Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[O:18][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]4)[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1.C(OCC)(=O)C>[C:22]1([CH:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH:13]=3)[O:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2CCc3cc(OC4CCC5(CC4)OCCO5)ccc3O2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
430 mg of 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2-phenyl-chroman were dissolved at room temperature in 5 ml of tetrahydrofuran. 5 ml of 10% aqueous hydrochloric acid were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed with saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried with sodium sulfate and filtered, and the volatile components removed under reduced pressure. 357 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:61]([O:65][C:66](=[O:75])[CH:67]=[C:68]1[CH2:71][CH:70]([C:72](O)=[O:73])[CH2:69]1)([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:72]([CH:70]2[CH2:69][C:68](=[CH:67][C:66]([O:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:75])[CH2:71]2)=[O:73])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C=C1CC(C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)C1CC(=CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.4 %

Procedure:
HATU (148 mg, 0.39 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (138 mg, 0.35 mmol), DIEA (0.068 mL, 0.39 mmol) and 3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (83 mg, 0.39 mmol) in DMF (4 mL), and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added water to give pale-yellow precipitates. The precipitate was collected by filtration to give tert-butyl 2-(3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutylidene)acetate (138 mg, 0.236 mmol, 67%).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:16]1[CH:21]=[CH:20][C:19]([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>O.O1CCOCC1>[Cl-:2].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: [Cl-]
Product: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Temperature: 110 °C
Yield: 89.4 %

Procedure:
To a stirred solution of 2-(chloromethyl)pyridine hydrochloride (8.0 g, 48.8 mmol) in water (20 mL) was added K2CO3 (6.74 g, 48.7 mmol) portionwise. The resulting mixture was extracted four times with diethyl ether. The extracts were combined and washed twice with brine, dried and concentrated. The residue (5.78 g, 45.3 mmol) was dissolved in 1,4-dioxane (19 mL) and Ph3P (11.89 g, 45.3 mmol) was added. The mixture was heated at 110° C. overnight and then cooled to ambient temperature. The solid product was filtered, washed with ether, and dried under vacuum to give (2-pyridylmethyl)triphenylphosphonium chloride (15.78 g, 83%) as a pale solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=1[CH3:27])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([O:28][CH3:29])=[N:23][C:22]=1[CH3:30]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1nc(C)c(N=C=S)c(C)n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)nc(OC)nc2C)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (11.4 g, 44.2 mmol) and 5-isothiocyanato-2-methoxy-4,6-dimethylpyrimidine (17.3 g, 88.4 mmol) in tetrahydrofuran (170 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow amorphous (13.1 g, 28.9 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11][Li]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-3-fluoro-benzaldehyde (5.14 g, 32.4 mmol) was dissolved in THF (100 mL) and place at −78° C. under nitrogen atmosphere. Methyl Lithium (1.6 M in diethyl ether, 22.3 mL) was added to the reaction during a period of 3 minutes maintianing the same temperature. After the addition, the reaction was stirred at room temperature for 1 h. Then, the reaction was poured over ice water and extracted with ethyl acetate and hydrochloric acid 1N. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel using 50% hexane-ethyl Acetate as solvent to yield 5.1 g of 1-(4-chloro-3-fluoro-phenyl)-ethanol. 1H NMR (400 MHz, Cl3CD) δ 7.37 (t, J=8.14 Hz, 1H), 7.20 (dd, J=1.86, 10.00 Hz, 1H), 7.09 (dd, J=1.86, 8.14 Hz, 1H), 4.89 (m, 1H), 1.93 (br s, 1H), 1.49 (d, J=6.51, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C@:8]1([OH:30])[C:13](=[CH2:14])[CH2:12][C@H:11]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:9]12[CH3:10])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH2:21][CH2:22]1)[C:17]([CH3:29])=[CH:16]3)#[CH:7].P([O-])([O-])([O-])=[O:32]>O.CO.C1COCC1>[C:6]([C@:8]1([OH:30])[C:13](=[CH2:14])[CH2:12][C@H:11]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:9]12[CH3:10])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH2:21][CH2:22]1)[C:17]([CH3:29])=[CH:16]3)(=[O:32])[CH3:7]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(C)=O
Reaction time: 8 h

Procedure:
Mercuric oxide (83 mg) dissolved in water (18 ml) containing sulfuric acid (0.11 ml) was added to 17α-ethynyl-17β-hydroxy-6-methyl-16-methyleneandrosta-4,6-diene-3-one (IVA, Example 20, 1.30 g) dissolved in a methanol (19 ml)-THF (3.8 ml) mixture. The mixture was heated at 40° (bath temperature) for 6 hr and then permitted to sit at 20°-25° overnight. Celite (1.7 g) and phosphate buffer (2 ml) were added, the mixture stirred and filtered. The solids were washed with methanol and THF. The filtrate was concentrated under reduced pressure until solids dropped out. Methanol was added and the mixture heated, seeded. The mixture was concentrated under reduced pressure, methylene chloride was added, the mixture was washed with buffer, dried over sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: C([O:8][C:9](=[O:47])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:46])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:45])[C@H:22]([CH2:30][CH2:31][CH2:32][CH:33](C(OCC1C=CC=CC=1)=O)[NH2:34])[NH:23][P:24]([CH2:28][CH3:29])([CH2:26][CH3:27])=[O:25])C1C=CC=CC=1.[OH-].[Ca+2:49].[OH-]>CO.O.[C].[Pd]>[Ca+2:49].[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([O-:47])=[O:8])=[O:46])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:28][CH3:29])=[O:25])[CH3:27].[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([O-:47])=[O:8])=[O:46])=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:28][CH3:29])=[O:25])[CH3:27]
Reactant: CCP(=O)(CC)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCP(=O)(CC)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]
Yield: 94.9 %

Procedure:
Diethylphosphoryl-ε-carbobenzoxy-L-lysyl-L-prolyl-L-proline benzyl ester (2.48 g, 3.5 mmole) was dissolved in methanol (25 ml), and calcium hydroxide (0.133 g) suspended in water (10 ml) was added thereto. The catalytic reduction reaction was carried out in the presence of 5% palladium-carbon as catalyst. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The thus obtained milk-white and candy-like residue was dissolved in water. After removal of insoluble matter by filtration, the solution was freeze-dried to obtain diethylphosphoryl-L-lysyl-L-prolyl-L-proline calcium salt (1.54 g, yield: 87.8%).
Reaction SMILES: C1(N2C(=O)C3=CNC4C=C[C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.CN1CCNCC1.N1CCNCC1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:49])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:22]5[CH2:23][CH2:24][N:19]([CH3:16])[CH2:20][CH2:21]5)=[N:29][C:30]=4[C:31]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(-n2nc3c4nc(F)ccc4[nH]cc-3c2=O)cc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Agent: C1CNCCN1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4nc(N5CCN(C)CC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described for 6a using 5c and 1-methylpiperazine instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 2.22 (3H, s), 2.56 (4H, m), 3.64 (4H, m), 6.98 (2H, d, J=9.07 Hz), 7.15 (1H, d, J=9.34 Hz), 7.78 (6H, d, J=9.34 Hz), 8.10 (2H, d, J=9.07 Hz), 8.45 (1H, s). m/z 391.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30][CH3:31])[C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CO.[OH:34]OS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30]([CH3:31])=[O:34])[C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(SC)cc3n2COCCOC)c1
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(C)=O)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a mixture of 1-[1-(2-methoxy-ethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from EXAMPLE 71, product from Step B) (0.300 g, 0.654 mmol) and methanol (3.3 mL) was added a solution of OXONE®/potassium peroxymonosulfate (0.402 g, 0.654 mmol) in water (3.3 mL). The mixture was allowed to stir for 4 h at 23° C. EtOAc (40 mL) and water (20 mL) were added and the biphasic mixture was stirred. The layers were separated and the aqueous layer was further extracted with EtOAc (30 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (20-100% EtOAc/hexanes) to yield the titled compound (0.249 g, 80% yield) as a 10:9 mixture of regioisomers. MS (ESI/CI): mass calcd. for C19H21F3N4O5S, 474.1; m/z found, 475.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.94 (d, J=0.6 Hz, 1H), 8.58 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 6.34-6.23 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.74-3.66 (m, 2H), 3.51-3.41 (m, 2H), 3.28 (s, 3H), 2.81 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(=O)C(C)Cl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title product of Example 2 (3.0 g, 0.0126 mole) was reacted with 3-chloro-2-butanone (1.27 ml) and triethylamine (1.7 ml) in ethyl ether (20 ml) at room temperature overnight. The mixture was filtered, the crystals washed with ethyl ether and the combined filtrates evaporated in vacuo. The crude product was chromatographed on silica then recrystallized from ethyl acetate/hexane to give the title compound, m.p. ca. 94-97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)(Oc1ccc(C)cc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Oc1ccc(CBr)cc1)c1ccccc1
Yield: 66.9 %

Procedure:
A solution of the product of Step B (26 mg, 0.096 mmol) NBS (16 mg, 0.95 eq) and AIBN (2 mg, catalytic amount) in CCl4 (2 mL) was heated to reflux for 1 hour and then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (125×20 mm) eluted with 5% ethyl acetate/hexane to yield 21 mg (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[F:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][CH2:27][CH2:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:22]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCF)ccc21
Yield: 44.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide (75.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-fluoro-ethylamine (38.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 419+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1Cl.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[C:19](#[N:21])[CH3:20]>[Cu]I>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH2:16][N:21]1[C:2]2[C:3](=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:20][CH2:19]1)[CH3:13]
Reactant: CCN(CC)CC
Reactant: CC#N
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: [Cu]I
Product: CCN(CC)CCN1CCc2cc(N)ccc21

Procedure:
Under a nitrogen atmosphere 12.5 mL (0.090 mol) of 3-N,N-diethylamino-propyne was added to 25.00 g (0.106 mol) of 4-bromo-3-chloro-nitrobenzene, 43.7 mL (0.315 mol) of triethylamine, 10.40 g (0.009 mol) of tetrakis[triphenylphosphine]-palladium(II) and 1.71 g (0.009 mol) of copper(I)-iodide in 250 mL acetonitrile and the mixture was refluxed for 18 hours. The reaction mixture was evaporated down i. vac., combined with EtOAc and the organic phase was washed with water. The org. phase was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 10:0→4:1) followed by column chromatography (silica gel, dichloromethane).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:13]1[S:9][C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
N-bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirred solution of 1.0 g (6.01 mmol) of 2,2'-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After stirring for 1 h at room temperature, the mixture was poured into ice-water and extracted into chloroform (75 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica gel using hexane to give 1.3 g (88%) of a light green solid, m.p. 55°-56° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.[O:20]1[CH2:25][CH2:24][NH:23][C@@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:21]12>>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]([N:23]3[CH2:24][CH2:25][O:20][C@@H:21]4[CH2:28][CH2:27][CH2:26][C@@H:22]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Reactant: C1C[C@H]2NCCO[C@@H]2C1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)CC1
Product: Cl

Procedure:
Using a procedure analagous to that described in Example 2.1 (Steps 1 and 2) and starting with 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3) and (trans)-octahydrocyclopenta[b][1,4]oxazine.HCl (purchased from Enamine), 4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic) was prepared.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH2:3][CH2:1][OH:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: NCCO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCCO)cn3)ccc2n1CC1CCOCC1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Ethanolamine (29 mg, 0.47 mmol) and DIPEA (122 uL, 90 mg, 0.70 mmol) were added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (4.0 mL, 0.23 mmol) (see following step B for preparation). Stirring for 20 min, HATU (117 mg, 0.47 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with H2O (100 mL), and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl saturated aqueous solution (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1-9:1) on silica gel to give 80 mg (71%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.25-2.36 (m, 1 H), 3.24-3.34 (m, 2 H), 3.40 (t, J=5.66 Hz, 2 H), 3.63 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 7.95 (d, J=8.8 Hz, 1 H), 8.02 (dd, J=8.8, 1.8 Hz, 1H), 8.06 (d, J=0.78 Hz, 1 H), 8.35 (d, J=1.17 Hz, 1 H), 8.78 (s, 1 H); MS (ESI) (M+H)+=490.3.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22]C[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:3][CH2:4][CH2:8][O:9][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)C3)cc1
Product: [Br-]
Yield: 101.9 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (33.2 mg, 0.119 mmol) and 1-(bromomethyl)-4-nitrobenzene (45.9 mg, 0.176 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (32.7 mg, 51%). EI-MS m/z 459 (M+) Rt (1.83 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([Br:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OCc2ccccc2)cc1Br
Reaction time: 1 h
Yield: 49 %

Procedure:
To a suspension of 4-benzyloxyphenol (30 g, 150 mmol) in chloroform (400 ml) was added, dropwise, a solution of bromine (24 g, 150 mmol) in chloroform (150 ml). After stirring for 1 hour the mixture was washed with 0.1M NaHSO3 (500 ml), then water (500 ml). The chloroform layer was separated, dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5, 10, 20% ethyl acetate/hexane. Recrystallisation from hexane afforded the title compound (20.5 g, 49%); δH (250MHz, CDCl3) 4.98 (2H, s, OCH2), 6.82--6.99 (2H, m, ArH), 7.09-7.12 (1H, d, J 2.75Hz, ArH), 7.30-7.42 (5H, m).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Reactant: NC1CC1
Agent: Cl
Product: COc1cc2nc(NC3CC3)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Yield: 25.3 %

Procedure:
Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.