 12 ml of DMF. The mixture was stirred for 25 min, and 6.0 g (12.7 mmol, about 75% pure) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 4 h while slowly warming to RT, water was then added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. In an ultrasonic bath, the crude product was treated with diethyl ether, and the solid was filtered off with suction and dried. This gave 3.40 g (65.2% of theory) of the target compound.
Reaction SMILES: CN(C)CCN(C)C.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>C1COCC1>[NH2:22][C:23]1[C:28]([CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Nc1cnccn1
Reactant: Cc1ccccc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1nccnc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a mixture of N,N,N′,N′-tetramethylethylendiamine (TMEDA, 15.00 mL, 0.10 mol) in toluene (22.00 mL, 0.21 mol) at 0° C., buthyllitium 1.6M in n-hexane (63.00 mL, 0.10 mol) was added dropwise. Then the mixture was heated at 60° C. and after 30 min was slowly added to a cooled solution of 2-aminopyrazine 11 (2.00 g, 0.02 mol) in anhydrous THF (20 mL). The reaction mixture was stirred at 0° C. for 30 min, poured into ice and extracted with ethyl acetate (3×20 mL). The organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography (EtOAc, dichloromethane; 65:35) to get 1.38 g (35% yield) of the title compound 12 as a yellow solid (mp 93-96° C.). 1H-NMR (CDCl3): 4.08 (s, 2H), 4.33 (br s, 2H), 7.18-7.35 (m, 5H), 7.91 (m, 2H). MS (ESI): m/z 186 (M+H−).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].[NH2:13][C:14]1[N:18]([C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[C:21]([F:31])[C:20]=2[F:32])[N:17]=[CH:16][CH:15]=1.O>C(#N)C.C(Cl)Cl>[Cl:7][CH:8]([Cl:12])[C:9]([NH:13][C:14]1[N:18]([C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[C:21]([F:31])[C:20]=2[F:32])[N:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F)C(Cl)Cl
Reaction time: 4 h
Yield: 85.4 %

Procedure:
1.8 ml (0.022 mol) of anhydrous pyridine and 2.1 ml (0.021 mol) of 98 percent pure dichloroacetyl chloride are added in succession to a solution of 6 g (0.02 mol) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-pyrazole in 35 ml of anhydrous acetonitrile. The temperature rises to 35° C. The mixture is subsequently stirred for four hours and then poured onto 150 ml of water. The oily precipitate is taken up in 50 ml of methylene chloride, the aqueous phase is separated off and the organic phase is washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution in succession, dried over magnesium sulphate and freed from the solvent in vacuo. 7.0 g (85% of theory) of 5-dichloroacetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 112° C.-114° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1.[C:17]([C:19]1[N:20]=[C:21]([C:32]([O-])=[O:33])[N:22]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=1)#[N:18].[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:32]([C:21]2[N:22]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[C:19]([C:17]#[N:18])[N:20]=2)=[O:33])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a mixture of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 770 mg, 2.75 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 840 mg, 2.75 mmol) and PyBroP (1.28 g, 2.75 mmol) in 20 mL of DMF was added DIEA (1.44 mL, 8.25 mmol). The resulting mixture was stirred at RT for 16 h under Ar. Treated with 80 mL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5-10% EtOAc/hexane) gave 1.28 g (88%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C25H33BrN4O2Si, 529.2 (M+H). found 528.9.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[N:31]=[C:30]([NH2:32])[S:29][N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:30]3[S:29][N:28]=[C:27]([CH3:26])[N:31]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1nsc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nsc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Temperature: 150 °C
Yield: 78.9 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 3-methyl-1,2,4-thiadiazol-5-amine (60.6 mg, 526 μmol), xantphos (60.9 mg, 105 μmol), Pd2(dba)3 (32.1 mg, 35.1 μmol) and cesium carbonate (229 mg, 702 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. Purification by chromatography (silica, 30-70% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-methyl-1,2,4-thiadiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (128 mg, 277 μmol, 79%) as an orange solid. (EI/CI) m/z: 462.3 [M+H].
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reactant: CN(C)CCN
Product: COc1ccc2sc3c([N+](=O)[O-])ccc(NCCN(C)C)c3c(=O)c2c1

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-7-methoxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 8.0 g of 1-chloro-7-methoxy-4-nitrothioxanthone and 5.6 g of N,N-dimethylethylenediamine affording 7.2 g, mp 190°-192°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:17]2[CH2:18][NH:19][CH2:20][CH:13]1[CH2:14][O:15][CH2:16]2)=[O:4].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[Cl:33])[N:7]=[C:8]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:9][C:10]=1[CH2:11][N:12]1[CH:13]2[CH2:20][N:19]([C:41](=[O:43])[CH3:42])[CH2:18][CH:17]1[CH2:16][O:15][CH2:14]2)=[O:4]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CN2C3COCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-(3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AC) (50 mg, 0.1 mmol) and triethylamine (0.042 mL, 0.3 mmol) in CH2Cl2 (5 mL) was added acetyl chloride (16 mg, 0.2 mmol) dropwise at ice-bath. The mixture was stirred at 0° C. for 2 hours. The mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL×2) and then washed with saturated aqueous sodium bicarbonate solution (20 mL×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by prep-HPLC to afford (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 15) as a light yellow solid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][F:13]>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][F:13]
Reactant: OCc1ccc(Cl)c(OCCF)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(OCCF)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [4-chloro-3-(2-fluoro-ethoxy)-phenyl]-methanol (1.19 g, 5.82 mmol, 1.0 equiv) in dichloromethane (60 mL) was added activated MnO2 (10.1 g, 116.31 mmol, 20.0 equiv). The reaction mixture was stirred vigorously for 6 h at ambient temperature and then filtered through Hyflo Super Cel providing after evaporation of the solvent under reduced pressure 0.91 g (77%) of the title compound. MS (EI): 202.0 [M]+.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C.C(C1C=CC(CCCCCCCCCCC)=CN=1)#N>C(#N)C>[C:19]([C:13]1[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:21]
Reactant: CCCCCCCCCCCc1ccc[n+]([O-])c1
Reactant: CCN(CC)CC
Agent: CCCCCCCCCCCc1ccc(C#N)nc1
Solvent: CC#N
Product: CCCCCCCCCCCc1cccnc1C#N
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a solution of 10.0 g (40 mmol) of 3-n-undecylpyridine N-oxide and 8.10 g (80 mmol) of triethylamine dissolved in 40 ml of acetonitrile was added 15.8 g of trimethylsilyl anilide, while stirring, at room temperature. After the dropwise addition, the mixture was refluxed for 66 hours and concentrated under a reduced pressure, followed by silica gel column chromatography (ethyl acetate:hexane=15:85), to give two kinds of solids A (4.40 g) and B (4.10 g). From the data of NMR, A was determined to be 2-cyano-5-n-undecylpyridine, and B the desired 2-cyano-3-n-undecylpyridine (yield 38.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][C:11]([C:12](O)=[O:13])=[C:4]2[CH2:3]1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][C:11]([C:12]([Cl:23])=[O:13])=[C:4]2[CH2:3]1
Reactant: CN1CCCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCn2c(-c3ccccc3)nc(C(=O)Cl)c2C1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 64C (0.12 g, 0.44 mmol) in 3 mL DCM was added thionyl chloride (0.16 mL, 2.21 mmol), followed by catalytic amount of DMF. The resulting mixture was stirred at 50° C. for 30 minutes, concentrated and the residual thionyl chloride was azeotroped with toluene. The resulting material 64D was dried under vacuum and used in the next step without purification.
Reaction SMILES: [CH3:1][S:2][C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7].C(OO)(=[O:21])C>O1CCOCC1.C(O)(=O)C>[CH3:1][S:2]([C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7])=[O:21]
Reactant: CSC1(NC(=O)COc2ccccc2)CNC1=O
Reactant: CC(=O)OO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CS(=O)C1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (25) (175 mg) in dry dioxan (7 ml) was treated with a solution of peracetic acid in glacial acetic acid (0.99 ml of a 5.07 % w/v solution). The mixture was stirred at room temperature for approximately 20 mins, then evaporated to dryness. The residue was evaporated once more from dry dioxan before drying thoroughly in vacuo. The residue was taken up in chloroform and chromatographed on a short column of silica gel eluting with 10% meOH/CHCl3 to give the product (26) (186 mg) a mixture of sulphoxide isomers (approximately 1:2) νmax (CHCl3) 3410, 1785, 1690, and 1490 cm-1 ; δppm (CDCl3) (90 MHz) 2.60 (major isomer) and 2.67 (minor isomer) (both s, together 3H), 3.79 and 4.12 (ABq, minor isomer, J 8 Hz) and 3.87 and 4.01 (ABq, major isomer, J 6 Hz) (together 2H), 4.53 (minor isomer) and 4.60 (major isomer) both s, together 2H), 6.52 (s, 1H, exch.), 6.80 to 7.45 (m, 5H), 7.78 (s, 1H, exch.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([Mg]Br)[CH2:17][CH:18]=[CH2:19].C(O)(=O)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:19][CH2:18][CH:17]=[CH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC[Mg]Br
Reactant: O=CCCOCCCCc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCCC(O)CCOCCCCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of Intermediate 13 (0.55 g, 2.66 mmol) in THF (5 mL) was cooled to −30° C. To this solution a 0.5 M solution of 3-butenylmagnesium bromide (5.8 mL, 2.92 mmol) in THF was added, and the resulting mixture was stirred 2 hours at −30° C. The reaction was allowed to reach room temperature; acetic acid (0.1 mL) was added and concentrated. Purification by column chromatography with silica gel and methylene chloride/acetone (20:1) as eluent afforded the title compound (410 mg, 54%) as oil.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:6]([C:5]2[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=2)[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C(c2ccc(O)cc2)c2ccc(O)cc2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 4,4′-dihydroxybenzophenone (3.0 g, 14.0 mmol), 1 equiv of TiCl4 (1.54 ml, 14.0 mmol), and 2 equiv of Zn dust (1.83 g, 28.0 mmol) in 100 ml of dry THF was refluxed for 20 h. The reaction mixture was cooled to room temperature and filtered. The filtrates were evaporated and the crude product was purified by a silica gel column using ethyl acetate (EA) as eluent. DHTPE was obtained as slight yellow powder of 83% yield.