Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[N:19]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.8 mmol) in CH2Cl2 at 0° C. was rapidly added a solution of piperazine (2.01 g, 23.4 mmol) and triethylamine (2.17 mL, 15.6 mmol) in 10 mL CH2Cl2. The reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched with 25 mL of water and extracted with (3×15) mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (1.98 g, 83%). LC/MS: m/z 307.3 (M+H)+ at 1.47 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=10.1 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.85 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 6.95 (m, 2H), 3.85 (t, J=4.8 Hz, 4H), 2.94 (t, J=4.8 Hz, 4H) ppm.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:29][C:30]([NH2:32])=[S:31].C(OCC)(=O)C.CCCCCC>C(O)C.C(Cl)(Cl)Cl>[NH2:32][C:30]1[S:31][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:29]=1
Reactant: CCOC(=O)/C(=N\O[C@H]1CCC[C@@H](C)C1)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCCCCC
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(=N\O[C@H]1CCC[C@@H](C)C1)c1csc(N)n1
Reaction time: 2 h

Procedure:
Ethyl 4-bromo-(Z)-2-(cis 3-methylcyclohexyl)oxyimino-3-oxobutyrate (7.2 mmol) was treated with N,N-dimethylaniline (0.91 ml; 7.2 mmol) and thiourea (0.55 g, 7.2 mmol) in ethanol as described in Example 4d, except that the reaction was worked up after 2 h. The title compound was obtained as a white crystalline solid (1.78 g; 79%) m.p. 91°-93° C. (ethyl acetate/hexane), (Found: C, 54.29; H, 6.88; N, 13.57. C14H21N3O3S requires C, 54; H, 6.79; N, 13.49%), νmax (CHCl3) 3480, 3400, 1730, and 1610 cm-1 ; δH (CDCl3) 0.64-1.1 (2H, m, partially obscured by d, δ 0.92), 0.92 (3H, d, J 5.5 Hz), 1.1-1.55 (3H, m, partially obscured by t, δ 1.36), 1.36 (3H, t, J 7.1 Hz), 1.55-1.70 (1H, m) 1.70-1.86 (1H, m), 2.03-2.25 (2H, m), 4.20 (1H, tt, J 11.1 and 4.3 Hz), 4.39 (2H, q, J 7.1 Hz), 5.31 (2H, broad s), and 6.7 (1H, s).
Reaction SMILES: C[O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: COCCS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)CCO)cc3)nc2)CC1
Temperature: 10 °C
Yield: 52.8 %

Procedure:
A solution of 1-methylethyl 4-({[6-(4-{[2-(methoxy)ethyl]sulfonyl}phenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (Example 81, 0.13 g, 0.27 mmol) in CH2Cl2 (10 mL) was treated with BBr3 (1.0M in CH2Cl2, 1.64 mL, 1.64 mmol) at −78° C. The reaction mixture was allowed to warm up to 10° C., and poured onto ice and aqueous NaHCO3. The mixture was extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown solid. The crude product was purified by chromatography on a silica gel column eluted with 2:4:0.1 EtOAc/CH2Cl2/MeOH to give 66 mg (53%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.36 (d, 1H, J=2.9 Hz), 8.17 (d, 2H, J=8.5 Hz), 8.00 (d, 2H, J=8.3 Hz), 7.92 (d, 1H, J=8.8 Hz), 7.49 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.90-4.80 (m, 1H), 4.25-4.10 (m, 2H), 3.99 (d, 2H, J=6.1 Hz), 3.88 (t, 2H, J=6.2 Hz), 3.42 (t, 2H, J=6.2 Hz), 2.95-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 463 (M+H).
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: Cc1c(N)cccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
3.6 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 9.2 mmol, 1 eq.), 1.1 g 3-amino-2-methyl phenol (9.2 mmol, 1 eq.) and 4.5 g caesium carbonate (13.8 mmol, 1.5 eq.) were suspended in 35 mL DMF and stirred at rt for 16 h. LCMS analysis showed complete turnover. The reaction mixture was diluted with ethyl acetate, quenched with saturated sodium chloride solution, the layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 1.18 of the desired product (26% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[C:22](=[O:23])[C:14]3[CH:15]=[C:16]4[N:21]([C:13]=3[CH:12]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:5]([CH:6]=[O:7])=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH:43]5[CH2:46][O:45][CH2:44]5)[CH2:39][CH:38]4[CH3:47])=[CH:33][N:32]=3)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=2)[CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH:43]5[CH2:44][O:45][CH2:46]5)[CH2:39][C@@H:38]4[CH3:47])=[CH:33][N:32]=3)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=2)[C:5]([CH2:6][OH:7])=[C:8]([N:10]2[C:22](=[O:23])[C:14]3[CH:15]=[C:16]4[N:21]([C:13]=3[CH:12]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:9]=1
Reactant: CC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c(cc6n5CCCC6)c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c(cc6n5CCCC6)c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 127g (100.0 mg, 0.15 mmol) in methanol (20 mL) was added NaBH4 (17.0 mg, 0.45 mmol). The mixture was stirred at room temperature for 2 h. It was then quenched with water (1 mL) and the mixture was evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 127 (56 mg, yield 56%) as a white solid. MS: [M+H]+ 667.4. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J=2.0, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=2.5, 1H), 7.39 (d, J=2.0, 1H), 7.37-7.34 (m, 1H), 7.30-7.28 (m, 1H), 7.25-7.22 (m, 2H), 6.48 (s, 1H), 4.57-4.53 (m, 2H), 4.46 (m, 2H), 4.41 (m, 1H), 4.25 (m, 2H), 4.20 (s, 2H), 3.69-3.64 (m, 1H), 3.58 (s, 3H), 3.41-3.36 (m, 1H), 3.10-3.07 (m, 1H), 2.96-2.92 (m, 3H), 2.54-2.50 (m, 1H), 2.35-2.28 (m, 2H), 2.18 (m, 1H), 2.04-2.00 (m, 2H), 1.87-1.82 (m, 2H), 0.92 (d, J=6.0, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(C)(C)C>>[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: N#Cc1ccc2nccc(Br)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: N#Cc1ccc2nccc(N3CCC(N)CC3)c2c1

Procedure:
Starting from 4-bromo-6-cyanoquinoline (commercial) and piperidin-4-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (382 mg, 69% over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:2]=2[CH3:1])[CH2:9][CH3:10])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CCC(Oc1c(C)cc(C)cc1C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1c(C)cc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 800 mg of (2RS)-2-(2,4,6-trimethylphenoxy)butyric acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl)ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.44 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:33]([CH3:42])[C:32]=2[CH:43]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:39]2[CH2:40][CH2:41][N:36]([C:34]3[N:33]([CH3:42])[C:32]4[CH:43]=[C:28]([F:27])[CH:29]=[CH:30][C:31]=4[N:35]=3)[CH2:37][CH2:38]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccc(F)cc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccc(F)cc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:8])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-methoxy-4-nitrobenzoic acid (6.81 g, 34.54 mmol) in sulfurous dichloride (50 mL) was stirred at reflux for 8 hours. After cooling to ambient temperature, the mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (60 mL). 1-Methylpiperazine (3.6 g, 36.27 mmol) was added at 0° C. and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (2×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide the crude title compound. MS: 280.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
3-Nitro-1-butyl-1H-pyrazole (111 mg, 0.66 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-butyl-1H-pyrazol-3-ylamine (82 mg, 90%) as a golden oil: ESI-LRMS m/e calcd for C7H13N3 [M+] 139.12, found 140.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:1][C:2]([F:30])([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
26 g (60.4 mmol) of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-phenyl)prop-2-enoate is dissolved in 400 ml of dioxane. 30 ml of NaOH (30%) diluted in 250 ml of water is added to the solution. The mixture is heated to 55° C. for 2 hours. The mixture is cooled to room temperature and is carefully acidified to pH=2 with a HCl solution (25%) and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 20 g of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-phenyl)prop-2-enoic acid as a colourless powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:33])[CH:11]=1>>[F:33][C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)nc1C
Yield: 32.4 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (152 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (305 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 4, the title compound (112 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:28][CH:27]=2)[CH:10]([CH2:46][OH:47])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:48](Br)[CH:49]=[CH2:50]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:30][CH:31]=2)[CH:10]([CH2:46][O:47][CH2:50][CH:49]=[CH2:48])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCBr
Reactant: COc1ccccc1COCCCOc1ccc(C2C(CO)CN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil; MS: 682 (M+H)+.
Reaction SMILES: CC(S([NH:7][CH:8]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)[C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)=O)(C)C.Cl.O1CCOCC1>CO>[CH3:19][C:16]1[O:15][C:14]([CH:8]([C:9]2([CH3:13])[CH2:10][O:11][CH2:12]2)[NH2:7])=[N:18][N:17]=1
Reactant: Cc1nnc(C(NS(=O)C(C)(C)C)C2(C)COC2)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nnc(C(N)C2(C)COC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of 2-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methyl]propane-2-sulfinamide (example 245a, 1.23 g, 4.28 mmol) in methanol (20 ml) was added a 4M solution of hydrochloric acid in dioxane (1.61 ml, 6.42 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with 5 ml of a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (179 mg, 23%). MS (ESI, m/z): 184.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][C@@H:13]([OH:12])[CH2:14]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1
Temperature: 160 °C
Yield: 44 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)-3-hydroxypyrrolidine (607 mg, 9.96 mmol) in NMP (4 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (170 mg, 44%). LCMS (Method 1): Rt 0.39 min, m/z 223 [MH+].
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[ClH:16].C(O)C>COCCOCCOC>[Cl:16][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=1)=[O:15]
Reactant: Cl
Reactant: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1
Solvent: CCO
Solvent: COCCOCCOC
Product: NS(=O)(=O)c1cccc(C(=O)CCl)c1

Procedure:
9.5 g of 3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with 37% HCl in diethylene glycol dimethyl ether and worked up. Colorless crystals, melting point: 118° C (from a small amount of ethanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]([O:7]COCCOCCOC)[CH2:5][C:4]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:17][CH3:18])[O:3]1.Cl>CO>[CH3:28][C:2]1([CH3:1])[CH:6]([OH:7])[CH2:5][C:4]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:17][CH3:18])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(OCOCCOCCOC)C(C)(C)O1
Agent: Cl
Solvent: CO
Product: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Yield: 112.4 %

Procedure:
The compound of Example 1 (33.5 g) was added to methanol (500 ml) containing 5 ml concentrated hydrochloric acid, and the resulting mixture was refluxed for 21/2 hours. It was then cooled, the solvent was evaporated off and the residue was dissolved in diethyl ether. The solution was washed with neutral brine, dried over magnesium sulphate and evaporated to give 25.1 g of the desired product. This corresponds to a 100% yield. NMR showed the product to be a mixture of geometric isomers.
Reaction SMILES: [B:1]1([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[O:5]C(C)(C)C(C)(C)[O:2]1.[C:15]([Si:19]([O:22][CH2:23][CH2:24]I)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[Si:19]([O:22][CH2:23][CH2:24][N:13]1[CH:12]=[CH:11][C:10]([B:1]([OH:2])[OH:5])=[N:14]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(B(O)O)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
In a sealed tube, a suspension of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole (100.0 mg, 0.5154 mmol), tert-butyl-(2-iodoethoxy)-dimethylsilane (196 mg, 0.685 mmol), and Cs2CO3 (271 mg, 0.832 mmol) in DMF (3 mL) was stirred at 100° C. for 16 h. The sample was suspended between EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, giving the title material as the boronic acid, as a yellow oil (203.4 mg). MS (ES+): m/z 270.18/271.13/272.15 (19/79/15) [MH+]. HPLC: tR=3.33 min (CAD, ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([OH:16])=O)[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.Cl.[Cl:29][CH2:30][CH2:31][NH2:32].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:32][CH2:31][CH2:30][Cl:29])=[O:16])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1
Reactant: NCCCl
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCl)C3)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid of Example 8 (40 mg), 2-chloroethylamine hydrochloride (24 mg), 1-hydroxybenzotriazole monohydrate (24 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg), triethylamine (44 μL) and dehydrated N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (dichloromethane-ethyl acetate) to obtain the title compound (10 mg, 22%) as a solid.