Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:27]5[CH:26]=[N:25][C:34]6[C:29]([CH:28]=5)=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cnc6ccccc6c5)n4n3)cc2)CC1

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-(7-quinolin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 3-quinolineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (49 mg, 40%). m.p.=235-241° C.; LCMS (m/e) 436 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.38 (s, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 8.13 (d, 1H, J=9.1 Hz), 7.85 (d, 1H, J=7.0 Hz), 7.80-7.69 (m, 1H), 7.63-7.52 (m, 3H), 7.25-7.17 (m, 1H), 6.98 (d, 2H, J=7.9 Hz), 6.93-6.86 (m, 1H), 6.70 (s, 1H), 3.29-3.19 (m, 4H), 2.69-2.57 (m, 4H), 2.39 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[Na]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:30]1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: [Na]
Product: O=C(C1CCCCC1)C(CCN1CCN(c2ccccn2)CC1)c1ccccc1
Yield: 78.3 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55 mmol) and 1-(2-pyridyl)piperazine (1.55 mmol) with sodium triacetoxyboranehydride (2.0 mmol) gave pure product 1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (475 mg) in 78% yield. The oxalate salt was prepared as described above.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C([O-])(=O)C.[K+].CCOC(C)=O>O1CCOCC1.O.CC(O)C.C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH3:9])=[CH:4][C:3]=1[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a 5 mL microwave reaction tube was added 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (0.523 g, 1.55 mmol), 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 3, 0.322 g, 1.28 mmol), Am-Phos (Aldrich, 0.0531 g, 0.075 mmol) and potassium acetate (Aldrich, 0.379 g, 3.87 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 15 min. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and saturated NH4Cl (30 mL) was added to the aqueous phase. The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: EtOAc in hexanes 20% to 70% then IPA/CHCl3 0% to 12.5%) to afford 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.30 g, 55% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.27-8.37 (m, 3H) 5.86 (d, J=10.37 Hz, 1H) 4.15-4.24 (m, 1H) 3.78-3.88 (m, 1H) 3.64-3.75 (m, 4H) 3.53 (q, J=6.72 Hz, 1H) 2.89 (s, 3H) 2.50-2.60 (m, 2H) 2.38-2.48 (m, 2H) 2.01-2.22 (m, 3H) 1.69-1.91 (m, 3H) 1.43 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion) δ 427.1 (M+H)+.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC2)ncn1
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 71 mg of pyrrolidine was added therein, and the mixture was stirred for 4 hours at 55-60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 170 mg of 4-(2-butynyloxy)-6-(1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (17)).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH:14](C)C)[O:9][CH:10](C)C)=[CH:4][CH:3]=1.CO>C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH3:14])[O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)O[Si](C)(OC(C)C)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CO[Si](C)(OC)c1ccc(I)cc1
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Compound 4-iodo-1-(methyldiisopropyloxysilyl)benzene (11.27 g, 35.5 mmol) was dissolved in dry methanol (12.87 g, 400 mmol). 1% molar of p-toluene sulfonic acid (53 mg, 0.3 mmol) was added all at once. The yellow suspension was stirred for 4 hours. The organic solvent was pumped off and the corresponding crude orange oil was distilled under vacuum (B.p. 59-69° C., 3.10−1 mbar) to afford 4-iodo-1-(methyldimethoxysilyl)benzene as a colourless oil (9 g, 30 mmol) in 82% yield. 1H NMR (CDCl3, δ, ppm) 7.78 (2H, d); 7.37 (2H, d); 3.58 (6H, s); 0.37 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[NH:32][CH3:33]>>[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[N:32]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[CH3:33]
Reactant: CNc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2,4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (96% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH:17][CH3:18])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29](O)=[O:30])=[O:23].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:25]=[C:24]([CH:34]=[CH:33][CH:32]=3)[C:22]([O:21][CH3:20])=[O:23])=[C:12]([NH:17][CH3:18])[CH:11]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1N
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Yield: 61.9 %

Procedure:
The reaction and post-treatment were carried out according to Example (16e) using 4-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N2-methylbenzene-1,2-diamine produced in Example (17c) (4.13 g, 15.9 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.68 g, 17.5 mmol), triethylamine (4.44 mL, 31.8 mmol), pivaloyl chloride (1.96 mL, 15.9 mmol) and dichloromethane (80 mL) to obtain the title compound (4.44 g, 64%) as a white powder.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1ccc(C=O)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Sodium hydride (2.4 g (60%), 60 mmol) was added to 4-hydroxybenzaldehyde (6.0 g, 50 mmol) in N, N-dimethylformamide (100 mL). The suspension was stirred for 1 hour and then treated with 2-methoxyethoxymethyl chloride (6.8 mL, 60 mmol), and allowed to stir an additional 16 hours. The reaction was then partitioned between water and ether:ethyl acetate (1:1). The organics were then washed with water (4×), dried (potassium carbonate), and concentrated. The crude materials were then purified by silica gel chromatography (hexanes:ethyl acetate) to afford the title compound (9.0 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].CCOCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 40 h. Ether (100 mL) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50-75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:11]3=[O:34])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:46][CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:11](=[O:34])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH2:3][CH2:2]4)[CH:9]=3)[N:14]=2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3ccc(N4CCCN(CC5CCOCC5)CC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
2-(6-(1,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (EXAMPLE 1i) (30 mg, 0.064 mmol), (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (35 mg, 0.128 mmol) and DIPEA (17 mg, 21 μl, 0.128 mmol) were dissolved in DMF (1 mL) and stirred at room temperature overnight. Purification by preparative HPLC afforded 2-{2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-[4-(tetrahydropyran-4-ylmethyl)perhydro-1,4-diazepin-1-yl]-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 11a) (5 mg, 0.0088 mmol, 14%).
Reaction SMILES: C(NCCS[C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:17])[C@H:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=O)C.N12CCC1CC=C2.C(N(C(C)C)CC)(C)C.[C:47]([NH:50][CH2:51][CH2:52]S)(=[O:49])[CH3:48]>C(#N)C>[C:47]([NH:50][CH2:51][CH2:52][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=[O:49])[CH3:48]
Reactant: CC(=O)NCCS
Reactant: CC[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(C)=O)C[C@H]12
Agent: C1=CN2CCC2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(CCNC(C)=O)CC12
Reaction time: 0.25 h

Procedure:
Preparation of trans (±)-3-[[2-(acetylamino)ethyl)thio]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester (XVII, R=CH3CH2 --, R'"=CH3CONH--CH2 --CH2 --, R4 = ##STR19## A solution of the bicyclic keto ester obtained in step (c) above (XV R=CH3CH2 --) (2.49 g) in acetonitrile (15 ml) is cooled to 0° C. and diisopropylethylamine (1.42 ml) is added. Then chlorodiphenylphosphate (1.72 ml) is added drop by drop keeping the temperature at 0°/-2° C. Stirring is continued for 15 minutes at 0° C., after which thin layer chromatography confirms the complete transformation of the bicyclic keto ester XV into the enol phosphate derivative XVI (R=CH3CH2 --). An additional portion of diisopropylethylamine (1.55 ml) is added followed by the slow addition of N-acetylcysteamine (1.07 g) dissolved in acetonitrile (5 ml). The reaction mixture is then stirred at 0° C. for 30 minutes and the solid which precipitates is filtered, washed with cold acetonitrile (10 ml) and diethyl ether (20 ml), and dried in vacuo at room temperature yielding 2.03 g of trans (±)-3-[[2 -(acetylamino)ethyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester which melts at 174°-76° C. Additional 0.46 g of equally pure product is obtained on cooling the filtrate to -20° C. for 2 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(Cl)c2)[C@@H](N)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of the compound (14.4 g) obtained in step 5 in toluene (120 mL) was added DPPA (16.5 g) and triethylamine (8.36 mL) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction solution was cooled, 8N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried, and concentrated under reduced pressure to give tert-butyl (3R*,4S*)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (13.3 g, 100%) as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29](=[O:31])[CH3:30])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(N)cc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(NC(C)=O)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
Combine 3-(4-aminophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in CH2Cl2 (5 mL) and stir. Add triethylamine (1.5 eq) and acetyl chloride (1.0 eq) at room temperature. Stir the mixture overnight. Add a saturated solution of NH4Cl and extract with CH2Cl2 (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purification by chromatography (hexane: ethyl acetate 4:1) provides the title compound (0.125 g, yield 90%). MS (ES+, m/e): 361 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].N1CCCCC1.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Reactant: COCC(=O)Cl
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A stirred solution of d 6-amino-5-fluoro-1,3-dihydro-indol-2-one (2.028 g, 12.2 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with piperidine (1.3 ml). The mixture was cooled to −50° C. in an ethanol-dry ice bath and added with methoxyacetyl chloride (1.35 g, 12.5 mmol) in 20 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide (2.0 g, 69.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][N:20](C)[C:21](=O)OC(C)(C)C)[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29]>>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH2:18][CH2:19][NH:20][CH3:21])[N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(CCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 112c (900 mg, 1.99 mmol) in HCl (5 mL, 4 M in 1,4-dioxane, 20 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated to give 5-bromo-1-methyl-3-(6-(2-(methylamino)ethoxy)pyridin-2-ylamino)pyridin-2(1H)-one hydrochloride 112d (660 mg, 85%) as yellow solid. This material was used for next step directly. ESI-LCMS: m/z=354.9 (free base)
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.ClN1C(=O)CCC1=O.[F:30][C:31]1[C:36]([CH:37]=[CH2:38])=[C:35]([F:39])[CH:34]=[CH:33][C:32]=1[OH:40].C(=O)([O-])O.[K+]>C(OCC)(=O)C.O>[F:30][C:31]1[C:32]([OH:40])=[CH:33][CH:34]=[C:35]([F:39])[C:36]=1[CH:37]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4c(F)ccc(O)c4F)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.278 g) in ethyl acetate (80 ml) was added, at room temperature, N-chlorosuccinimide (658 mg). After stirring at 60° C. for 30 min, 2,4-difluoro-3-vinylphenol (705 mg), potassium hydrogencarbonate (822 mg) and then one drop of water were added, at room temperature, to the reaction mixture. After stirring overnight at room temperature, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2,6-difluoro-3-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (658 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][C:10]([CH3:13])([O-])[CH3:11].[K+].BrCC1CC1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][CH:10]2[CH2:13][CH2:11]2)[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (10 mL) at RT, potassium tert-butoxide (0.68 g, 6.07 mmol) was added and the mixture was stirred for 30 min. To this mixture, (bromomethyl)cyclopropane (1.03 g, 8.62 mmol) was added, and the resulting mixture was stirred at 70° C. for 2 h. The mixture was allowed to cool to RT, diluted with EtOAc (50 mL) and quenched with water (20 mL). The organic layer was washed with water (2×20 mL) and brine (20 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford 5-bromo-1-(cyclopropylmethyl)pyridin-2(1H)-one.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]([N:20]3[CH2:26][C:25]4([CH3:28])[CH2:27][CH:21]3[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24]4)=[O:19])=[CH:17][C:11]=2[N:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:28][C:25]12[CH2:27][CH:21]([N:20]([C:18]([C:16]3[CH:15]=[CH:14][C:12]4[NH:13][C:9]([CH:7]5[CH2:8][CH:6]5[C:4]([OH:5])=[O:3])=[N:10][C:11]=4[CH:17]=3)=[O:19])[CH2:26]1)[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24]2
Reactant: CCOC(=O)C1CC1c1nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3[nH]c(C4CC4C(=O)O)nc3c2)C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester (60 mg, 0.147 mmol) in 96% ethanol (3 mL) at room temperature under an inert atmosphere of nitrogen was added 1N NaOH (aq) (0.36 mL, 0.36 mmol). The mixture was stirred for 16 hrs at 50° C. The reaction was quenched by the addition of water (3 mL) and acidified to pH 2 with 1N HCl followed by extraction with diethyl ether (2×5 mL). The combined organic phases were washed with water (2×5 mL), brine (5 mL), dried (MgSO4), filtered, and evaporated in vacuo affording 49 mg (88%) of the title compound as a solid. MS-ESI m/z 382; 1H NMR (400 MHz, CDCl3) δ 0.87-1.06 (m, 6H), 1.08-1.20 (m, 4H), 1.30-1.38 (m, 1H), 1.39-1.45 (m) and 1.48-1.64 (m, 3H), 1.70-1.90 (m, 2H), 1.91-2.01 (m, 1H), 2.18-2.30 (m) and 2.43-2.61 (m) and 2.85-3.02 (m, 2H), 3.15 (t) and 3.66 (t, 1H), 3.20-3.34 (m, 1H), 3.88-4.01 (m) and 4.54-4.65 (m, 1H), 7.39-7.50 (m, 1H), 7.69-7.85 (m, 2H).