Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:3]=1[N+:15]([O-])=O.Cl[Sn]Cl>CCOCC.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:3]=1[NH2:15]
Reactant: CC[C@H](COC)Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Product: CC[C@H](COC)Nc1nccc(Cl)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
(R)-(4-Chloro-3-nitropyridin-2-yl)-(1-methoxymethyl-propyl)-amine (2.09 g, 8.05 mmol) was dissolved in ether (30 mL) and cooled to 0° C. Next, SnCl2.2H20 (18.1 g, 80.5 mmol) in conc. HCl (10 mL) was added, dropwise at 0° C. and stirred at room temperature for 4 h. The reaction mixture was poured over ice water containing 50% NaOH solution (20 mL) and extracted with EtOAc (2×). The aqueous layer was filtered through celite, then extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (20% EtOAc/Hex) to yield 0.24 g, 13% of (R)-4-chloro-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 229.71 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:7]=[CH:6][N+:5]([O-:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cccc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 71 °C
Yield: 49 %

Procedure:
A mixture of 2-n-propylpyridine-N-oxide (137.2 g, 1.0 mol) in 200 ml of sulfuric acid (sp.gr. 1.84) was stirred in an ice-salt bath and 320 ml of nitric acid (sp.gr. 1.52) was added. The mixture was carefully heated to 70-72° C. and reacted for 22 hours. The reaction mixture was cooled and poured onto ice and, with stirring, neutralized with portions of sodium carbonate (500 g). The resulting precipitate was collected, washed with water and dried. The dried substance was slurried in 1 liter of dichloromethane and anhydrous sodium sulfate was added. The mixture was filtered and the solvent was evaporated. The yellow residue from evaporation of the dichloromethane solution was dried to afford 89.2 g (49%) of 4-nitro-2-n-propylpyridine-N-oxide. M.p. 89-91° C. 1H-NMR (CDCl3, 200 MHz) δ: 1.10 (t, 3H), 1.70 (sext, 2H), 2.94 (t, 2H), 7.96 (dd, 1H), 8.08 (dd, 1H), 8.30 (dd, 1H).
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9](C)[C:8](=O)[CH:7]=[CH:6]2.[H][H]>O=[Pt]=O>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Product: c1ccc2c(c1)CCCN2

Procedure:
The alkylation step was carried out using 6-bromomethyl-1-methyl-2-oxo-1,2-dihydroquinoline, as in Example 1, and the intermediate was reduced with hydrogen over an Adam's catalyst to give 1,2,3,4-tetrahydroquinoline intermediate which was then deprotected as in Example 13. This provided the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C@@H:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C@H:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: C[C@@H](N=C=O)c1ccccc1
Product: C[C@@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1O)c1ccccc1
Yield: 70.9 %

Procedure:
(R)-N-(2-Hydroxy4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (R)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (427 mg, 71%). EI-MS m/z 300(M−H)−
Reaction SMILES: C(NCC)C.[CH2:6]([CH2:8][NH2:9])[OH:7].[C:10]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[C:16]([NH:9][CH2:8][CH2:6][OH:7])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: CCNCC
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of isopropanol (750 ml), diethylamine (75 ml), ethanolamine (98%, 62.3 g, 1 mole) and triphenylchloromethane (97%, 143.7 g, 0.50 moles) was stirred at room temperature for 3 hours. The resulting solution was then poured into ice-cold water (4 l) under continuous stirring and the resulting precipitate was filtered off and dried. The crude product was digested in toluene (340 ml), then filtered off and dried in vacuo at 60° C. Thus 130 g (85%) of the pure desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])[CH2:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH3:30][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2([CH2:16][CH2:17][N:13]([C:10]3[N:11]=[N:12][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:8][CH:9]=3)[CH2:14]2)[C:18]1=[O:26]
Reactant: Cc1noc(-c2ccc(N3CCC4(C3)C(=O)Nc3ccccc34)nn2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(N3CCC4(C3)C(=O)N(C)c3ccccc34)nn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
1′-[6-(3-Methyl-1,2,4-oxadiazol-5-yl)pyridazin-3-yl]spiro[indole-3,3′-pyrrolidin]-2(1H)-one (300 mg) obtained in Example 158 was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (60 w %, 35 mg) was added, and the mixture was stirred at room temperature for 30 min. Iodomethane (0.054 mL) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction was quenched with saturated aqueous ammonium chloride solution, and water (20 mL) was added. The resulting precipitate was collected by filtration to give the object product (198 mg, 64%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl[CH:37]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:38].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH3:42][C:41]([CH3:44])([CH3:43])[C:40]([O:39][CH:37]([O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[N:18][C:17]=1[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30])[CH3:38])=[O:45]
Reactant: CC(Cl)OC(=O)C(C)(C)C
Reactant: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC(C)OC(=O)C(C)(C)C

Procedure:
A solution of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (70.2 mg, 0.137 mmol), 2,2-Dimethyl-propionic acid 1-chloro-ethyl ester (51 mg, 0.310 mmol), triethylamine (22 mg, 0.217 mmol) and sodium iodide (15 mg, 0.10 mmol) in anhydrous DMF (2.5 mL) was microwaved at 150° C. for 10 min and then concentrated at reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (50% to 80% EtOAc in hexanes) to give(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 1-(2,2-dimethyl-propionyloxy)-ethyl ester (25.4 mg, 28.9%) as a yellow solid. MS m/e 641.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([F:25])[CH:16]=1)[C:9]([C:31]1[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=1)=[O:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-trifluoromethyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 5) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 522.1 (M−H)−.
Reaction SMILES: C1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCC1.O[C@H]1CC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)CC1.C1(=O)CCCCCC1.BrCC(C)=C.C(OC(=O)C(SC1SC(N)=NC=1)C)C.[CH:73]1([NH:79][C@H:80]2[CH2:85][CH2:84][C@H:83]([O:86][CH2:87][C:88]([CH3:90])=[CH2:89])[CH2:82][CH2:81]2)[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1.C1(NC2CCC(OCC(C)=C)CC2)CCCCC1>CC(O)=O>[CH:73]1([NH:79][C@H:80]2[CH2:85][CH2:84][C@H:83]([O:86][CH2:87][CH:88]([CH3:90])[CH3:89])[CH2:82][CH2:81]2)[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78]1
Reactant: C=C(C)CO[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: C=C(C)CBr
Agent: C=C(C)COC1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Solvent: CC(=O)O
Product: CC(C)CO[C@H]1CC[C@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Prepared according to the procedure for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 3-bromo-2-methylpropene cycloheptanone and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-acetic acid ethyl ester. The intermediate cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine was hydrogenated using the following procedure: Cyclo-hexyl-[4-(2-methyl-allyloxy)-cyclohexyl]-amine (540 mg, 2.15 mmol) was dissolved in 10 mL AcOH and the setup was flushed with N2 before 50 mg Pd/C was added. A balloon was charged with N2 and connected to the setup. The reaction mixture was stirred for three days at room temperature before the Pd was filtered off using a pad of celite. The filtrate was poured on 1 N NaOH (pH>12) and the mixture was extracted 3× with diethylether (50 mL), and dried (MgSO4) to give cyclohexyl-(trans-4-isobutoxy-cyclohexyl)-amine which was trans-formed to the title compound according to the procedure for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(Cl)cc3)CC2)ccc1Cl
Yield: 66 %

Procedure:
The title compound (27 mg, 66%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-chlorobenzoyl chloride. MS: 407.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:15][CH2:16][F:17].Cl>CN(C=O)C>[F:17][CH2:16][CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Under nitrogen atmosphere to a cold (5° C.) solution of 4-hydroxy-benzoic acid methyl ester (7 g, 46 mmol) in DMF (30 ml) was added NaH (60%; 2.2 g) portion wise over 20 minutes. After the addition was completed, the ice bath was removed and the resulting white suspension was heated up to room temperature and stirred for 3 hours. A prepared solution of 1-Bromo-2-fluoro-ethane (6.42 g, 50 56 mmol) in DMF (20 mL) was added and the new mixture was stirred at 50° C. for 18 hours. After cooling to room temperature the mixture was poured into a mixture of ice and 1 N HCl (1:1) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave a white solid (7.75. 85% yield); 1H NMR (400 MHZ, CDCl3) δ 3.86 (s, 3H), 4.20 (m, 1H), 4.21 (m, 1H), 4.27 (m, 1H), 4.28 (m, 1H), 6.93 (d, 2H), 7.98 (d, 2H); MS m/e (M+H)+ 198; mp 77° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].[CH3:46][C@@H:47]([NH2:50])[CH2:48][CH3:49]>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:12][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:50][C@H:47]([CH3:46])[CH2:48][CH3:49])=[O:21])=[CH:17][CH:16]=2)[CH2:14]1)#[N:9]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Reactant: CC[C@@H](C)N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-azetidin-1-yl}benzoic acid and (2R)-butan-2-amine (Aldrich: Cat. #296651). LCMS (M+H)+: m/z=455.2. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.76 (d, 8.7 Hz, 2H), 7.68 (dd, J=3.3, 2.5 Hz, 1H), 7.14 (dd, J=3.4, 1.5 Hz, 1H), 6.59 (d, J=8.7 Hz, 2H), 4.55 (s, 2H), 4.30 (d, J=8.6 Hz, 2H), 3.89 (m, 1H), 3.75 (s, 2H), 1.58-1.39 (m, 2H), 1.10 (d, J=6.6 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[Li][CH2:14]CCC.CI>C1COCC1>[Cl:12][C:7]1[N:8]=[C:9]([Cl:11])[C:10]2[C:2]([CH3:14])=[CH:3][NH:4][C:5]=2[N:6]=1
Reactant: [Li]CCCC
Reactant: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: -78 °C

Procedure:
1.4 g 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4) (5.2 mmol) was dissolved in 200 mL of THF. After cooling to −78° C., 9.75 mL of BuLi (1.6M solution in Hexanes, 15.6 mmol) was slowly added over a period of 30 minutes, then stirred for 30 minutes at −78° C. before 396 uL of MeI (6.24 mmol) was dropwise added into the reaction mixture over a period of one hour. The reaction mixture was stirred at −78° C. for one more hour and quenched by adding 20 mL of saturated aqueous NH4Cl solution at this temperature. The reaction mixture was then partitioned between 100 mL of saturated NaHCO3 and 100 mL of EtOAc. The organic layer was separated and the aqueous layer is extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:19]1[CH2:22][CH2:21][CH2:20]1)=[O:7]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a solution of 3-chloro-4-fluorobenzoic acid (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at ambient temperature for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at ambient temperature for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried (MgSO4), and evaporated. The residue was crystallized from ethyl acetate/isohexane to give the title compound (1.64 g).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]([OH:29])=O)[CH2:20][CH2:19]1)[CH3:17].[Br:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH2:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1>O1CCCC1.N1C=CC=CC=1>[Br:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH:48][C:27](=[O:29])[C:26]#[C:25][CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:23][CH2:22]4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Isobutyl chloroformate (0.847 g, 6.2 mmol) and N-methylmorpholine (1.460 g, 14.4 mmol) were added to an ice cold solution of 1.900 g (9.52 mmol) of 4-(4-ethyl-piperazin-1-yl)-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (30:70), gave 1.450 g of 4-(4-Ethyl-piperazin-1-yl)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 493.
Reaction SMILES: C(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[C:16]3[S:20][C:19]([NH:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:18][C:17]3=[O:28])[N:13]=2)[N:8]=[CH:7][C:6]=1[C:29]#[N:30])(C)C.C(O[Na])(C)=O.C(C1N=C2C(=CC=1)N=CC(C#N)=C2)=O>CC(O)=O>[O:28]=[C:17]1[C:16](=[CH:15][C:12]2[N:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:29]#[N:30])=[CH:5]3)[S:20][C:19]([NH:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:18]1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: N#Cc1cnc2ccc(C=O)nc2c1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
To a mixture of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one one (34.0 mg, 0.16 mmol) (see Example 4), AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (38.5 mg, 0.21 mmol) (prepared as described below) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 4.5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then dissolved in DMF (1 mL) with heating and then poured into ice water, and filtered. The solid was washed with AcOEt and dried to give 6-{4-oxo-2-[(thiophen-2-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a dark brown solid (12.8 mg, 21.2%). HR-ES (+) m/e calcd for C18H11N5OS2 (M+H)+ 400.0297. found 400.0298.
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH:25]([NH:33][C:34]([C:36]2[CH:44]=[C:43]3[C:39]([CH:40]=[CH:41][NH:42]3)=[CH:38][CH:37]=2)=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:25]([NH:33][C:34]([C:36]2[CH:44]=[C:43]3[C:39]([CH:40]=[CH:41][NH:42]3)=[CH:38][CH:37]=2)=[O:35])[CH2:24][O:23][CH2:22][CH:19]2[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccc(F)cc2)CC1
Solvent: COc1ccccc1
Product: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2cc[nH]c2c1
Yield: 102.7 %

Procedure:
Using deprotection method B, but without addition of anisole, 4-{2-[(1H-indole-6-carbonyl)amino]-2-(4-fluoro-phenyl)ethoxymethyl}piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.2 mmol) afforded 1.3 g (100%) of the title compound as a crude residue which was used without further purification.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]CC)=O.Cl.[NH2:23][OH:24].[OH-].[K+].C(O)(=O)C>CO>[OH:24][NH:23][C:17]([C:2]1[S:1][C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=1)=[O:19]
Reactant: NO
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NO)cc2C1
Temperature: 75 °C
Yield: 50.1 %

Procedure:
A mixture of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g, 0.18 mmol; prepared as described in J. Med. Chem. 2006, 49(15): 4623), hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and potassium hydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was heated at 75° C. for 1 hour. Upon cooling to room temperature the reaction was quenched by the addition of acetic acid (100 μL, 1.8 mmol) and the solvent was evaporated to dryness. The residue was dissolved in DMSO (1 mL) and purified using a Gilson prep to afford a white solid (26.9 mg, 50%). LCMS (FA) ES+ 299; 1H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 4.46 (s, 2H), 3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([CH:21]=[O:22])[CH:8]=1)(=O)=O.[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>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>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:16]3[C:15]([CH3:17])([CH3:18])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=3[CH:10]=[C:9]([CH:21]=[O:22])[CH:8]=2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2c(OS(=O)(=O)C(F)(F)F)cc(C=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 65 %

Procedure:
In a manner similar to that of Example 21 b, by reacting 5 g (14 mmol) of 3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthyl 1,1,1-trifluoromethanesulfonate (Example 21a) with 2.85 g (16 mmol) of 4-tert-butylphenylboronic acid, in the presence of 1.17 g (28 mmol) of lithium chloride, 16 mL (32 mmol) of 2 M potassium carbonate solution and 800 mg of tetrakis(triphenylphosphine)palladium. The product is obtained in the form of white crystals (m=3.1 g; yield=65%, m.p.=129° C.).