Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]\[CH2:13][OH:14])[CH:2]=1.[C:15]([O:22]C(OC(C)(C)C)=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.CCCCCCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]\[CH2:13][OH:14])[CH:2]=1.[C:18]([O:17][C:15](=[O:16])[O-:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OC/C=C\c1cnc2ccccc2c1
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[O-]

Procedure:
The solid cis-3-(3-quinolyl)-2-propen-1-ol (10.0 g, 54.1 mmol), di-t-butyl dicarbonate (17.6 g, 80.6 mmol, 1.5 equiv), toluene (43 g) and tetra-n-butylammonium hydrogensulfate (0.68 g, 2.0 mmol) were combined and stirred (mechanically) in a three-necked round-bottom flask. To this stirring mixture was slowly added an aqueous sodium hydroxide solution (28 g H2O and 7.0 g, NaOH) over 10 minutes. The temperature of the biphasic mixture warmed from 18° C. to 31° C. over 1.5 hours and was allowed to stir overnight at room temperature. The reaction was then diluted with toluene (33 mL) and water (19 mL). The layers were separated (aq. pH 12) and the organic was washed consecutively with water (1×28 mL) and 5% aq. NaCl (1×28 mL). The organic layer was then washed with an aqueous sodium chloride solution (7 g NaCl, 28 g H2O) before concentration under reduced pressure and a bath temperature of 50° C. The oil which resulted was dissolved in heptane (100 g) and concentrated by rotary evaporation (2×). The resulting residue was dissolved in 55 mL of heptane for crystallization. The product was collected at −5° C., washed with cold heptane (10 mL) and vacuum dried at room temperature to provide a white to off-white colored solid (13.6 g, 88.3%). Purity as determined by HPLC was 98.7%.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][C:14]2[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=2[O:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]([CH2:27][CH2:28][CH3:29])C(=O)C(F)(F)F)[NH:4][CH:3]=1.Cl.[OH-:36].[Na+]>O>[OH:30][CH:18]([CH2:19][NH:20][CH2:27][CH2:28][CH3:29])[CH2:17][O:16][C:15]1[CH:31]=[CH:32][CH:33]=[CH:34][C:14]=1[CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:36])[NH:4]2
Reactant: CCCN(CC(O)COc1ccccc1CCCc1cccc2[nH]cc(Cl)c12)C(=O)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCNCC(O)COc1ccccc1CCCc1cccc2c1CC(=O)N2

Procedure:
A mixture of 4.66 g of the product of Step B and 260 ml of N hydrochloric acid was refluxed under an inert atmosphere for 3 hours and was diluted with water. The mixture was made alkaline by sodium hydroxide addition and was extracted with ethyl acetate. The organic was washed with water, dried and evaporated to dryness. The residue was triturated with ether and dried at 100° C. under reduced pressure to obtain 2.19 g of 1,3-dihydro-4-[3-[2-[2-hydroxy-3-propylamino-propoxy]-phenyl]-propyl]-2H-indol-2-one which melted at 122° C. after crystallization from isopropanol.
Reaction SMILES: C(OCC)(=O)C.[CH:7]1([NH:10][C:11](=[O:26])[C@@H:12]([OH:25])[C@@H:13]([NH:17]C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]1.[ClH:27].C(O)(C)C>C(O)(C)C>[ClH:27].[CH:7]1([NH:10][C:11](=[O:26])[C@@H:12]([OH:25])[C@@H:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (92.2 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (69.63 g). The solution was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (18.2 g) was dropwise added, taking 1 hour. After stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 6 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (30 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (7.06 g, isolation yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[CH:22]1([NH:25][C:11](=[O:13])[CH:10]([OH:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Reactant: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.8 %

Procedure:
To 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (3 g, 10.16 mmol), cyclopropanamine (780 μL, 11.26 mmol) in dichloromethane (70 ml) at 5° C. EDC (2.4 g, 12.52 mmol), HOBt (1.9 g, 12.41 mmol) and Et3N (3 ml, 21.52 mmol) were added and the mixture stirred at room temperature for 48 h. After completion of reaction dichloromethane (100 ml) was added, the solution washed with water and brine, dried, filtered off with suction and concentrated to give 3.9 g of a brown oil which was purified further via chromatography on silica gel (eluent: CH2Cl2+5-30% (v/v) methanol). After evaporation of the combined product fractions 0.82 g of a pale oil were obtained; ESI-MS [M-Boc+H]±: 235.1.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:19]3[S:20][C:21]([C:25]([O-:27])=[O:26])=[C:22]([CH3:24])[N:23]=3)[CH:9]=[CH:10][C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:6]2[CH:7]=[C:8]([C:19]3[S:20][C:21]([C:25]([OH:27])=[O:26])=[C:22]([CH3:24])[N:23]=3)[CH:9]=[CH:10][C:11]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1nc(-c2ccc(Oc3ccccc3)c(-n3ccnc3)c2)sc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Oc3ccccc3)c(-n3ccnc3)c2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A reaction mixture solution was prepared by dissolving 20.2 mg of 2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 1 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxide aqueous solution. The reaction mixture was stirred at 50° C. for 2 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated, followed by purifying using a conventional method to obtain 9.0 mg of 2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: C[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1.Cl.Cl.NCC1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[C:22]([C:33]([NH2:35])=[O:34])=[CH:21][N:20]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[C:6]([NH:2][CH2:3][C:4]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[C:22]([C:33]([NH2:35])=[O:34])=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(=[O:7])[CH3:5]
Reactant: CN1CCCC1=O
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(Nc2ncc(C(N)=O)c(Nc3cccc(C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10 ml portion of NMP solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride synthesized by the method described in Example 8 of WO 99/31073 was mixed with 0.53 ml of triethylamine and 0.12 ml of acetic anhydride, followed by stirring overnight at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate, the organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was triturated with methanol, and washed to obtain 270 mg of 2-({4-[(acetylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32][CH:33]2CC[CH2:35][CH2:34]2)[CH:3]=1.Br[CH2:39]C1CC1>>[CH3:39][O:24][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[CH:15][CH:16]=1
Reactant: BrCC1CC1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, from 3-{4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester (Example 59, intermediate b) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Brown solid (54%). MS (Turbo Spray): m/z=511.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 634.0 [(M−H−]; mp 251° C.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)=O.[ClH:22]>C(O)C>[ClH:22].[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:9]([N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)(=[O:11])=[O:10]
Reactant: O=CN1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reaction time: 5 h

Procedure:
To 1-formyl-4-(2-naphthalenesulfonyl)piperazine was added ethanol (30 ml) and 1 N hydrochloric acid (100 ml), and the solution was stirred for 5 hours under reflux. The reaction solution was concentrated, and the residue was washed with ethyl acetate and dried under reduced pressure to give 1-(2-naphthalenesulfonyl)piperazine hydrochloride (43.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][C:11]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(OC(=O)COC1C=CC(CCC([N:71]2[CH2:92][CH2:91][C:74]3([NH:78]/[C:77](=[N:79]/[C:80]([C:82]4[C:87]([NH2:88])=[N:86][C:85]([NH2:89])=[C:84]([Cl:90])[N:83]=4)=[O:81])/[NH:76][CH2:75]3)[CH2:73][CH2:72]2)=O)=CC=1)(C)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:71]2[CH2:92][CH2:91][C:74]3([NH:78]/[C:77](=[N:79]/[C:80]([C:82]4[C:87]([NH2:88])=[N:86][C:85]([NH2:89])=[C:84]([Cl:90])[N:83]=4)=[O:81])/[NH:76][CH2:75]3)[CH2:73][CH2:72]2)=[O:20])=[CH:12][C:11]=1[Cl:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-(4-tert-butoxycarbonylmethoxy-3-chloro-phenyl)-propionic acid (Intermediate B) (4 g, 12.71 mol) in DMF (80 ml) at RT was treated with HATU (4.83 g, 12.71 mmol), N-methylmorpholine (5.73 ml, 52.1 mmol) followed by 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (WO09074575, Ex. 38, page 123) (5.31 g, 13.34 mmol). The resulting mixture was stirred at RT for 1 h and then diluted with water (500 ml). The resulting solid was collected by filtration and rinsed with water. Purification by chromatography on silica eluting with 0-7% 7N ammonia in MeOH/DCM afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (2H, br hump), 7.34 (1H, d), 7.14 (1H, dd), 6.90 (1H, d), 6.87 (2H, br hump), 4.74 (2H, s), 3.65 (1H, m), 3.57 (1H, m), 3.43 (2H, s), 3.37 (2H, m), 2.75 (2H, t), 2.62 (2H, t), 1.62 (4H, m), 1.43 (9H, s).
Reaction SMILES: ClC1C=CC=CC=1.C([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:28])=[C:15]([NH:17][C:18](=[O:27])[CH:19]=[CH:20]C2C=CC=CC=2)[CH:16]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:28])=[C:15]2[C:16]=1[CH:20]=[CH:19][C:18](=[O:27])[NH:17]2
Reactant: CCOc1ccc(C)c(NC(=O)C=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: Cc1ccc(O)c2ccc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Chlorobenzene (28.6 ml) was added to N-(5-ethoxy-2-methylphenyl)cinnamamide (3.9 g, 14.8 mmol). While stirring the mixture in a hot bath (125° C.), aluminum chloride (9.2 g, 69.0 mmol) was added to the mixture, followed by stirring for 30 minutes. After the mixture was cooled, it was poured into ice-water, to which n-hexane was added. Precipitated crystals were collected. The crystals were dissolved in chloroform-methanol (4:1). The solution was dried and condensed. The resultant residue was washed with chloroform, then dissolved in chloroform-methanol (4:1) again. The solution was condensed again. The residue was washed with chloroform and then dissolved in methanol. The resultant solution was treated with activated carbon. 2.4 g of 5-hydroxy-8-methylcarbostyril was obtained as colorless crystals (92.7%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)([O-:22])=[O:21]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were added 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (195 mg, 0.65 mmol), 4-(trifluoromethyl)-benzylamine (112 mg, 0.65 mmol), acetonitrile (1 mL) and DIPEA (0.34 mL, 1.96 mmol). The mixture was heated to 80° C. for 24 h at which point the reaction was cooled to RT and concentrated to dryness. The resulting residue was washed with water (2×20 mL) and then dissolved in EtOAc, dried over Na2SO4, filtered and then concentrated. The material was used without further purification. MS (ESI): mass calcd. for C24H18F3N3O3, 453.13; m/z found, 454.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:38]1
Reactant: F[C@H]1CCNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC[C@H](F)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and (S)-(+)-3-fluoropyrrolidine hydrochloride (Oakwood, Cat. No. 013157). LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[Li+].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O:12][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C(=O)[O-])N2CCCCC2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(C(=O)O[C@H]2CN3CCC2CC3)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
Lithium 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (384 mg, 1.50 mmol), DCC (621 mg, 3.01 mmol), and HOBT (461 mg, 3.01 mmol) were dissolved in dry THF (16 ml). (R)-quinuclidin-3-ol (574 mg, 4.51 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the crude was dissolved in EtOAc, washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=9/1/0.02) to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (207 mg, 38.4% yield) as a colourless oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[N:59]=[C:58]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:57]=[C:56]([O:70][C@H:71]([CH3:75])[C@H:72]([OH:74])[CH3:73])[CH:55]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:69][C:63]1[C:64]([F:68])=[CH:65][CH:66]=[CH:67][C:62]=1[CH2:61][S:60][C:58]1[N:59]=[C:54]([NH:12][S:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]2)(=[O:10])=[O:11])[CH:55]=[C:56]([O:70][C@H:71]([CH3:75])[C@H:72]([OH:74])[CH3:73])[N:57]=1
Reactant: C[C@@H](O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(=O)(=O)Nc2cc(O[C@H](C)[C@@H](C)O)nc(SCc3cccc(F)c3F)n2)C[C@H](C)N1
Temperature: 100 °C

Procedure:
To a solution of (2R,6S)-2,6-Dimethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 3d. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (1.05 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.541 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.731 g) and (2R,3R)-3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)butan-2-ol ((the product of example 4 step i), 0.541 g) in dioxane (40 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. The reaction mixture was then reduced in vacuo and the residue separated between DCM (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by prep HPLC to give the title compound as a white solid. Yield: 80 mg
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (30 mg) in dimethylformamide (1 ml), there were added potassium carbonate (10 mg) and ethyl bromoacetate (20 mg), and the mixture was stirred at 80° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was purified by thin layer chromatography to give 1.8 mg of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxycarbonylmethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1) as a glassy substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C2C=CC(S(C)(=O)=O)=CC=2)=N1)C(C)C.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.9 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 75.9%).