Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(bromomethyl)benzonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile was obtained (85%) as a colorless solid: mp 69-72° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.67-7.58 (m, 2H), 7.49-7.39 (m, 2H), 7.23-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.10 (d, J=16.1 Hz, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.85 (d, J=16.1 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H); MS (ES+) m/z 410.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:29]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)([CH3:31])[CH3:30]>>[CH:29]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine from Example 111 (0.1 g) was reacted with 2-isopropyl-1H-benzo[d]imidazole via General Procedure C to produce 10.2 mg of 113 following reverse phase HPLC purification. MS (Q1) 528.3 (M)+
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:45][C:42]2[CH:43]=[CH:44][C:39]([NH:38][CH2:37][CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:40][CH:41]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(NCCN2CCCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NCCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24.9 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added N-(2-Pyrrolidin-1-yl-ethyl)-benzene-1,4-diamine (prepared below, 70.8 mg, 0.345 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and then diluted with Hexanes (˜40 mL). The black precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (˜5 mL) and triturated with Hexane (˜50 mL) to give a yellow precipitate. The precipitate was filtered and washed with 0° C. i-prOH (˜5 mL) yielding 25% (0.0366 g, 0.062 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]3)[CH:25]=[CH:24][C:23]=2[CH3:40])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)CCl.CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])[C:21]([C:22]4[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]5([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[CH2:32][CH2:31]5)[CH:25]=[CH:24][C:23]=4[CH3:40])=[CH:20][C:5]=3[C:6]=2[C:16]([NH:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Reaction time: 22 h

Procedure:
To a mixture of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (53.3 mg, 0.100 mmol) (crude) in ClCH2CH2Cl (1 ml) at r.t. under N2 was added pyridine (0.024 mL, 0.300 mmol). The mixture was then added a solution of methanesulfonyl chloride (22.88 mg, 0.200 mmol) in ClCH2CH2Cl (0.3 ml), and stirred for about 22 hours. The mixture was diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.75-7.37 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=8.85, 5.19, 2H), 7.85 (dd, J=8.09, 1.98, 1H), 7.79 (s, 1H), 7.75 (d, J=1.53, 1H), 7.51 (s, 1H), 7.47 (d, J=7.93, 1H), 7.17 (m, 1H), 7.30-7.26 (overlapping m, 5H), 7.29 (s, 1H), 2.93 (s, 3H), 2.88 (s, 3H), 2.23 (s, 3H), 1.35 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=612.34, HPLC Rt=1.583 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=7.48 min; XBridge phenyl 3.5 um, 4.6×150 mm, Rt=6.24 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: XBridge phenyl, Rt=11.46 min.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[N:7]1([CH2:12][CH2:13][C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[C:23]([C:25]2[N:26]=[CH:27][S:28][CH:29]=2)=[CH2:24])[CH2:11][CH2:10][CH2:9][CH2:8]1.NN.N>O.CCO>[N:7]1([CH2:12][CH2:13][C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH:23]([C:25]2[N:26]=[CH:27][S:28][CH:29]=2)[CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C=C(c1cscn1)c1c(CCN2CCCC2)sc2ccccc12
Agent: N
Agent: NN
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(c1cscn1)c1c(CCN2CCCC2)sc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of EtOH (7 mL) and water (2 mL), sodium periodate (1.4 g, 6.62 mmol), 4-{1-[2-(2-pyrrolidin-1-yl-ethyl)-benzo[b]thiophen-3-yl]-vinyl}-thiazole (225 mg, 0.66 mmol) and hydrazine (880 uL, 27 mmol) were added. The reaction was refluxed for 90 min, cooled down to room temperature and additional hydrazine (880 uL, 27 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added. The reaction was refluxed for an additional hour, cooled down and additional aliquots of hydrazine (880 uL, 27 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added. After refluxing overnight, water and ammonia were added (pH ˜9), which was followed by extraction with EtOAc, drying (MgSO4), filtration, and concentration in vacuo. Mass triggered preparative HPLC afforded 4-{1-[2-(2-pyrrolidin-1-yl-ethyl)-benzo[b]thiophen-3-yl]-ethyl}-thiazole (Compound 19-4). MH+=343.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
A yellow solution of 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (step 1) (1.0 g, 3.04 mmol) and ethyl 7-bromoheptanoate (1.440 g, 6.07 mmol) in DMF (20 ml), under a nitrogen atmosphere, was treated with potassium carbonate (2.098 g, 15.18 mmol) and the resultant suspension was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water (×2) and brine, dried (MgSO4) and evaporated under vacuum to a brown oil. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound as a pale solid;
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.05 eq) was added to the reaction. Hydrogen gas was introduced via a balloon; and the reaction was stirred for 2 hours at room temperature. The mixture was filtered through Celite and washed with MeOH. The solvent was removed en vacuo and the crude material was purified by flash chromatography on a COMBIFLASH™ system using 0-10% MeOH/DCM with 0.5% NH3 to give diethyl 2-(2-(2-aminoethoxy)ethoxy)ethylphosphonate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1cc(Br)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1cc(Br)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethanesulfonic anhydride (0.469 mL) was added to an ice-cooled mixture of 4-bromo-2-isopropylphenol (0.5 g) and pyridine (0.28 mL) in methylene chloride (5 mL). The mixture was stirred for 10 minutes, and poured into a mixture of ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford 4-bromo-2-isopropylphenyl trifluoromethanesulfonate (0.705 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(Cl)cc1N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)cc1N
Temperature: 0 °C

Procedure:
85.3 g of 2-amino-4-chlorobenzamide obtained in Step (1) was dissolved in 350 ml of pyridine, and to the resulting solution, while maintaining it at 10° to 20° C., there was added dropwise 92 g of phosphorus oxychloride. After being reacted at room temperature for 1 hour, the reaction mixture was poured into ice water. The crystals thus-deposited were collected by filtration, washed with water and dried. Yield: 39 g (51.1%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:56][CH2:55][CH2:54][N:53]([CH3:57])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)CCN
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethylethylenediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:37]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])=[O:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 529.8.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl.[CH3:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][N:45]=1>[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:44]([CH3:43])=[N:45][CH:46]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)c1ccc(C)nc1

Procedure:
0.415 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and 0.18 g of 6-methylnicotinoyl chloride hydrochloride are converted into the title compound analogously to Example 1.
Reaction SMILES: [CH3:1][N:2]([C:12]1[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:13]=1)[C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH2:35][NH2:36].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH2:35][NH:36][C:9]([C@H:6]1[CH2:7][CH2:8][C@@H:3]([N:2]([CH3:1])[C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:13]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: CNc1nc(N2CCN(C)CC2)nc(N(C)[C@H]2CC[C@@H](C(=O)O)CC2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNc1nc(N2CCN(C)CC2)nc(N(C)[C@H]2CC[C@@H](C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of cis-4-{methyl[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (50 mg, 0.138 mmol), [(2,4-dichlorophenyl)methyl]amine (30 mg, 0.17 mmol), and DMAP (3.37 mg, 0.028 mmol) in DMF/DCM was cooled in an ice bath. EDCl (40 mg, 0.21 mmol) was added. The reaction mixture was stirred at 0° C. for 0.5 hour, and then at room temperature for 2 hours. The solution was diluted with DCM and then washed with a saturated NaCl solution. The organic layer was dried over NaSO4 and concentrated to give the crude product which was purified by HPLC. After purification, 29 mg (0.06 mmol, 40% yield) of product was obtained as a white solid. MS (ES+): m/e 521.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:31])([F:30])[F:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[C:9]2=[O:32])=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+].B1(/[CH:49]=[CH:50]/[CH2:51][O:52][CH3:53])OC(C)(C)C(C)(C)O1>C(O)C.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.C1(C)C=CC=CC=1>[CH3:53][O:52][CH2:51]/[CH:50]=[CH:49]/[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:13][CH2:14][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:29])[F:31])(=[O:19])=[O:20])[CH2:16][CH2:17]3)[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=C1N(c2ccc(I)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC/C=C/c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Iodo-phenyl)-8-(2-trifluoromethoxy-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.01 g), product of example 104), was taken up in a mixture of ethanol (1 ml), water (1 ml) and toluene (8 ml), treated with K2CO3 (0.071 g) and (E)-2-(3-methoxypropenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaboroane and stirred 30 minutes at RT under an argon atmosphere. Then tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added and the mixture was heated at 85° C. for 4 h. It was then cooled to RT, partitioned between AcOEt and water, the layers were separated, the organic layer was dried over sodium sulphate, the solvent was removed in vacuo and the residue chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 50%) to give the desired 2-[4-((E)-3-methoxy-propenyl)-phenyl]-8-(2-trifluoromethoxy-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.077 g) as an off white solid. MS (ESI): 525.16 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (120 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (196 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D85) (164 mg). The crude product was used for next step without further purification. MS (ES): C29H35ClN2O3S requires 526. found 527.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](O)[N:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:17])[N:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc(N)cc(O)n1
Product: CCOC(=O)Cc1nc(N)cc(Cl)n1
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(4-amino-6-hydroxypyrimidin-2-yl)acetate (15.8 g.) and phosphoryl chloride (75 ml.) was stirred for 4 hours under heating at 80° to 90° C. The resultant solution was allowed to cool and phosphoryl chloride was distilled off. The remaining oily substance was poured into a mixture of ice-water (200 ml.) and ethyl acetate (200 ml.). The resultant mixture was neutralized with an aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was distilled off. The resultant residue was washed with diisopropyl ether and then dried to give pale brown crystals of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (8.1 g.), mp. 127° to 128° C.