Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[N:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25](N(OC)C)=[O:26])=[N:17]1>C1COCC1>[C:25]([C:18]1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[CH:21][N:16]([C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[CH:10][C:5]=2[F:4])[N:17]=1)(=[O:26])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 72.3 %

Procedure:
MeMgBr (1 M solution in THF, 2.8 mL, 2.8 mmol) was added dropwise at −78° C. to a solution of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (351 mg, 0.94 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (223 mg, 72% yield) as a pale yellow solid: mp 159-161° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.93 (3H, s), 6.56 (1H, dd, J=1.5, 2.3 Hz), 7.64 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.79 (4H, m), 7.99 (1H, d, J=2.6 Hz). Anal. Calcd for C16H13FN4O3: C, 58.54; H, 3.99; N, 17.07. Found: C, 58.42; H, 4.01; N, 16.98.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35]([C:49]2([OH:53])[CH2:52][O:51][CH2:50]2)[CH:36]=[C:37]([F:48])[C:38]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:33]([F:32])=[CH:34][C:35]([C:49]4([OH:53])[CH2:50][O:51][CH2:52]4)=[CH:36][C:37]=3[F:48])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)COC3)cc2F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4(O)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (see US2012/225062) gave 224. LCMS (ES+) m/z 524 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:37]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1)[CH3:38]
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.6 %

Procedure:
A mixture of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (32) (74 mg, 0.15 mmol), bromoethane (12 μL, 0.16 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (5 mL) was stirred for 48 h at room temperature under an inert atmosphere. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and saturated sodium hydrogen carbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organics were washed with brine then dried (MgSO4). The solvent was removed under reduced pressure and the resulting solid was chromatographed (Biotage Isolera: C-18 reverse phase column, 0-100% MeCN in H2O) to give the title compound (38) (22 mg, 28%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.65 (s, 1H), 8.37 (dd, J=4.8, 1.7 Hz, 1H), 7.65-7.57 (m, 3H), 7.55 (s, 1H), 7.26-7.13 (m, 3H), 7.02 (s, 1H), 3.54 (s, 2H), 3.25 (s, 4H), 2.98 (d, J=11.3 Hz, 2H), 2.48-2.30 (m, 3H), 1.95 (q, J=11.7, 11.3 Hz, 2H), 1.73 (d, J=10.5 Hz, 2H), 1.63 (qd, J=12.4, 3.6 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). LCMS Method C: rt 4.16 min; m/z 513 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])([CH3:18])[CH2:9][S:10][C:11]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12]2)[CH:7]=1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@@:8]2([CH3:18])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:15](=[O:17])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSC2(C(=O)O)CCC2)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C3(CCC3)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of (R)-1-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)cyclobutanecarboxylic acid (1.8 g, 3.51 mmol, Eq: 1.00) and diisopropylethylamine (1.36 g, 1.84 ml, 10.5 mmol, Eq: 3.0) in ethyl acetate (70.3 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (3.35 g, 3.08 ml, 5.27 mmol, Eq: 1.5). The colourless reaction solution was stirred at 23° C. for 16 hours. The reaction mixture was washed with sat. NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the crude and pure (R)-7-(5-bromo-2-fluorophenyl)-8-(2,4-dimethoxybenzyl)-7-methyl-5-thia-8-azaspiro[3.5]nonan-9-one (1.75 g, 3.54 mmol, 101% yield) as a white foam. MS (ISP): m/z=494.0 [M+H]+ and 496.4 [M+2+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:32]([OH:34])=O)[CH2:22][C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[C:25]([CH3:31])[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:22][C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[C:25]([CH3:31])[CH:24]=3)[C:32](=[O:34])[N:44]3[CH2:43][CH2:42][N:41]([CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:46][CH2:45]3)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared analogously to Example 8i from 80.0 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidine-1-carboxylate and 29.2 mg (0.17 mmol) 1-(tetrahydropyran-4-yl)-piperazine, the reaction mixture being stirred overnight at RT.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[I-].[Na+]>CS(C)=O>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:15]=[N+:16]=[N-:17]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
To a solution of 2-(bromomethyl)biphenyl (1.5 g, 6 mmol) in DMSO (15 mL) was added sodium azide (0.59 g, 9 mmol) and a catalytic amount of sodium iodide. The mixture was stirred at room temperature for 2 days. After concentration under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with brine (2×60 mL), dried on sodium sulphate and after filtration was evaporated to dryness to give the title compound as an oil (1.1 g, 87%). 1H NMR (300 MHz, CDCl3, ppm) δ: 7.56-7.38 (m, 9H), 4.37 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 11 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (11%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].Cl.[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=3)[N:20]=[C:19]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH2:9][CH3:10])[CH2:37][CH2:38]2)[CH2:13][CH2:14][CH2:15]1
Reactant: CCc1c(N)ncnc1Cl
Reactant: FC(F)(F)c1cncc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg; 0.32 mmol; 1.00 eq.), 3-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-5-trifluoromethyl-pyridine hydrochloride (3) (155.08 mg; 0.32 mmol; 1.00 eq.), and Cs2CO3 (206.74 mg; 0.63 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2 days, purified by HPLC, title compound 81 mg, 41.5%. LC-MS: (M+1=501, obsd.=501).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[C:3]=1[CH3:17].S(OC)(O[CH3:22])(=O)=O>>[CH3:22][O:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: COS(=O)(=O)OC
Reactant: CCCCCCCCC1(C)SC(=O)C(C)=C1O
Product: CCCCCCCCC1(C)SC(=O)C(C)=C1OC
Yield: 69.3 %

Procedure:
From 34 (40 mg, 0.16 mmol), KH (27 mg, 0.20 mmol, 30% in mineral oil) and dimethyl sulfate (30 μL, 0.31 mmol) following general procedure H was obtained 37 (30 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=7 Hz, 3H), 1.06-1.09 (m, 1H), 1.24 (s, 10H), 1.41-1.48 (m, 1H), 1.55 (s, 3H), 1.71-1.79 (m, 2H), 1.98 (s, 3H), 4.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 9.59, 14.1, 22.6, 25.2, 26.5, 29.2, 29.4, 29.6, 31.8, 38.9, 58.7, 59.8, 111.3, 180.2, 195.7. IR (NaCl) 2927, 1676, 1631, 1582 cm−1. Analysis Calculated for C15H26O2S: C, 66.6; H, 9.69; Found: C, 66.5; H, 9.67.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[O:8][C:7]2[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[CH:3][C:2]=2[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Cc1cc(N)c(O)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(C)c([N+](=O)[O-])cc2o1

Procedure:
To a stirred solution of 2-amino-5-nitro-p-cresol (3.3 g, 0.0146 mol) in xylene (35 ml) was added the triethylorthoacetate (6.4 g, 0.0392 mol) in one portion. The mixture was refluxed for one hour, filtered through a pad of decolorizing carbon and concentrated to dryness under reduced pressure. The residue was triturated with ligroin and 2.7 g (71 percent) of white solid was collected. NMR was consistent for the product.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]2[CH:21]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[C:20](=O)[C:19]3[C:18]([C:29]([O:31]CC)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13]2)[CH:8]=[CH:9][C:10]=1[F:11])=[O:4].O.[NH2:36][NH2:37]>CO>[F:11][C:10]1[CH:9]=[CH:8][C:7]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:29](=[O:31])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:21]2[C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:34])=[O:4]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)c(C(=O)N(C)C)c1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1cc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (130 mg) in hydrazine monohydrate (85%, 2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain the title compound (30.0 mg, yield 30%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.72 (s, 3H), 2.97 (s, 3H), 3.43 (s, 3H), 4.67-4.70 (d, J=10.8 Hz, 1H), 4.95-4.97 (d, J=10.8 Hz, 1H), 6.72-6.73 (d, J=1.2 Hz, 1H), 6.89-6.89 (d, J=0.8 Hz, 1H), 7.15-7.23 (m, 2H), 7.34-7.41 (m, 3H), 7.48-7.49 (m, 1H), 7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([CH3:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2cc(C(F)(F)F)nn2C)cc2scc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a mixture of methyl(4-methyl-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (132.1 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (0.663 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The mixture was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (117 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16]C)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20](OC1C(OC)=CC=CC=1C(CC(C)C)CC(O)=O)C1C=CC=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:20])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cccc(C(CC(=O)O)CC(C)C)c1OCc1ccccc1
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Product: COC(=O)CC(CC(C)C)c1ccc(O)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 58A, but using 3-(2-benzyloxy-3-methoxyphenyl)-5-methylhexanoic acid (prepared as described in Preparation 30H), the title compound was obtained as an oily substance.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:32]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH:29]([CH3:30])[CH3:31])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=2[CH3:32])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-4-(isopropylsulfonyl)-1-methylbenzene (Intermediate 64), the title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:6][C:7](O)=[O:8])=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH2:14]([O:13][C:11]([NH:10][C@@H:5]([CH2:6][C:7]([Cl:29])=[O:8])[C:3]([O:2][CH3:1])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Z-asp-OMe (175 g, 622 mmol) was dissolved in THF (1750 ml) and admixed with 2 ml of DMF. 86.9 g (684 mmol) of oxalyl chloride were dissolved in 200 ml of THF (slightly exothermic), cooled back to room temperature (RT) and added dropwise to the solution of the amino acid over 1 hour (h). After a further hour at RT, the solution was initially sparged with nitrogen for 10 min, concentrated on a rotary evaporator at a maximum of 30° C. and coevaporated repeatedly with toluene. The resulting dirty white solid was dried to constant weight under in-house vacuum (about 1.5 mbar) and reacted further without further purification. Yield: 186.6 g (quantitative).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 57 %

Procedure:
The title compound was prepared in a yield of 57% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and α-(4-methoxyphenyl)benzylamine.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([CH:17]=[N:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[NH2:27])[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:27][C:26](=[O:28])[C:20]2[C:19](=[CH:24][C:23]([Cl:25])=[CH:22][CH:21]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(N)=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle, and a water condenser, is charged with 60 mL of THF, 3.70 g (10 mmol) of (R)-{1[(2-carbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (the compound of Formula 201 prepared, e.g., as described in Example 6.1), and 0.46 g (11 mmol) of lithium hydroxide monohydrate. The mixture is heated to reflux and the reaction monitored by TLC (hexanes/ethyl acetate 7:3) by which, after 1 h of refluxing, the reaction is shown to be complete. The mixture is allowed to cool to room temperature and transferred to a round bottom 1-necked flask followed by dilution with 60 mL of water. The stirring mixture is then slowly acidified to pH=5 by adding 1N hydrochloric acid and the THF is removed by rotary evaporation. The white suspension is separated by filtration and dried in high vacuum to afford the title compound of Formula 202, (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][N:5]=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:20]([O:19][C:17]([N:11]1[CH2:12][CH2:13][N:14]([C:2]2[C:7]([O:8][CH2:9][CH3:10])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:15][CH2:16]1)=[O:18])[CH3:21]
Reactant: CCOc1cncnc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(c2ncncc2OCC)CC1
Temperature: 23 °C
Yield: 65.4 %

Procedure:
A mixture of 4-chloro-5-ethoxypyrimidine (1.98 g, 12.5 mmol), ethyl 1-piperazinecarboxylate (5.93 g, 37.5 mmol) and micropulverized K2CO3 (5.18 g, 37.5 mmol) was heated at reflux in CH3CN (75 mL) for 4 h. Upon cooling to 23° C., the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water (5 mL). The organic phase was dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH;98:2) of the concentrate yielded product (2.29 g, 65%).