Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CCl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CN2CCOCC2)cc1
Yield: 31.6 %

Procedure:
To a solution of 200 mg (0.38 mmol) 4-chloromethyl-benzoic acid-(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 10 ml CH2Cl2 were added 53 □l (0.38 mmol) Et3N and 33 μl (0.38 mmol) morpholine. After 16 hours the reaction mixture was purified by chromatography over silica gel to give 70 mg (0.12 mmol, 32%) 4-morpholin-4-ylmethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:15](O)=[O:16])=[CH:5][CH:4]=1.[NH:42]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>>[CH2:53]([O:52][C:50](=[O:51])[CH2:49][N:42]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:40]=[CH:41][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=1)[CH3:54]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1

Procedure:
3-[3-(4-Methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid was converted to the acid chloride which was treated with diethyl iminodiacetate using the procedure of Example 17 to give N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(4-methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as an oil which exhibited nmr and mass spectra consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].C1COCC1>CO.[Ni]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(Br)c1O

Procedure:
A solution of 5.3 g (22.7 mmol) 2-bromo-6-nitro-phenol in 100 ml MeOH:THF=1:1 is hydrogenated in the presence of 0.2 g Ra—Ni (in EtOH, Degussa B113W). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the crude title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>CN(C=O)C>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OCc2ccc3ccccc3n2)cc1)CCc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Yield: 113.1 %

Procedure:
A solution of 1,5-bis(4-hydroxyphenyl)-3-pentanone (2.0 g, 8 mmol), prepared as in step 2, and potassium carbonate (2.76 g, 20 mmol) in DMF (40 mL) was treated with chloromethylquinoline (3.55 g, 20 mmol) at room temperature for 36 hours. The mixture was then poured into ice water (200 mL), and the precipitated solid was filtered, washed with water and dried in vacuo to afford crude 1,5-bis(4-(2-quinolylmethoxy)phenyl)-3-pentanone (5 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine (Enantiomer B) and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=1[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CCOc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Ethoxy-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c10) the title compound is obtained as off-white solid.
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][Zr:4]([CH3:26])(=[SiH2:25])([CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:24])[CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:14].[H][H]>ClCCl.[Pt]=O>[Cl-:1].[Cl-:1].[CH3:26][Zr:4]([CH3:3])(=[SiH2:25])([CH:5]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH3:14])[CH:15]1[C:23]2[CH:18]([CH2:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH3:24]
Reactant: [H][H]
Reactant: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: O=[Pt]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1CC2CC=CC=C2C1[Zr](C)(C)(=[SiH2])C1C2=CC=CCC2CC1C
Reaction time: 8 h

Procedure:
A 0.5 g portion of dimethylsilylenebis(2-methylindenyl)zirconium dichloride obtained in Example 1 was dissolved in 250 ml of dichloromethane and introduced into a 1.0 liter autoclave, and 0.5 g of platinum oxide was then introduced. Hydrogen pressure was increased to 50 kg/cm2 ·G to carry out hydrogenation at 30° C. for 4 hours. After the reaction was completed, the slurry was filtered to separate the platinum catalyst, and the solvent was removed by distillation. The product was dissolved in 200 ml of toluene, and the solution was concentrated into about 50 ml, which was left standing overnight at -20° C. to form crystals. The crystals formed were filtered, and desiccated to give 0.22 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([CH3:32])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:34]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: Cc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution Of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methylbenzoic acid N-isopropyl-N-cyclohexyl amide (1.12 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:25][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: NC1CCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NC4CCc5ccccc54)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 1-aminoindane were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 449 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]C)=O)[CH2:3][CH2:2]1.O.[NH2:13][NH2:14]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:13][NH2:14])=[O:10])[CH2:3][CH2:2]1
Reactant: COC(=O)CN1CCOCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCOCC1
Temperature: 95 °C
Yield: 92 %

Procedure:
In a 25 mL, 3-neck round-bottom flask, methyl 2-morpholinoacetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.087 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-morpholinoacetohydrazide (0.23 g) which was used without further purification in the following step.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:4](=[O:20])[C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH4-].[Na+].Cl>CO>[NH2:1][C:2]1[N:3]([CH2:21][O:22][CH:23]([CH3:24])[CH3:25])[C:4](=[O:20])[C:5]2[C:10]([CH2:11][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: CC(C)OCn1c(N)nc2c(c(C=O)cn2Cc2ccccc2)c1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OCn1c(N)nc2c(c(CNc3ccccc3)cn2Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
In 10 ml of dry methanol is dissolved 340 mg of 2-amino-7-benzyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one-5-carbaldehyde and 93 mg of aniline and the mixture is allowed to stand under stirring at room temperature for 60 min. The mixture is then cooled to 0° C. and treated with 38 mg of sodium borohydride for 2 hrs. The excess reagent is decomposed with HCl, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography to give 285 mg of 2-amino-7-benzyl-5-phenylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of the above product is dissolved in 28.5 ml of liquid ammonia-dimethoxyethane (1:1) and an excess of sodium metal shavings are added until a permanent blue color is observed for more than 5 min. To this mixture is added ammonium chloride to terminate the reaction and the whole system is allowed to stand at room temperature until the liquid ammonia is removed. The dimethoxyethane is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography to give 128 mg of 2-amino-5-phenylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. This product is further dissolved in 50 ml of 2 N--HCl and after nitrogen purging, hydrolyzed by heating at 70° C. for 5 hrs. The solvent is then evaporated to dryness under reduced pressure to give 120 mg of the desired compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (10 mg, 27%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH:75][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (800 mg, 1.74 mmol) in methylene chloride (10 mL), HATU (Aldrich, 662 mg, 1.74 mmol) was added followed by the addition of DIPEA (1.74 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (Aldrich, 1.74 mmol). The mixture was stirred at rt for 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, EtOAc/Hexanes, 20%) to give a white solid. 810 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[C:21]3[O:20][C:19]([CH3:23])([CH3:22])[CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>>[CH3:22][C:19]1([CH3:23])[CH2:18][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=5)[CH:3]=4)[N:8]=3)[C:21]=2[O:20]1
Reactant: CC1(C)Cc2cccc(Nc3ccc4cc(Br)ccc4n3)c2O1
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(Nc2ccc3nc(Nc4cccc5c4OC(C)(C)C5)ccc3c2)n1

Procedure:
The title compound, yellow foam, MS: m/e=397.2 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-amine and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Reaction time: 144 h
Yield: 94.8 %

Procedure:
To a solution of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.55 g) in ethanol/THF (30/30 ml) was added at room temperature 1N sodium hydroxide solution (1.8 ml), and the mixture was stirred for 6 days and then refluxed for 2 hours. To the mixture was added 1N hydrochloric acid (1.8 ml). The resulting solid was collected by filtration, which was washed with ethanol and diethylether to give yellow powder of 7-(4-morpholinophenyl)-2,3-dihydro-l-benzo-thiepine-4-carboxylic acid (502.2 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]([NH:27][NH2:28])=[NH:2])[N:4]=[C:5]2[O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(F)cc23)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(F)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (400 mg, 1.12 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The reaction mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a white solid, which was used in next step without purification (450 mg, 100%). ESI-MS m/z [M+H]+ 390.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([CH2:28][C:29]5[C:30]([F:40])=[C:31]6[C:36](=[CH:37][C:38]=5[F:39])[N:35]=[CH:34][CH:33]=[CH:32]6)=[CH:26][N:27]=4)[N:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:30]1[C:29]([CH2:28][C:25]2[N:23]3[N:24]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:18]=4)[CH:20]=[CH:21][C:22]3=[N:27][CH:26]=2)=[C:38]([F:39])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[N:35]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-{4-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 244, 219 mg, 0.401 mmol) was dissolved in DCM (3 mL) with TFA (0.619 mL, 8.03 mmol). The RM was stirred at rt for 1 h 15 min and it was quenched with ice water. It was extracted with EtOAc twice. The combined organic layers was washed with brine and dried over Na2SO4. It was filtered and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and the acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.8 min (conditions 2), MH+=446).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC1CCNCC1
Reactant: Brc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCN(c2ccccn2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a stirred solution of ethyl 2-(piperidin-4-yl)acetate, hydrochloride (2.0 g, 9.63 mmol) in DMF (40 mL) was added K2CO3 (3.99 g, 28.9 mmol) followed by 2-bromopyridine (1.521 g, 9.63 mmol) and stirred at 130° C. for 16 h. Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (2×100 mL), brine (100 mL) and dried over Na2SO4 filtered and concentrated under reduced pressure. The residues was purified by column chromatography using 100-200 silica gel by eluting with 20% ethyl acetate in petroleum ether to afford ethyl 2-(1-(pyridin-2-yl)piperidin-4-yl)acetate (600 mg, 19.86% yield) as color less liquid. LCMS (ES) m/e 249.20 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[NH2:19][OH:20].[OH-].[K+].CO>C1COCC1>[OH:20][NH:19][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)CCCCCS(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCS(=O)c1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 6-(4-chloro-benzenesulfinyl)-hexanoic acid methyl ester (2.0 g, 7 mmol) in distilled THF (40 mL) containing 50% aqueous hydroxylamine (4.1 mL, 62 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (12 mL, 1M, 12 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (40 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with brine (75 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (1.8 g, 89%) as a white powder, mp 125° C.