Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[S:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH2:56]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([NH:56][C:52]2[S:51][CH:55]=[CH:54][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Reactant: Nc1nccs1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (0.31 g, 1.09 mmol) in methylene chloride (6.10 mL, 0.18M) at 25° C. was treated with N,N-diisopropylethylamine (0.57 mL, 3.29 mmol) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.39 g, 1.31 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with thiazol-2-ylamine (143 mg, 1.42 mmol). The resulting solution was stirred at 25° C. overnight. After this time, the reaction was partitioned between water (100 mL) and methylene chloride (3×75 mL). The combined organics were washed with water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-N-thiazol-2-yl-propionamide as a white solid (247.7 mg, 61%); ES+-HRMS m/e calcd for C19H20N4O2S [M+H+] 369.1380 found 369.1378. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.17 (m, 1H), 1.20-1.80 (m, 8H), 2.04-2.18 (m, 1H), 2.23-2.36 (m, 1H), 5.73 (dd, J=10.4, 4.4 Hz, 1H), 7.22 (d, J=3.4 Hz, 1H), 7.47 (d, J=3.4 Hz, 1H), 7.83-7.93 (m, 1H), 7.94-8.02 (m, 2H), 8.26 (d, J=7.8 Hz, 1H), 8.52 (s, 1H), 12.46 (s, 1H).
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[C:70]([Br:75])[CH:71]=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1>CN(C=O)C.O>[C:11]([O:10][C:8](=[O:9])[N:1]([C@H:2]([C:4](=[O:6])[NH:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[C:70]([Br:75])[CH:71]=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1)[CH3:3])[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
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
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Yield: 95.8 %

Procedure:
Boc-N-Me-Ala-OH (107.91 mg, 0.532 mmol), DIPEA (0.251 mL, 1.45 mmol) and HATU (220.37 mg, 0.58 mmol) were added to a solution of (S)-3-amino-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (260 mg) in DMF (4 mL) at 0° C. After 3 h the mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate solution, dried and concentrated. The residue was purified by silica gel chromatography to afford the title compound (282 mg, 51%) as an off white solid. LC-MS: 613.2 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)=O)(C)(C)C.[ClH:24].CO>>[ClH:24].[CH:19]1[C:20]2[C:15](=[C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCCNc1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 30 (316 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (276 mg) as light yellow powdery solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>CS(C)=O.CN(C1C=CN=CC=1)C>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(=O)Nc1nc2ccc(-c3cccc(N)n3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cccc(NS(=O)(=O)c4ccccc4F)n3)cc2s1

Procedure:
N-(6-(6-Aminopyridin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.220 g, 0.775 mmol) was dissolved in DMSO (3 mL). TEA (0.3 mL, 2 mmol), DMAP (0.020 g, 0.16 mmol), and 2-fluorobenzene-1-sulfonyl chloride (0.4 mL, 3 mmol) were added to the mixture while stirring. The mixture was allowed to stir under inert atmosphere overnight and then it was diluted with DMSO and purified by reverse phase HPLC to give N-(6-(6-(2-fluorophenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as a yellow solid. MS (ESI pos. ion) m/z: 443 (MH+). Calculated exact mass for C21H15FN4O3S2: 442. 1H NMR (400 MHz, DMSO-d6): 7.99 (s, 1H), 7.94 (t, J=7.3 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.32-7.47 (m, 3H), 7.28 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.41 (d, J=8.5 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: C([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:35](=[O:36])[C:34]1[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:42])[CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2C(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [500 mg, Reference Example 19(a)] in tetrahydrofuran (20 ml) was treated successively with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 mg). The mixture was stirred at 40° C. for 2 hours and then partitioned between ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was dissolved in trifluoroacetic acid (2 ml) and the clear solution was left at room temperature for 30 minutes then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated to give the title compound (200 mg) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:17]([CH:18]=O)=[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[O:9][C:5]2=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][OH:23].Cl>CCO.N1C(=O)CC[C@H]1C(O)=O>[OH:1][C:2]1[C:17]([CH:18]=[N:22][OH:23])=[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[O:9][C:5]2=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: NO
Reactant: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCO
Product: COc1cc(O)c(C=NO)c2cc(-c3ccc(O)cc3)oc12

Procedure:
Compound 71 (0.029 g, 0.1 mmol) in EtOH/Pyr (1 mL/0.5 mL) was treated with NH2OH HCl (0.040 g, 0.58 mmol) and the mixture heated briefly to reflux (approximately 5 minutes) and allowed to cool and then the solution was partitioned between EtOAc and 2 N HCl aq and the organic layer was then washed with NaHCO3 aq, brine, dried over MgSO4, filtered, concentrated and triturated with CH2Cl2 to render 29 mg of the desired oxime: Mp=205° C. (dec.); 1H NMR (DMSO-d6) δ 11.1 (s, 1 H), 10.0 (s, 1 H), 9,90 (s, 1 H), 8.53 (s, 1 H), 7.65 (d, 2 H, J=8.6 Hz), 7.39 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.47 (s, 1 H), 3.94 (s, 3 H); MS 300 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](N)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][N:3]=1.S(=O)(=O)(O)O.C(ON=O)(C)(C)C>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:6]=2[CH:7]=1
Reactant: COc1ccccc1-c1cnc(Cl)cc1N
Agent: CC(C)(C)ON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Clc1cc2oc3ccccc3c2cn1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
2-chloro-5-(2-methoxyphenyl)pyridin-4-amine (7.5 g, 31.96 mmol) was dissolved in glacial acetic acid (200 mL) and concentrated sulfuric acid (1 mL). A solution of t-butylnitrite (11.39 mL, 95.87 mmol) in 10 mL of acetic acid was added drop wise and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in methylene chloride. The reaction mixture was dried over sodium sulfate, concentrated and the residue was purified by silica column using hexanes and ethyl acetate as eluent to give 5.0 g of title compound.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9](Cl)C=2)=[C:4]([F:21])[CH:3]=1.COS(OC)(=O)=O.C(N(CC)CC)C.CC(O)=O.[CH3:40][CH2:41][OH:42]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]([CH3:9])[C:41](=[O:42])[CH:40]=2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1F
Reactant: CCO
Solvent: CC(=O)O
Solvent: COS(=O)(=O)OC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Yield: 77 %

Procedure:
Ethyl 4-(4-bromo-2-fluoroanilino)-6-chloronicotinate was dissolved in CHCl3 and reacted with Me2SO4, followed by triethylamine, AcOH and EtOH as described for example 33, step B. Purification by recrystallisation (EtOAc/Hexane) gave ethyl 4-(4-bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (77%); m.p. (EtOAc/Hexane) 159-162° C. 1H NMR [400 MHz, CDCl3] δ 9.34 (br s, 1H), 8.22 (s, 1H), 7.36-7.25 (m, 3H), 5.85 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 3.54 (s, 3H), 1.39 (t, J=7.1 Hz, 3H). LCMS (APCI−) 369 (100%), 367 (100%). Anal. Calcd for C15H14BrFN2O3: C, 48.8; H, 3.8; N, 7.6. Found C, 49.1; H, 3.8; N, 7.4.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]#[N:22]>>[C:21]([CH2:20][N:5]1[C:6]2[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]1[CH2:2][CH2:3]1)#[N:22]
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: N#CCBr
Product: N#CCn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 62 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and bromoacetonitrile: MS (ES) m/z 290 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[Si](Cl)(C)(C)C.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1)(=[O:28])[CH3:27]
Reactant: NC(Cc1ccc(I)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of 15 g (51 mmol) of 4-iodo-D,L-phenylalanine and 16.2 ml (127.5 mmol) of Me3SiCl in 150 mL of dichloromethane was heated at reflux for 1 h under N2. The reaction mixture was cooled to 0° C. with an ice bath and 17.7 mL (127 mmol) of triethyl amine was added, followed by 5.83 mL (61.2 mmol) of acetic anhydride. The mixture was stirred at 0° C. for 30 min, then warmed up to room temperature and stirred for another 30 min. The reaction was quenched by adding 1M aqueous sodium hydroxide and then the mixture was acidified with 2M aqueous hydrogen chloride to pH 1. The precipitate was collected by filtration and dried under vacuum to afford 16 g (95%) of N-acetyl-4-iodophenylalanine as a white solid: 1H NMR (DMSO-d6) 8.19 (d, 1H), 7.61 (d, 2H), 7.02 (d, 2H), 4.39-4.31 (m, 1H), 3.01-2.92 (dd, 1H), 3.80-2.69 (dd, 1H), 2.67 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:32].[O:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:21][CH2:20]2)=[N:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-{4-[2-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.3 g, 3.03 mmol) was dissolved in 3 ml dichloromethane and 4N HCl in dioxane (15.2 ml, 60.7 mmol) was added. The white suspension was stirred for 4 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar, to get the desired salt as a white solid (1.2 g, quant.) [MS: m/e=329.2 (M+H+)].
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>C(O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3]#[N:4])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na]
Solvent: CCO
Product: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 80.8 %

Procedure:
A solution of 3.78 g (0.0500 mol) of chloroacetonitrile in 10 ml of anhydrous ethanol is run over the course of 20 minutes into a solution of 1.04 g (0.0453 mol) of sodium and 10 g (0.0453 mol) of p-(p-chlorophenoxy)-phenol in 50 ml of anhydrous ethanol and the mixture is then heated to the reflux temperature for 4 hours. It is evaporated to dryness under reduced pressure and the residue is dissolved in diethyl ether, which is washed with water and with dilute sodium hydroxide solution. After drying over dry sodium sulphate and evaporating the solvent from the organic phase, 12 g of an orange-coloured oil are obtained. Purification of this oil by distillation under reduced pressure gives 9.5 g of a limpid pale yellow oil which is insoluble in water.
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7](=[O:16])[C:8]3[C:13]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(S)[CH2:18][S:19]([O-])(=O)=O.[Na+]>O1CCCC1.O>[CH3:18][S:19][C:2]1[O:6][C:5]2[C:7](=[O:16])[C:8]3[C:13]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1c2ccccc2C(=O)c2oc(Br)cc21
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc2c(o1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To the solution of 0.7 gram (2.5 mmoles) of 2-bromo-naphtho[2,3-b]furan-4,9-dione in 20 mL of tetrahydrofuran at room temperature, 0.4 grams (5.0 mmoles) of MeSNa in 5 mL of water was added dropwise over 1 minute. The mixture was further stirred for 2 hours at room temperature, and then evaporated to remove tetrahydrofuran. To the residue, 20 mL of 1N hydrochloric acid was added, and the resulting mixture was filtered. The solid was washed with water, and then crystallized in ethanol/water. Pure crystal product was filtered and dried under vacuum. 0.55 grams of product (yield 90%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 2.66 (s, 3H), 6.79 (s, 1H), 7.75-7.79 (m, 2H), 8.18-8.25 (m, 2H). Mass (M+H) is 245.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH:30]4[CH2:32][CH2:31]4)=[O:28])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:35]#[N:36])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH3:33][C:22]1[C:21]([CH3:34])=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([C:35]#[N:36])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH:30]1[CH2:31][CH2:32]1)=[O:28]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
After adding N-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2,3-dimethylphenyl]-N′-cyclopropylurea (1600 mg) to tetrahydrofuran (400 ml), palladium-carbon (2000 mg) was further added and the mixture was stirred overnight at room temperature under a hydrogen stream. The palladium-carbon was removed by filtration, washing was performed with dimethylformamide, and the filtrate was concentrated under reduced pressure to obtain the title compound (827 mg).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[C:23]1([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
(R)-1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (example 1) (3.0 g, 0.079 mol) was dissolved in ethanol (20 ml) and 12N sodium hydroxide solution (2.0 ml) was introduced. After stirring the solution at room temperature for 2.5 h, 37% hydrochloric acid (ca. 2.2 ml) was added, with acidity measured at pH 2. Dichloromethane (300 ml) was introduced, and the mixture was dried (MgSO4). Filtration and evaporation of the filtrate gave a solid, which was triturated with diethyl ether, to give the title compound (2.65 g, 86%) as a white solid, m.p. 210°-216° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][C:22]1[C:23](B(O)O)=[CH:24][S:25][CH:26]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[C:22]([CH3:21])=[CH:26][S:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: Cc1cscc1B(O)O
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cscc3C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-methyl-thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-methyl-thiophen-3-yl)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])C(O)=O.[P:16]([O-:33])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([Br:53])[CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([Br:53])[CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50].[CH3:15][O:14][C:10]1[CH:9]=[C:5]([P:16](=[O:33])([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: [Pd]
Agent: COc1cc(Br)cc(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybromobenzene is prepared from 3,4,5-trimethoxybenzoic acid following the procedure of Tetrahedron Lett. 26 (1985):5939-5942. Dibenzyl phosphite is heated in the presence of tetrakis(triphenylphosphine) palladium (0), triethylamine and toluene with 3,4,5-trimethoxybromobenzene to give dibenzyl 3,4,5-trimethoxyphenylphosphonate 2 following the procedure of J. Med. Chem. 32 (1989):1580-1590.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([O:19][CH2:20][CH3:21])=[CH2:18]>ClCCl>[CH2:17]([O:19][CH2:20][CH2:21][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C=COCC
Solvent: ClCCl
Product: CCOCCOC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
Diphenylacetic acid 2-ethoxyethyl ester was prepared in the following manner: To a mixture of 2.0 g (9.4 mmol) of diphenylacetic acid in 10 ml of dichloromethane was added 1.1 ml (0.82 g, 11.4 mmol) of ethyl vinyl ether. The mixture was allowed to stir overnight at which point the reaction mixture was washed with aqueous sodium bicarbonate, dried with MgO-MgSO4, and concentrated in vacuo to give 1.7 g (6.0 mmol, 63% yield) of the corresponding ethoxy ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][C:14](=O)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:20]1([NH2:24])[CH2:23][CH2:22][CH2:21]1.C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH:16]4[CH2:17][CH2:18][CH:12]3[CH2:13][CH:14]([NH:24][CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:15]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1csc2ncnc(N3C4CCC3CC(NC3CCC3)C4)c12
Temperature: 30 °C
Yield: 89.6 %

Procedure:
8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (1.5 g, 4.43 mmol) in toluene (60 mL) was treated with cyclobutylamine (3.145 g, 44.3 mmol) and heated with stirring to reflux for 2 h. Ethanol (100 mL) and sodium triacetoxyborohydride (9.347 g, 44.3 mmol) were added and the reaction stirred and warmed at 30° C. over 3 days. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (50 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid (1.799 g, 3.97 mmol, 89%). 1H NMR (CDCl3) δ: 1.5 (3H, d, J=12 Hz), 1.65 (3H, br s), 1.93 (2H, br s), 2.1 (2H, d, J=6 Hz), 2.22 (2H, m), 2.4 (2H, m), 3.0 (1H, br s), 3.3 (1H, m), 4.63 (2H, br s), 7.3 (1H, s), 8.45 (1H, s).