Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]#[C:28][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(C#Cc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D of Procedure 9 (100 mg, 0.31 mmol), tributyl((4-chlorophenyl)ethynyl)stannane Part A (237 mg, 0.56 mmol), copper (I) iodide (17.6 mg, 0.09 mmol), and PalladiumTetrakis (54 mg, 0.05 mmol) in DMF (1.5 mL) was stirred under nitrogen at 70° C. overnight. The reaction was diluted with DCM, filtered, washed with 1N HCl, sat. NaHCO3, dried (MgSO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient). The product was repurified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:100.1 MeOH—H2O-TFA) to afford the desired product 4-((4-chlorophenyl)ethynyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyepyridin-2(1H)-one F-4 (90 mg, 0.21 mmol, 66.7% yield) as a light yellow solid. LC/MS 424 (M+H)+, tR 1.00 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.54 (2H, m), 7.37-7.44 (3H, m), 6.96-7.02 (2H, m), 6.93 (1H, d, J=2.26 Hz), 6.89 (1H, dd), 6.50 (1H, d, Hz), 3.88 (5H, s), 1.38 (6H, s)
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)C.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20]>C(O)C.O>[NH2:21][C:19]([NH:18][N:17]=[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]=[O:13])=[O:20]
Reactant: NNC(N)=O
Reactant: CCOC(OCC)C(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(C=O)c1ccccc1
Temperature: 120 °C
Yield: 59.3 %

Procedure:
A mixture of 2,2-diethoxy-1-phenylethanone (6.25 g, 0.0300 mol) and semicarbazide hydrochloride (3.34 g, 0.0300 mol) in ethanol-water (1:1 v/v, 50 mL) was heated at 120° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was treated with methanol, filtered, and washed with methanol to give the desired product (3.40 g, 59.3%). Analytical LCMS: (M+H)+=192.1. 1H-NMR (400 MHz, DMSO-D6): δ 11.03 (s, 1H), 7.97-8.01 (m, 2H), 7.61-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.34 (b, 1H), 6.54 (b, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[NH:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:21]=[N:20]1>C1COCC1>[NH:20]1[CH:21]=[C:22]([C:24]2[S:25][C:26]([C:29]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:23]=[N:19]1
Reactant: Ic1ccncc1
Reactant: CCC(=O)c1cnc(-c2cn[nH]c2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(c1ccncc1)c1cnc(-c2cn[nH]c2)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A solution of 4-iodopyridine (133 mg, 0.65 mmol) in THF (15 mL) was cooled to −78° C., 1.6 M n-BuLi in hexane (0.81 mL, 1.3 mmol) slowly added at −78° C., the reaction mixture stirred for 20 min at −78° C., and 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-one (135 mg, 0.65 mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×250 mL). The combined extracts were washed with brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (mobile phase: 5% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol as pale yellow liquid (13 mg, 5% yield) in 99.4% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.51 (d, 2H), 8.24 (br s, 1H), 7.87 (br s, 1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.29 (s, 1H), 2.32-2.23 (m, 2H), 0.77 (t, 3H); LC-MS m/z calculated for [M+H]+287.09, found 287.1
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][CH2:23][CH2:24]CCC1C=CC=C2C(NC(=O)C=12)=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:39]N.[CH2:41](O)[CH3:42]>>[C:1]([S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:41][CH2:42][NH2:39])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21
Reactant: CCO
Solvent: O
Product: NCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
6-(S-Trityl-)mercaptohexylphthalimide (14.27 g, 28.2 mmol) was suspended in ethanol (250 mL). Hydrazine hydrate (3.45 mL, 70.5 mmol) was added, and the mixture was heated to reflux for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. Chloroform (180 mL) was added to the residual oil and the resulting suspension was stirred at room temperature for 1.5 h. The mixture was filtered, and the filtrate was extracted with water (60 mL) and brine (60 mL), dried over MgSO4 and concentrated to yield crude 6-(tritylmercapto)-hexylamine (10.10 g, 26.87 mmol, 95%). MS: m/z 376.22=[M+H]+, (calculated=376.20).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:31])[CH:28]([SH:30])[CH3:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1)[CH3:29]
Reactant: COC(=O)C(C)S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)C(C)Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 27.9 %

Procedure:
{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid methyl ester (125 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol), and mercapto-propionic acid methyl ester (240 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.37 g, 0.007 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (4.30 g, 0.033 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.00 g, 0.007 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 15%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[C:4]2[O:9][CH2:8][C@@H:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]3[CH:16]=[C:17]([C:32]([OH:34])=[O:33])[C:18](=[O:31])[C:19]([C:20]=1[NH:21]CC1C=CC(OC)=CC=1)=[C:5]23.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:20]1[C:19]2[C:18](=[O:31])[C:17]([C:32]([OH:34])=[O:33])=[CH:16][N:6]3[C@H:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:2]=1[F:1]
Reactant: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@H](c2ccccc2)CO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@H](c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of (R)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (366 mg, 0.614 mmol) in CH2Cl2 (10 mL) was added TFA (2.0 mL, 26.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The solution of the residue in DMSO (3 mL) was added water and 2M aq. NaOH to adjust pH=7. A precipitate formed and was collected by filtration. The cake was added EtOH (10 mL), and boiled on water-bath. A precipitate was collected by and then dried to give (R)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (124 mg, 42%) as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) was added to a suspension of sodium hydride (60 wt %, 0.238 g, 5.96 mmol) in DMF (16.56 mL) and stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (1.11 g, 7.45 mmol) was added to the reaction mixture and stirred for 2 hours at room temperature. The mixture was then diluted with ethyl acetate (100 mL) and washed with 1:1 water:brine (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[CH:9]=2)[N:4]=1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2nc(C(F)(F)F)c(C(=O)Cl)c(O)c2c1
Reactant: Nc1nccs1
Product: COc1ccc2nc(C(F)(F)F)c(C(=O)Nc3nccs3)c(O)c2c1

Procedure:
Using the procedure of Step F of Example 1, the product of Step F and 1.05 g of 2-amino-thiazole were reacted to obtain after crystallization from ethanol 1.6 g of 2-trifluoromethyl-6-methoxy-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at >270° C.
Reaction SMILES: [Na:1].[Na].[C:3]([NH:6][C@@H:7]1[C@@H:12]([O:13]CC2C=CC=CC=2)[C@H:11]([O:21]CC2C=CC=CC=2)[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([O:51]CC2C=CC=CC=2)[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[O:65]CC1C=CC=CC=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[Na:1].[Na:1].[C:3]([NH:6][C@@H:7]1[C@@H:12]([OH:13])[C@H:11]([OH:21])[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([OH:51])[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[OH:65])(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](OCc2ccccc2)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2NC(C)=O)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](O)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reaction time: 4 h
Yield: 180.6 %

Procedure:
Compound 21 (170 mg, 0.160 mmol) was dissolved in a mixture of methanol and water (3:1, 15 mL) and palladium hydroxide/carbon (180 mg) was added thereto. Inside of the reaction system was replaced with hydrogen gas, and catalytic reduction was performed at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3), further purified with a column of Dowex-50 (Na+) type (CHCl3:MeOH:H2O=1:3:1), and finally purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3) again to obtain Compound 22 (101.4 mg, 90.6%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=[O:11].[C:16]1([CH3:22])[CH:21]=CC=C[CH:17]=1.Cl.[C:24]([O:27]CC)(=[O:26])C>CN(C=O)C>[CH3:17][C:16]([O:27][C:24]([N:8]1[C@@H:9]([C:10]([OH:12])=[O:11])[CH2:13][CH2:14][CH2:15]1)=[O:26])([CH3:22])[CH3:21]
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: O=C(O)[C@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 36 h
Yield: 99 %

Procedure:
Triethylamine (0.2 g, 2 mmoles) was slowly added to a solution of (D-proline (0.23 g, 2 mmoles) and t-BOC-ON (0.5 g, 2 mmoles) in DMF (3 mL) at room temperature and the mixture stirred for 36 h. The DMF was coevaporated with toluene under vacuum. Aqueous hydrochloric acid (1×10-4M) (20 mL) and ethyl acetate (20 mL) were added to the flask to dissolve the residue. The organic layer was washed with water (3×20 mL) and brine (2×20 mL); dried (5 g of MgSO4) and evaporated under reduced pressure. The residue, containing the product, was chromatographed on 5 g of silica gel column (1×25 cm). Upon evaporation under reduced pressure a transparent oil was obtained. The oil was crystallized from ethyl acetate/diethyl ether to give 0.4 g (2 mmoles) (99% yield) of a crystalline powder, mp 133°-134° C. (lit.91 mp 132°-133° C.). 1H-NMR (CDCl3) δ 1.46(9Ha,s); 1.86-2.40(4Hb,m); 3.43-3.80(2Hc,m); 4.26-4.66(1Hd,m); 11.43(1He,s). IR (Nujol) 1740, 1635 cm-1.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:32]=2)=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCc1ccc(C#N)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
N-methyl-N-(phenylsulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-butyl-2-chlorobenzonitrile (0.60 g) and anhydrous aluminum chloride (0.50 g) are added to o-dichlorobenzene (10 ml) and stirred at 120° C. for 1 hour. On completion of the reaction, chloroform (100 ml) is added and washed with dilute hydrochloric acid. After washing with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 0.70 g of compound (refractive index: 1.5667).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH2:21][C:20]#[CH:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature for several minutes, propargyl bromide (14 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature, water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 13.5 g of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene. M.P., 88°-89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH:9]([N:6]2[C:5]3[CH:27]=[CH:28][C:2]([NH:1][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-ylpropanoate (15 mg, 40 μmol) in dichloromethane (500 μL) was added benzenesulfonyl chloride (6.0 μL, 47 μmol) and N,N-diisopropylethylamine (8.0 μL, 46 μmol). The solution was stirred at room temperature for 48 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4), to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.50 min, MH+ 513].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]O)[N:6]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][Br:20])[N:6]=1
Reactant: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1nn(CBr)c(=O)c2ccccc12

Procedure:
A solution of methyl-3-hydroxymethyl-4-oxophthalazin-1-ylacetate (0.49 g), phosphorous tribromide (0.54 g) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The solution was poured onto ice-water (5 ml) and the separated methylene chloride layer was collected, dried and evaporated to obtain a light yellow solid (yield: 0.43 g; m.p. 98°-104° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])[CH3:32]>>[CH2:31]([N:33]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: CCNCc1ccccc1F
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCN(Cc1ccccc1F)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-(2-fluoro-benzyl)-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 494.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.CC1(C)C(C)(C)OB([C:45]2[CH:57]=[CH:56][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:47][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[C:2]([C:45]2[CH:46]=[CH:47][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:56][CH:57]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(methyl)amino)piperidine-1-carboxylate