Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10](=O)[CH3:11])=[C:5]([CH3:14])[CH:4]=1.C(O)(=O)C.[NH2:19][CH2:20][C:21]([NH2:23])=[O:22].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:23][C:21](=[O:22])[CH:20]=[N:19][C:10]=2[CH3:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COc1ccc(C(=O)C(C)=O)c(C)c1
Reactant: NCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2[nH]c(=O)cnc2C)c(C)c1
Temperature: -10 °C
Reaction time: 72 h

Procedure:
C9 (4.0 g, 21 mmol) and glycinamide acetate (2.79 g, 20.8 mmol) were dissolved in methanol (40 mL) and cooled to −10° C. Aqueous sodium hydroxide solution (12 N, 3.5 mL, 42 mmol) was added, and the resulting mixture was slowly warmed to room temperature. After stirring for 3 days, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and 1 N aqueous hydrochloric acid was added until the pH was approximately 7. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was slurried with 3:1 ethyl acetate/heptane, stirred for 5 minutes, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: ethyl acetate) provided the product as a tan solid that contained 15% of an undesired regioisomer; this material was used without further purification. Yield: 2.0 g. LCMS m/z 231.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)[CH3:13].[NH3:32]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH3:13])[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)(=[O:31])[NH2:32]
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2OCC(N)=O)ccc1Cl
Temperature: 25 °C

Procedure:
(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (28 mg, 0.06 mmol) was dissolved in 7N ammonia in MeOH (1 mL) and stirred at room temperature until starting material was consumed. The mixture was concentrated and taken up in MeOH, filtered and washed with methanol to yield N-(2-carbamoylmethoxy-phenyl)-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide 6-1. MS [M+H]+: 444.0; tR=6.25 min; (method 2)
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1C(O)=O.[N:15](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1[NH2:15]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)[C@H]1CCc2ccccc2[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@H]1CCc2ccccc2[C@@H]1O

Procedure:
One gram of the hydroxamic acid of (1S,2S)-1-hydroxy-2-carboxyteralin is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2S)-1-hydroxy-2-aminotetralin is isolated as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc21
Temperature: 40 °C

Procedure:
3-(4-Bromophenyl)propionyl chloride (36.9 g, 0.15 mol) was dissolved in 300 mL DCM and AlCl3 (23.76 g, 0.18 mol) was added slowly. At the completion of the reaction, the mixture was heated to 40° C. and refluxed for 90 minutes and then poured onto ice. Dilute HCl aqueous solution was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2M HCl aqueous solution, water and brine. The product was purified by column chromatography on silica gel eluting with PE:EA (20:1) to obtain a pale brown solid. After removing solvent under vacuum, 23 g (75%) of the desired product 6-bromo-2,3-dihydro-1H-inden-1-one (1B): 1H NMR (DMSO-d6, 400 MHz) δ2.6 (m, 2H), 3.1 (m, 2H), 7.55 (m, 1H), 7.1 (m, 1H), 7.85 (m, 1H).
Reaction SMILES: [C:1]1([CH2:11][C:12](O)=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([NH:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:27]([NH:32][CH2:33][CH2:34][NH:35][C:12](=[S:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCNCCN
Reactant: OC(=S)Cc1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCNCCNC(=S)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
In 10 ml of anhydrous tetrahydrofuran was dissolved 1.5 g of 1-naphthylthioacetic acid and 1.16 g of carbonyldiimidazole was added to the solution followed by stirring at room temperature for 0.5 hours. After 1.08 g of N-pentylethylenediamine was added to the reaction solution, the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure followed by extraction with water and ethyl ether. After the organic layer was taken by fractionation, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 300 g, methylene chloride/methanol=50/1→10/1) to give 1.06 g (yield: 46%) of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:28][CH3:27])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 65 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
4-(4-chloro-2,5-difluorophenyl)nicotinic acid (170 mg, 0.630 mmol) was taken in thionyl chloride (0.14 mL, 1.89 mmol) and heated at 65° C. for 1 h. The solvent was evaporated under reduced pressure to afford a crude oil which was dissolved in dichloromethane and added to a mixture of methanamine hydrochloride (63.9 mg, 0.946 mmol) and DIEA (0.11 mL, 0.63 mmol) in DCM (8 mL) dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (3×5 mL) followed by brine (1×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide the crude product which was purified by preparative thin layer chromatography (3:2 Ethyl acetate:hexane) to afford 4-(4-chloro-2,5-difluorophenyl)-N-methylnicotinamide (90 mg, 0.264 mmol, 42% yield) as a white solid. LC/MS (ESI) m/e 283.0 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method A): tR=1.46 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH:31](OS(C)(=O)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)n1nc(C(=O)OC)c(OCc2ccccc2)c1C(=O)OC
Temperature: 50 °C

Procedure:
To a solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (4.0 g, 13.8 mmol) and ethyl 3-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyloxy)propanoate (4.29 g, 13.8 mmol) in anhydrous CH3CN (200 mL) was added Cs2CO3 (4.49 g, 13.8 mmol). The mixture was heated to 50° C. overnight, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to afford the title product as a pale yellow oil. ES MS (M+H)=506.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:18]([C:21]1[CH:22]=[C:23]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])=[C:19]=[O:20]>C(Cl)Cl>[C:3]1([CH2:2][O:9][NH:10][C:19]([NH:18][C:21]2[CH:22]=[C:23]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])[CH2:30]3)[CH:24]=[CH:25][C:26]=2[O:27][CH3:28])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N=C=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1NC(=O)NOCc1ccccc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
1.68 g of O-benzyl-hydroxylamine hydrochloride suspended in 30 ml of methylene chloride were added to 1.52 ml of triethylamine and then 3.2 g of the product of Step A in 10 ml of methylene chloride were added dropwise with stirring for 2 hours, followed by evaporating to dryness under reduced pressure. The residue was chromatographed on silica, (eluent: methylene chloride-ethyl acetate 96-4) to obtain 3.75 g of the expected product melting at 134° C. after crystallization from a 1-1 mixture of methylene chloride and isopropyl ether.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][C:5](=O)[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[NH2:2][C:3]1[N:4]=[C:5]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COc1ccc(-c2ccc3nc(N)[nH]c(=O)c3n2)cc1OC
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3nc(N)nc(N4CCOCC4)c3n2)cc1OC
Yield: 32.7 %

Procedure:
2-amino-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one hydrochloride (332 mg; 1 mmole) was suspended in toluene (10 ml) with a catalytic amount of p-toluenesulfonic acid and ammonium sulfate. Then, 1,1,1,3,3,3-hexamethyldisilizane (3.2 ml; 15 mmole) and morpholine (0.53 ml; 6 mmole) were added. The mixture was refluxed for 24 hours and evaporated to dryness. The residue was purified by silica gel column chromatography, using a mixture of CH2Cl2/MeOH: 96:4 as eluent, resulting in the pure title compound (120 mg; yield 32%) which was characterized by its mass spectrum as follows: MS (m/z): 368 ([M+H]+, 100).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:20])=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Product: Cc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(adamantan-1-yl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.01 (m, 2H), 7.75 (dd, J=6.9, 2.1 Hz, 1H), 7.29-7.35 (m, 3H), 3.56 (s, 1H), 2.33 (s, 2H), 2.32 (s, 3H), 2.05 (d, J=3.0 Hz, 2H), 1.93-1.97 (m, 3H), 1.54-1.72 (m, 12H); MS (APCI+) M/Z 442 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH3:28])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br.O>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:10]3[C:11]([CH3:13])=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:8]([CH3:28])[CH:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(O)c(OC)cc23)cc1C
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N-ethyl-N′-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}urea, 76 mg), potassium carbonate (138 mg), and 1,2-dibromoethane (0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N′-ethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 72 mg (yield 73%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:38][N:39]1[CH:43]=[C:42]([C:44](Cl)=[O:45])[N:41]=[CH:40]1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:44]([C:42]2[N:41]=[CH:40][N:39]([CH3:38])[CH:43]=2)=[O:45])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2C(CNCc3cccc(OC(F)(F)F)c3)C2C1
Reactant: Cn1cnc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(C(=O)OC(C)(C)C)CC32)c1
Reaction time: 24 h

Procedure:
To a stirring solution of 6-[(3-Trifluoromethoxy-benzylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (5.9 gm, 15.4 mmol) in 192 mL of CH3CN at room temperature under N2 was added DIEA (8.0 mL, 46.1 mmol) and 1-Methyl-1H-imidazole-4-carbonyl chloride HCL (5.6 gm, 30.7 mmol). After 24 hours, reaction was quenched with H2O, extracted with EtOAc. Organic layer was then washed with a 10% Citric acid solution, H2O, NaHCO3, and brine. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, to yield 6.7 gm of 6-{[(1-Methyl-1H-imidazole-4-carbonyl)-(3-trifluoromethoxy-benzyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 400 MHz 1H NMR (CDCl3) δ 7.8 (d, J=1.2 Hz, 1H), 7.3-7.1 (m, 5H), 5.4 (s, 1H), 4.8-4.7 (m, 1H), 4.2 (m, 1H), 3.7 (s, 1H), 3.7 (s, 3H), 3.4-3.2 (m, 3H), 1.4 (s, 9H), 1.3 (m, 2H), 0.8 (m, 1H); MS (M+1) 495.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:12][C@H:10]([C:8]2[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:28]=[CH:27][N:26]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COCCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCn1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 63.7 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methoxyethyl)-7-pyridin-2-yl-1H-benzoimidazol-2-yl]ethylamine (167 mg, 0.53 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86 mg, 0.56 mmol) and DIPEA (0.28 mL, 1.6 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 420 as a white solid (146 mg, 63%). LCMS (Method K): RT 3.15 min [M+H]+ 433. 1H NMR (DMSO-d6, 400 MHz): δ 8.73 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.03 (1H, s), 7.97 (1H, ddd, J=7.5, 7.5, 2.0 Hz), 7.74 (1H, dd, J=9.0, 5.0 Hz), 7.70-7.66 (2H, m), 7.51 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 7.30 (2H, bs), 7.18 (1H, dd, J=10.5, 9.0), 5.69 (1H, dq, J=6.5, 6.5 Hz), 4.14-4.07 (1H, m), 3.82 (1H, ddd, J=15.0, 5.0, 5.0 Hz), 3.07-2.99 (2H, m), 2.93 (1H, s), 1.59 (3H, d, J=6.5 Hz)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:14][C:4]1[N:3]=[C:2]([NH:24][C@H:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH3:23])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Cn1cc(-c2cc(Cl)nc(Cl)c2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
257 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine obtained by Step 1, 164 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 66 mg of 2-(di-t-butylphosphino)biphenyl, 271 mg of sodium t-butoxide and 25 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 240 mg of the objective compound as pale yellow powder.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:7][CH:6]=1)(C)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:7][CH:6]=1
Reactant: CC(C)Oc1ccc(CCC2SC(=O)NC2=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)C(CCc2ccc(O)cc2)S1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Titanium tetrachloride (3.67 g) was added dropwise to a solution of 5-[2-(4-isopropoxyphenyl)ethyl]-2,4-thiazolidinedione (1.35 g) in dichloromethane (70 ml) at 0° C. After stirring for 2 hours, the mixture was poured into ice-cooled water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:3, v/v) gave 5-[2-(4-hydroxyphenyl)ethyl]-2,4-thiazolidinedione (0.72 g, 63%). This product was recrystallized from acetone-isopropyl ether. Colorless prisms, mp: 175-176° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([N:20]([CH3:42])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:30]([CH3:41])[CH2:29]3)=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:42])[C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C@@H:30]([CH3:41])[CH2:29]4)=[CH:23][CH:22]=3)=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Oc4ccc(F)cc4)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 190 °C
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
To sodium hydride (0.0174 g, 60% dispersion in mineral oil, 0.436 mmol) in DMF (4 mL) was added 4-fluorophenol (0.0488 g, 0.436 mmol) and the mixture stirred under an argon atmosphere for 20 minutes. 1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D107) (0.100 g, 0.218 mmol) was added and the reaction mixture was heated in a microwave at 190° C. for 1.5 h. The reaction mixture was concentrated and the residue partitioned between DCM and water. The aqueous layer was further extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to give a yellow oil which was purified by column chromatography to give the title compound as a colourless oil (0.0539 g). MS (ES): MH+ 535.4.
Reaction SMILES: [N+:1]([CH:4]([C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH3:6])([O-])=O.Cl.[N:21]#[C:22][NH2:23]>[Pd]>[CH2:5]([C:4]1[NH:1][C:22]([NH2:23])=[N:21][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:6]
Reactant: N#CN
Reactant: CCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: CCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
3-Nitro-9-phenylnonan-4-one (0.050 g, 0.19 mmol) reacted with concentrated HCl (0.95 mmol) and palladium, 5 wt. % on activated carbon (0.081 g, 0.038 mmol) under H2, then reacted with cyanamide (0.040 g, 0.95 mmol) according to the general procedure. Purification by column chromatography gave 0.014 g (29%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.25 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (m, 4H), 1.63 (m, 4H), 1.28 (m, 2H), 1.13 (t, J=7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 142.4, 128.2, 128.1, 125.5, 123.6, 121.3, 35.5, 31.1, 28.7, 28.1, 22.9, 16.5, 13.1 ppm; IR νmax (cm−1) 3327, 2934, 1680, 1453, 1016, 749; HRMS (FAB) calcd for C16H23N3 (MH+) 258.1965, found 258.1973.