Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH3:8].N([O-])=[O:11].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=N[O-]
Agent: [Na+]
Product: Cc1ccc(O)cc1Br

Procedure:
In a manner similar to that of Example 11(a), by reaction of 20 g (107 mmol) of 3-bromo-4-methylphenylamine with 8.9 g (129 mmol) of sodium nitrite, a brown oil is obtained, without purification (m=20 g; Y=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38].C[O-].[Na+:42]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O-:39])=[O:38].[Na+:42]
Reactant: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
6-Chloro-7-(4-(3-phenoxyphenethylcarbamoyl) phenoxy)chroman-4-carboxylic acid (56.4 mg, 0.104 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (207 μl, 0.104 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (58.0 mg, 0.102 mmol, 98.8% yield) as a solid. MS (apci) m/z=543.9 (M+2H-Na).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[CH2:29]CN>>[C:27]1([CH3:26])[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[CH2:29][CH2:1][NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10]
Reactant: Cc1ccccc1CCN
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: Cc1ccccc1CCNC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 39 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 2-methylphenethylamine instead of benzylamine and obtained in 39% yield (HPLC: 95%, RT: 6.67 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.43 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.42-8.36 (m, 2H), 7.76 (d, J=5.5 Hz, 1H), 7.37 (dd, J=3.3, 2.2 Hz, 1H), 7.18-7.10 (m, 4H), 6.46 (dd, J=3.7, 1.8 Hz, 1H), 3.47-3.43 (m, 2H), 2.86 (t, J=7.9 Hz, 2H), 2.36 (s, 3H); MS (m/z) 378 [M+H]+.
Reaction SMILES: [N+]([O-])(O)=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13](C)[C:14]=2C)[O:9][C:8](=[O:19])[CH:7]=1.[CH:20](Cl)(Cl)Cl>>[CH3:18][C:12]1[C:11]([CH3:20])=[C:10]2[C:15]([C:6]([OH:5])=[CH:7][C:8](=[O:19])[O:9]2)=[CH:14][CH:13]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1cc2oc(=O)cc(O)c2c(C)c1C
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (18 ml) was added to a stirred suspension of 4-hydroxy-5,6,7-trimethylcoumarin (m.p. 262°-4°; 3.38g) in chloroform (250 ml) at room temperature over 1.5 hours. After a further 30 minutes, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (70 ml) added to the residue. Filtration gave the product, m.p. 134°-7°(d), (C12H11NO5 requires C, 57.83; H, 4.45; N, 5.62. Found: C, 57.92; H, 4.57; N, 5.65).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:27]([C:26]2[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=2[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3nccs3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (Example Q) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 524.3 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1cccc(CO)c1
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To the product from Example 176a (2.0 g. 7.2 mmol) in ethanol (25 mL) was added sodium borohydride (0.32 g, 8.6 mmol). The reaction was stirred for 4 h. The excess sodium borohydride was destroyed by the addition of acetic acid. The reaction was poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.9 g, 94%).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16](O)=[O:17])[CH2:12]2.[NH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>>[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16]([NH:19][N:20]1[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32])=[O:17])[CH2:12]2
Reactant: O=C(O)CC1C2CC3CC(C2)CC1C3
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC1C2CC3CC(C2)CC1C3
Temperature: 80 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Thionyl chloride (1.72 mL, 23.5 mmol) was added to adamant-2-yl acetic acid (241 mg, 1.24 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in a 25 mL round-bottom flask with stir bar. The resulting solution was heated at 80° C. for 1 hour, and then concentrated under vacuum. The residue was taken up in CH2Cl2 (3 mL) and concentrated under vacuum. This process was repeated twice more to ensure removal of excess thionyl chloride. The residue was taken up in fresh CH2Cl2 (2 mL) and 3-amino-2-isopropyl-4(3H)-quinazolinone (252 mg, 1.24 mmol) was added. The mixture was stirred at 20-25° C. After 18 hours, diisopropylethylamine (0.40 mL) was added and the solution was stirred for 1 hour longer, and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 90:10-70:30). Unreacted quinazolinone (80 mg, 31% recovered) eluted first, followed closely by a second fraction from which crystals precipitated on standing at room temperature for 1 hour. The crystals were collected by filtration and dried at 50° C. under vacuum to provide the title compound (102 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (2 d, J=6.7 Hz, 6H), 1.58-1.96 (m, 14H), 2.41 (br. t, J=7.3 Hz, 1H), 2.64 (d, J=7.5 Hz, 2H), 3.16 (hept, J=6.7 Hz, 1H), 7.43 (td, J=7.3, 1.2 Hz, 1H), 7.68 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 8.21 ppm (d, J=7.5 Hz, 1H); MS (DCI) m/z 380 (M+H)+; Elemental Analysis calculated for C23H29N3O2.0.3H2O: C, 71.77; H, 7.75; N, 10.92. Found: C, 71.70; H, 7.68; N, 10.76.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>CS(C)=O>[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: COC[C@@H]1CCCN1
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1c1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
To a solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg, 0.51 mmol) in DMSO (2 mL) was added (s)-(+)-2-(methoxymethyl)-pyrrolidine (0.29 mL, 2.55 mmol). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, followed by reverse-phase preparative HPLC using a Phenomenex Gemini™ column (10 micron, C18, 110 Å, 150×30 mm), 0.1% TFA in CH3CN/H2O as mobile phase, gradient 10% to 90% over 15 min., then treated with Si-carbonate resin to provide (S)—N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 434.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]1[O:10][N:9]=[C:8](Cl)[CH2:7]1)[C:3]([OH:5])=[O:4].[OH-:12].[Na+].Cl>>[CH2:7]1[C:8]([OH:12])=[N:9][O:10][CH:6]1[CH:2]([NH2:1])[C:3]([OH:5])=[O:4]
Reactant: [OH-]
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Agent: Cl
Agent: [Na+]
Product: NC(C(=O)O)C1CC(O)=NO1
Yield: 80 %

Procedure:
To 1.20 g. (6.75 mmole) of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazol-acetic acid (AT-125), is added 20 ml. of 2N sodium hydroxide and stirred at 25° for 36 hours. The solution is brought to ~3.5 pH with 6N hydrochloric acid (dropwise addition) and then stored at -10° (freezer) overnight. The crystals are collected by filtration, washed twice with cold water, and then dried giving 720 mg. of trichloromic acid. The initial filtrate is lyophilized and the resulting powder is taken up in 4 ml. of water, filtered, and washed with two 4 ml. portions of cold water, and dried yielding an extra 160 mg. of tricholomic acid (total 80% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[O:17]=[C:16]1[NH:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C=NCCCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(N2CCNC2=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of methyl 2-aminoisonicotinate (5.00 g, 32.9 mmol) and 2-chloroethyl isocyanate (4.51 g, 42.7 mmol) in anhydrous tetrahydrofuran (85 mL) was stirred at ambient temperature for 17 hours and refluxed for 3 hours, followed by the addition of triethylamine (10 mL) and potassium carbonate (9.60 g, 69.50 mmol). The reaction mixture was refluxed for 23 hours, cooled to ambient temperature and filtered. The solid residue was washed with water (2×20 mL hexanes (2×20 mL) and dried in vacuo to give methyl 2-(2-oxoimidazolidin-1-yl)isonicotinate as a colorless solid (4.22 g, 58%): 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.35-7.33 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 3.85 (s, 3H), 3.41-3.36 (m, 2H); MS (ES+) m/z 222.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[C:15]([F:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: CC1(N)COC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(F)c2)c(C)c1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)c(F)c2)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-3-fluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.053 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 465 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19](=[S:21])[NH2:20])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)C>[CH:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([C:19]3[S:21][CH:23]=[C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:20]=3)[CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Yield: 83.5 %

Procedure:
A solution of the compound (236 mg, 0.78 mmol) obtained in step 2 and ethyl 4-chloroacetoacetate (0.126 ml, 0.93 mmol) in ethanol (4 mL) was stirred at 90° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from hexane to give ethyl 2-(2-(1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (269 mg, 0.651 mmol, 84%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[NH2:15][OH:16]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH:12]2[CH2:14][CH2:13]2)([CH3:11])[CH:9]=[N:15][OH:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: C[C@](C=O)(c1ccc(Br)cc1)C1CC1
Solvent: CCO
Product: C[C@](C=NO)(c1ccc(Br)cc1)C1CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To the crude solution from the previous step (solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal) retained in the reactor is charged 6.2 kg of 200 proof ethanol. The batch was then concentrated via vacuum distillation (Tjacket NMT 50° C.) to ˜7 L. To the batch was charged 6.2 kg of 200 proof ethanol. The batch temperature is then adjusted to 0±5° C. To the cooled batch is charged hydroxylamine (50 wt % aqueous solution, 1.0 kg, 15.4 mol, 1.5 equiv) at a rate to maintain the internal temperature of the batch <30° C. The batch is then agitated at an internal temperature of 20±5° C. for 2 h. An HPLC sample is removed to determine conversion (target >97 A % conversion 220 nm, for this batch: >99 A % conversion). To the batch is charged isopropyl acetate (19 kg) and 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 7.6 kg). To the batch is charged 5 wt % aqueous sodium chloride (9.2 kg). The batch is agitated for 20 min and then the layers are allowed to settle. The aqueous layer is cut (mass aqueous cut 14.5 kg). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). To the batch is charged acetonitrile (10 L). The batch volume is adjusted to 7 L via vacuum distillation (external temperature NMT 60° C.). The batch was drained and the reactor rinsed with acetonitrile (2 L). The rinse was combined with the original batch and the resulting solution massed 7.75 kg (HPLC purity: 80.4 A % (220 nm), Karl Fisher 3.2% water and the Proton NMR wt % assay (with dimethyl fumarate as an internal standard) is 28.0 wt % (2.76 kg, 78.7% yield) of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (8) for the two step process. The solution is used as is for the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:29])[C:10](=[O:28])[N:11]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:30].N1CC[O:38]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:29])[C:10](=[O:28])[N:11]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][O:38][CH2:25][CH2:24]3)[C:12]=2[C:16]([N:18]([CH3:19])[CH3:20])=[O:17])[C:7]1=[O:30]
Reactant: CN(C)C(=O)c1c2c(c(O)c(=O)n1CCN1CCCC1)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: C1COCCN1
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1CCN1CCOCC1)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-(2-pyrrolidin-1-ylethyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 66), substituting pyrrolidine with morpholine. (ES MS M+1=507)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH2:11]([CH2:14][OH:15])[CH2:12][NH2:13]>>[OH:15][CH2:14][CH2:11][CH2:12][NH:13][S:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:9])=[O:8]
Reactant: NCCCO
Reactant: O=S(=O)(Cl)CCCCCCl
Product: O=S(=O)(CCCCCCl)NCCCO

Procedure:
The reaction was carried out in the same manner as in Preparation Example 4 except for using 5-chloropentanesulfonyl chloride (3.08 g, 15 mmol) in place of 6-chlorohexanesulfonyl chloride, and n-propanolamine (2.48 g, 33 mmol) in place of ethanolamine in Preparation Example 4, to give a by-product [N,O-bis(5-chloropetanesulfonyl)propanolamine] from a first eluted fraction in the amount of 0.64 g and N-(3-hydroxypropyl)-5-chloropentanesulfonamide from a second eluted fraction as a colorless waxy product in the amount of 2.76 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[F:12][CH:13]([F:17])[C:14]([CH3:16])=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:14]([CH:13]([F:17])[F:12])([CH3:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)cc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C(F)F)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (8.07 g, 47.3 mmol), MeOH (81 mL), 1,1-difluoroacetone (4.89 g, 52.0 mmol), and pyrrolidine (4.30 ml, 52.0 mmol) were stirred at ambient temperature for 45 hours, at 35° C. for 7 hours, then at 50° C. for 3 hours. The reaction mixture was concentrated, diluted with MTBE (75 mL), then washed with water (40 mL), 2N HCl (2×25 mL), brine (20 mL), 2N NaOH (2×20 mL), and brine (2×20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (9.78 g, 39.7 mmol, 84% yield) as a brown oil. MS (DCI/NH3) m/z 264 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)C(OC)=O.[Cl-].[Li+].O.[CH3:21]S(C)=O>>[CH2:1]([O:2][C:3](=[O:17])[CH2:4][C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:21]
Reactant: CS(C)=O
Reactant: COC(=O)C(C(=O)OC)C1(C#N)CCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CCOC(=O)CC1(C#N)CCCCC1
Yield: 74 %

Procedure:
26.9 g (100 mmol) of (1-cyanocyclohexyl)malonic acid dimethyl ester, 4.3 g (100 mmol) or lithium chloride and 3.6 g (200 mmol) of water were heated in 300 ml of dimethyl sulfoxide for 22 hours to 150° C. Then it was cooled, mixed with 700 ml of water and extracted with 1000 ml of pentane. 14.4 g of (1-cyanocyclohexyl)acetic acid ethyl ester was obtained by distillation of the organic phase, corresponding to a yield of 74 percent (relative to the (1-cyanocyclohexyl)malonic acid dimethyl ester used). Data for the product was:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:15]([CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH:16]=1
Reactant: Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.8 %

Procedure:
To a solution of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (297 mg, 0.72 mmol) produced in Example (104e) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous solution of sodium hydrogencarbonate was added to the residue and extraction was performed with ethyl acetate. The organic layer was dried with a desiccant and then filtered. The filtrate was concentrated under reduced pressure to give 280 mg of a crude product of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[NH:18]C(=O)C)[CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)C.O1CCOCC1.Cl>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[C:12]([NH2:18])=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: CSc1nc(Cl)cc(Nc2ccc(C)cc2NC(C)=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(Nc2ccc(C)cc2N)n1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
N-(2-{[6-Chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-5-methylphenyl)acetamide (270 mg) was dissolved in a mixed solvent of ethanol (2.8 mL) and 1,4-dioxane (2.8 mL), and 6 M hydrochloric acid (9.6 mL) was added thereto, followed by heating and refluxing for 3 hours. After air-cooling to room temperature, the pH was adjusted to 6 to 7 using saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain N1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (230 mg).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:29])[CH3:30])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(CC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 18 H), 1.91 (tdd, J=7.0, 7.0, 1.0, 2 H), 2.68 (q, J=7.4 Hz, 2 H), 3.3-3.5 (m, 2 H), 4.41 (d, J=5.5 Hz, 2 H), 5.20-5.40 (m, 1 H), 6.0 (dt, J=16.0, 1.0 Hz, 1 H), 7.0 (d, J=8.5 Hz, 2 H), 7.23 (d, J=8.5 Hz, 2 H). FAB-MS: calculated for C25H35NO 366; found 366 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane).