Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCN(C1C=CC(C=O)=CC=1)CCCl.[Cl:16][CH2:17][CH2:18][N:19]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][Cl:22].N[C:32]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CO>[Cl:16][CH2:17][CH2:18][N:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]2[NH:40][C:39]3[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:38]=3[N:28]=2)=[CH:29][CH:30]=1)[CH2:20][CH2:21][Cl:22]
Reactant: N#Cc1cccc(N)c1N
Reactant: N#Cc1ccc(N(CCCl)CCCl)cc1
Agent: O=Cc1ccc(N(CCCl)CCCl)cc1
Solvent: CO
Product: N#Cc1ccc2nc(-c3ccc(N(CCCl)CCCl)cc3)[nH]c2c1
Yield: 40 %

Procedure:
A solution of 4-(N,N-bis(2-chloroethyl)amino)-benzaldehyde (IX, n=0) [Anker, R. M., Cook, A. H., "Quinoxaline cyanines. Part IV. Some halogenated styryl derivatives", J. Chem. Soc., 1944 489-4927] (1.32 g, 5.4 mmol) in MeOH (25 mL) was added to a stirred solution of 2,3-diaminobenzonitrile (X) [Stephens, F. F., Bower, J. D., "The preparation of benzimindazoles and benzoxazoles from Schiff's bases. Part II.", J. Chem. Soc., 1950 1722-1726] (0.72 g, 5.4 mmol) in aqueous MeOH (25 mL), immediately followed by a 0.05M aqueous solution of cupric acetate (1.1 mol equiv.). The suspension was brought briefly to the boil and filtered hot. The precipitate was washed with aqueous MeOH and redissolved in conc. HCl. This acid solution was treated with an aqueous solution of Na2S (1.5 mol equiv.) and the precipitated CuS removed by filtration. The filtrate was then basified with conc. ammonia, diluted with water and repeatedly extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated, and the residue was chromatographed on SiO2. Elution with CH2Cl2 /EtOAc (3:1) yielded 2-[4-(N,N-bis(2-chloroethyl)amino)phenyl]-5-cyanobenzimidazole (XI, n=0) [compound 7 of Table 1] (0.80 g, 40% yield), mp (EtOAc/petroleum ether) 80° C. (dec.). 1H NMR ((CD3)2CO) δ 8.15 (d, J2',3' =9.0 Hz, 2 H, H-2',H-6'), 7.94 (d, J4,6 =1.5 Hz, 1 H, H-4), 7.69 (d, J6,7 =8.5 Hz, 1 H, H-7), 7.50 (dd, J6,7 =8.5 Hz and J4,6 =1.5 Hz, 1 H, H-6), 6.99 (d, J2',3' =9.0 Hz, 2 H, H-3',H-5'), 3.94 (br t, J=7.5 Hz, 4 H, NCH2CH2Cl), 3.83 (br t, J=7.5 Hz, 4 H, NCH2CH2Cl). 13C NMR δ 155.98, 149.75, 143.08, 140.50, 129.62, 126.31, 120.58, 120.13, 118.40, 116.15, 112.93, 105.47, 53.52, 41.43. Anal. (C18H16Cl2N4) C,H,N,Cl.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:17]3[CH2:23][CH2:22][N:21]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2ccc(F)cc2)C3)cc1

Procedure:
The compound ru was prepared following the general procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt with 4-Fluorobenzoic acid chloride: LC-MS m/z=505 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[C:18]1([CH2:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(Cc1ccccc1)OCC1CCNCC1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[(phenylacetoxy)methyl]piperidine (318 mg, 0.95 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[(phenylacetoxy)methyl]piperidine (173 mg, 78%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH2:19][CH3:20].O>CN(C=O)C.CCOC(C)=O.CCCCCC>[CH2:19]([N:13]1[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:14]1)[CH3:20]
Reactant: CCI
Reactant: O=c1ccc(C#Cc2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCn1nc(C#Cc2ccccc2)ccc1=O
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 6-(phenylethynyl)-3(2H)-pyridazinone (15.54 g) was added to a suspension of NaH (60% in oil suspension) (3.33 g) in DMF (90 ml) and the mixture was stirred at 50-55° C. for 30 minutes. Under ice-cooling, iodoethane (6.97 ml) was added to the mixture and the mixture was stirred at 50-55° C. for 3 hours. After addition of water, the reaction mixture was extracted with EtOAc, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 2-ethyl-6-(phenylethynyl)-3(2H)-pyridazinone as a solid (14.06 g).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[S:25][C:26]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nc4ccc(F)cc4s3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for C26H22FN3OS, 443.55; m/z found, 444.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([C:28]1[N:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:34][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:33]=1)=[O:15]
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(C(=O)c2ccccc2)n1

Procedure:
Using the procedure of Example 1, the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with (6-benzoyl-2-pyridyl)methanol to yield (6-benzoyl-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 490 (M+).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[N:18][CH:19]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc([Sn](C)(C)C)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(OC)c(OC)c2)cn1
Temperature: 90 °C

Procedure:
A solution of 2.00 g (6.64 mmol) of 4-trimethylstannylveratrole, 2.49 g (13.2 mmol) of 2-methoxy-5-bromopyridine and 370 mg (0.332 mmol) of Pd (PPh3)4 in 30 mL of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer is back extracted with ethyl acetate (100 mL) and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to give a crude yellow oil. The oil is chromatographed on silica gel (eluting with 95:5 hexane/ethyl acetate and then with 9:1 hexane/ethyl acetate) which gives 5-(3,4-dimethoxy-phenyl)-2-methoxypyridine m.p 83°-84° C.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][OH:18])[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 75 Step 1 using 4-fluorophenylboronic acid. The isomers were separated by chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[NH:52]1[CH:56]=[CH:55][N:54]=[C:53]1[C:57](O)=[O:58]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([C:57]([C:53]4[NH:52][CH:56]=[CH:55][N:54]=4)=[O:58])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1ncc[nH]1)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (85 mg, 0.28 mmol) in DMF (3 mL) was added HOBt (45 mg, 0.33 mmol), EDCI (64 mg, 0.33 mmol), NMM (76 μL, 0.69 mmol) followed by imidazole-2-carboxylic acid (34 mg, 0.30 mmol) and the mixture stirred for 16 hours at room temperature. The volatiles were removed in vacuo and the residue purified directly by Biotage flash chromatography, eluting with 2-6% MeOH/DCM to yield a clear gum. Ether was added (5 mL) and the mix sonicated to give a white precipitate that was filtered off, washed with ether and dried in-vacuo to yield the title compound as a white solid, 78 mg, 70%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.04-13.12 (m, 1 H), 8.54 (d, 2 H), 7.74 (d, 2 H), 7.25-7.32 (m, 2 H), 7.18 (t, 2 H), 7.03-7.12 (m, 1 H), 6.66 (s, 1 H), 5.33-5.46 (m, 1 H), 4.77-4.92 (m, 2 H), 4.26-4.36 (m, 2 H), 4.12 (s, 2 H); m/z (APCI+) for C22H19N6FO 403.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[CH2:27]([Mg]Br)[CH3:28]>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6]([CH:1]([OH:3])[CH2:27][CH3:28])=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:16])[CH3:17]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.15 (m, 4 H), 4.40 (dq, J=3.7, J=5.2 Hz, 1 H), 4.30 (d, 5.5 Hz, 2 H), 3.72 (septet, J=6.6 Hz, 1 H), 3.42 (septet, 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, J=5.5 Hz, 1 H), 1.27 (m, 14 H), 0.804 (t, J=7.36 Hz, 3 H). FAB-MS: calcd for (C21H28NFO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175° C. Rf=0.2 (20% ethyl acetate/hexane);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:23]([O:25]CC)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[C:5]3[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
The title compound was prepared from ethyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 1 Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H, 2.85 (dd, J=13.9, 10.9 Hz, 1H, 3.16 (dd, J=13.9, 4.2 Hz, 1H, 3.48 (s, 3H, 4.66 (ddd, J=13.9, 10.9, 4.2 Hz, 1H, 7.05 (dd, J=8.9, 2.0 Hz, 1H, 7.12-7.32 (m, 11H, 7.40 (d, J=8.8 Hz, 1H, 7.53 (d, J=8.9 Hz, 2H, 7.58 (d, J=8.7 Hz, 2H, 8.98 (d, J=8.2 Hz, 1H, 9.83 (s, 1H, 12.89 (br s, 1H; MS (ESI) m/z 610 (MH+); MS (ESI) m/z 608 [M-H]−; HRMS calcd for C35H36N3O5S: 610.2373; found (ESI+): 610.2362; Anal. calcd for C35H35N3O5S.0.7H2O: C, 67.55; H, 5.90; N, 6.75. Found: C, 67.30; H, 5.93; N, 6.80.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1>CN(C=O)C.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:22]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[N:26]3[C:33](=[O:43])[N:34]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:35]=[C:25]3[C:24]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc3c4cc(Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of benzyltributyltin (69 mg, 0.184 mmol) and 8a (19.5 mg, 0.0525 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(PPh3)4 (6.0 mg, 5.3 μmol). The seal tube was sealed under argon and the mixture was stirred at 110° C. for 18 h. The reaction the mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 16a as a white solid (13 mg, 65%). mp: 299° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(O)CCCC=C(c1cccnc1)c1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 1 h

Procedure:
2.4 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.5 g of 4-chlorophenylisocyanate are stirred in 50 ml of tetrahydrofuran at ambient temperature for one hour. The reaction mixture is evaporated down, the residue is mixed with water and extracted with ethyl acetate/ethanol (9:I). The organic phase is evaporated down and the residue is saponified in 60 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50° C. for one hour. The reaction mixture is evaporated down, the residue is taken up in 100 ml of water and extracted with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid, whereupon the product is precipitated. The precipitate is suction filtered, washed with water and diisopropylether and recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:27]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:26])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:25])[F:24])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)[N:6]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[NH2:27][C:4]1[S:3][C:2]([C:40]2[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=2[F:42])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:24])[F:25])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Reactant: OB(O)c1cc(F)ccc1F
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 57.6 %

Procedure:
Following the procedure for Example 105, tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (130 mg, 0.23 mmol) and 2,5-difluorobenzeneboronic acid (55 mg, 0.35 mmol) were reacted to give 118 as a dark green solid (66 mg, 57% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.10-8.00 (m, 1H), 7.68 (s, 1H), 7.30-7.20 (m, 1H), 7.19-7.11 (m, 1H), 6.24 (tt, J=55.6, 4.2 Hz, 1H), 4.51-4.40 (m, 2H), 4.01-3.92 (m, 1H), 3.45-3.30 (m, 2H), 3.31-3.16 (m, 3H), 2.13-1.91 (m, 2H), 1.90-1.67 (m, 2H). LCMS (ES+) m/z 499 (M+1).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29].O1CCOCC1.[I-].[Na+]>O.P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:23]2[NH:26][C:25](=[O:27])[C@@H:24]2[O:28][CH3:29])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CO[C@H]1C(=O)N[C@@H]1Cl
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 350 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt in 4 ml of water is added dropwise to a solution of 135 mg of (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan in the presence of 150 mg of sodium iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (127 mg, 53.2%)
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2s1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3s2)cc1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A mixture of 4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenol (2.0 g), methyl 2-bromopropionate (1.16 g), potassium carbonate (1.05 g) and dimethylformamide was heated at a temperature of 100° C. for a period of 1 hr with vigorous stirring. After cooling the mixture was poured into water and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was recrystallised from methanol to give methyl 2-{4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenoxy}propionate (1.55 g) as colourless crystals, mp 120° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>[OH-].[Na+]>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[NH2:11])=[N:7]2
Reactant: Clc1ccc2nccn2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1cccc(Oc2ccc3nccn3n2)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), 3-aminophenol (1419 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 48 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and precipitated from diisopropyl ether to give the title compound (932 mg, 41%) as a white powder.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=2)[CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[CH2:20]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH2:10])[CH2:19]2)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Cc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1ccc2c(c1)C[C@@H](N)C2
Reaction time: 18 h

Procedure:
(S)-(5-Isobutyl-indan-2-yl)-carbamic acid benzyl ester ( ) is dissolved in methanol (100 ml), 10% Pd—C (200 mg) is added and the flask is purged with H2(g) (0.35 bar). The reaction mixture is stirred for 18 hours, the catalyst is filtered off. The solvent is removed in vacuo to give title compound. 1H nmr (CDCl3, 400 MHz); 7.10 (d, 1H), 7.00 (s, 1H), 6.90 (d, 1H), 3.85 (m, 1H), 3.15 (dd, 2H), 2.65 (dt, 2H), 2.45 (d, 2H), 1.80 (br m, 3H), 0.90 (d, 6H).