Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)[C:5](=O)[CH3:6].[CH2:9]([O:16][C:17]1[C:27]2[NH:26][C:25](=[O:28])[C:24]([CH3:30])([CH3:29])[C:23](=[O:31])[N:22]([CH3:32])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(I)C>C(OCC)(=O)C.O>[CH2:9]([O:16][C:17]1[C:27]2[N:26]([CH2:5][CH3:6])[C:25](=[O:28])[C:24]([CH3:29])([CH3:30])[C:23](=[O:31])[N:22]([CH3:32])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C(C)(C)C(=O)Nc2c(OCc3ccccc3)cccc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cccc(OCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 100 %

Procedure:
60% sodium hydride (0.37 g, 8.5 mmol) was added to a N,N-dimethylacetamide (12.5 mL) solution of 6-benzyloxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.5 g, 7.7 mmol) under ice cooling, and the mixture was stirred for 30 minutes. Ethyl iodide (0.68 mL, 8.5 mmol) was added dropwise thereto, followed by stirring at 10-20° C. for 2 hours. Water (17.5 mL) was added to the reaction solution, and ethyl acetate (20 mL) was added, followed by ethyl acetate extraction. The resulting organic layer was washed with water, and the solvent was distilled off. An aqueous solution of 70% methanol was added to the resulting residue, and the mixture was heated under reflux for 1 hour, followed by stirring for 30 minutes under ice cooling. Crystals were collected by filtration, then washed with an aqueous solution of 70% methanol, and dried at 60° C., thereby obtaining 2.71 g of a white, powdery target compound (yield: 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH2:8])=[S:7])(=[O:3])[CH3:2].Cl[CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[S:7][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[N:8]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCCC1Cl
Reactant: CC(=O)OCC(N)=S
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2c(s1)CCC2
Temperature: 80 °C
Reaction time: 24 h
Yield: 33.8 %

Procedure:
A mixture of 2-acetoxythioacetamide (10 g), 2-chlorocyclopentanone (10.6 g) and dimethylformamide (100 ml) was stirred for 24 hours at 80° C. The reaction mixture was cooled and poured into ice-water (500 ml), followed by extraction twice with ethyl acetate (200 ml). The extract was washed twice with water (100 ml), which was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×50 cm), eluting with ethyl acetate-hexane (3:7). The object fraction was concentrated to give 2-acetoxymethyl-5,6-dihydro-4H-cyclopentathiazole (5 g) as a yellow oily product.
Reaction SMILES: [CH2:1]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)CCCCC.CC1C2C(=CC=CC=2)N=CC=1.CC1C2C(=NC3C(C=2)=CC=CC=3)C=CC=1>>[CH3:1][C:7]1[N:8]=[CH:9][C:14]2[C:15]([CH:16]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CCCCCCc1ccc2ccccc2n1
Agent: Cc1cccc2nc3ccccc3cc12
Agent: Cc1ccnc2ccccc12
Product: Cc1cc2ccccc2cn1

Procedure:
2-hexylquinoline; 4-methylquinoline; 1-methylacridine;
Reaction SMILES: [Na].CO.CN(C)[CH:6]=[O:7].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:7][CH3:6])[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1cncc(Br)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
Add sodium (0.583 g, 25 mmol) to methanol (10 mL) at 0° C. Stir the mixture at 0° C. until obtain a solution and concentrate. Add N,N-dimethylformamide (25 mL) and add 3,5-dibromopyridine (3.0 g, 12.66 mmol). Stir at 70° C. for 4 h. Cool to room temperature and add water. Extract twice with diethyl ether. Combine the organic phases, wash once with water, dry over sodium sulfate and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 50:50 hexanes:ethyl acetate, to give the title compound as a solid (1.37 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[N:10](C)C1C=CC=CC=1>>[CH3:8][C:5]1[C:4]([NH2:10])=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: CN(C)c1ccccc1
Reactant: Cc1cnc(C)cn1
Product: Cc1cnc(C)c(N)n1
Temperature: 170 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
A mixture of 2,5-dimethylpyrazine (14 g, 0.13 mol) in N,N-dimethylaniline (50 mL) was heated to 170° C. and NaNH2 (22 g, 0.56 mol) was added in portions. The reaction mixture was stirred at 170° C. for 1 h, and the solvent was removed. The product was purified by silica gel column chromatography to give 3,6-dimethylpyrazin-2-amine as a brown solid (1.6 g, yield 10%). ESI MS: m/z 124 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1.[Br:11][CH2:12][CH:13](OC)OC.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CC#N.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=2
Reactant: COC(CBr)OC
Reactant: Nc1cc(Cl)ncc1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1cc2ncc(Br)cc2cn1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
Heat a mixture of 4-amino-6-chloronicotinaldehyde (2.00 g, 12.77 mmol), 2-bromo-1,1-dimethoxyethane (6.48 g, 38.3 mmol) and ytterbium(III) trifluoromethanesulfonate (1.981 g, 3.19 mmol) in MeCN (25 mL) at 80° C. overnight. Cool to RT, dilute with EtOAc, collect the solids via filtration, rinse with EtOAc and dry. Wash the filtrate with H2O, then brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex). Combine the two solids to afford the title compound (1.67 g, 53%) as an off-white solid. MS(ESI) m/z: 244.9 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2nc(OC3CCN(Cc4ccccc4)CC3)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(Cc5ccccc5)CC4)sc3c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 14A (0.68 g, 1.686 mmol) in dry THF (9.4 ml) at −78° C. under argon was added dropwise BuLi (0.742 ml, 1.855 mmol). After the completion of addition, the reaction mixture was stirred at −78° C. for 1 h. At the conclusion of this period, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.37 g, 1.855 mmol) in THF (1.9 ml) was transferred to the reaction mixture via cannulation. The resulting mixture was stirred and gradually warmed to −20° C., where it stirred for an additional hour. At the conclusion of this period, the mixture was quenched with aq. NaHCO3 (saturated, 20 mL) and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with H2O (3×10 mL) and brine (10 mL), dried (Na2SO4) and then filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to give Compound 14B′ as a white solid (0.63 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.36 (m, 4H), 7.24-7.29 (m, 1H), 5.21 (tt, J=7.9, 3.9 Hz, 1H), 3.98 (br. s., 2H), 3.54 (s, 2H), 3.25 (br. s., 2H), 2.73 (br. s., 2H), 2.38 (t, J=8.7 Hz, 2H), 2.08-2.18 (m, 2H), 1.85-2.03 (m, 5H), 1.75 (d, J=12.1 Hz, 2H), 1.47-1.50 (m, 9H). LC/MS (m/z)=524 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4F)cnc32)cc1
Yield: 83.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (130 g, 0.248 mmol) was coupled with tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69B) (151 mg, 0.372 mmol) using sodium carbonate (79 mg, 0.714 mmol) and Pd(PPh3)2Cl2 (9 mg, 0.124 mmol) in DME/water (5/2 mL). This afforded 150 mg (83.3% yield) after purification by column (Silica gel 60/120) using 50% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[CH:4]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH2:10][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: COc1ccc2c(C)noc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CCC3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 80.7 %

Procedure:
The procedure described in Example 1d was followed using 6-methoxy-3-methyl-1,2-benzisoxazole (0.32 g, 1.96 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.70 g, 2.15 mmol), and 1M LDA (2.0 mL, 2.0 mmol) in dry THF (3 mL). After purification, the title compound (0.57 g, 80%) was obtained as a white solid.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:2]2[S:23][C:22]([NH2:24])=[N:21][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)C(Br)Cc2ccc(F)cc2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-3-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 2 hours, hold overnight, filtered, washed with water, and dried to obtain a product. A single spot was shown by TLC. The product was not further purified. The product was a white solid in a yield of 81.9%, mp: 199-201 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.03 (2H, s, CH2), 6.84 (2H, s, NH2), 6.94 (2H, d, J=8.96 Hz, ArH), 7.13 (2H, t, 3JFH=3JHH=8.96 Hz, ArH), 7.23 (2H, dd, 3JHH=8.72, 4JFH=5.64 Hz, ArH), 7.46 (2H, d, J=8.96 Hz, ArH); EI-MS m/e (%): 314.2 (M+, 100), 109.1 (12); HREI-MS Calcd. for C17H15FN2OS: 314.0889. found: 314.0890. Anal. Calcd. for C17H15FN2OS: C, 64.95; H, 4.81; N, 8.91. found: C, 65.10; H, 5.24; N, 8.98.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17](I)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].[C:21]([C:23]1([OH:32])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1)#[CH:22]>N1CCCCC1.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.[Cu]I>[NH2:15][C:11]1[N:10]=[C:9]([N:8]2[C:7]3[CH:16]=[C:17]([C:22]#[C:21][C:23]4([OH:32])[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH2:25][CH2:24]4)[CH:18]=[CH:19][C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])[CH:14]=[CH:13][N:12]=1
Reactant: C#CC1(O)CCc2cccnc21
Reactant: CCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCOc1nc2ccc(C#CC3(O)CCc4cccnc43)cc2n1-c1ccnc(N)n1

Procedure:
A mixture of 4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (150 mg, 0.394 mmol) and 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol (118 mg, 0.59 mmol) was dissolved in piperidine (1 mL). The solution was de-gassed with nitrogen for 2 mins. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) and copper(I) iodide (6 mg, 0.031 mmol) were added and the resultant solution heated to 30° C. for 2 hr. The mixture was concentrated in vacuo, DCM (10 mL) added and re-concentrated in vacuo (twice). The residue was purified by column chromatography (Biotage, 0-10% MeOH gradient in DCM), followed by reverse phase preparative HPLC purification to give the title compound; 1H NMR (500 MHz, DMSO) delta 1.44 (3H, t, J=7.1 Hz), 2.36-2.42 (1H, m), 2.52-2.62 (1H, m), 2.83-2.95 (1H, m), 2.94-3.08 (1H, m), 4.63 (2H, q, J=7.0 Hz), 6.96 (1H, d, J=5.5 Hz), 7.08 (2H, s), 7.19-7.32 (2H, m), 7.44 (1H, d, J=8.2 Hz), 7.72 (1H, d, J=7.6 Hz), 8.13 (1H, s), 8.38 (1H, d, J=5.5 Hz), 8.44 (1H, d, J=4.8 Hz), 8.51 (1H, s); LC-MS: m/z=+413.05 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCSc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCSc2ccccc2)CC1
Yield: 27 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.5 g) as starting compound and 4-phenylthiobutyl bromide (2.48 g) were reacted and treated in the same manner as in Example 168 to give 0.84 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenylthiobutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:3]=1[C:4]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10]C)=[O:9])=[O:5].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:3]=1[C:4]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC(C)(C)C(=O)O)c(Cl)cc2F)c1=O
Yield: 68.4 %

Procedure:
1.0 g (2.1 mmol) of methyl 2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-4-fluoro-benzoyloxy]-2-methylpropionate from example 4.1 was dissolved in 50 ml of acetic acid, 50 ml of conc. hydrochloric acid were added and the reaction mixture was heated under reflux for 5 hours. Most of the acetic acid was distilled off, and the solution that remained was poured into ice-water. The precipitate was filtered off and dried, which gave 0.65 g of 2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-4-fluorobenzoyloxy]-2-methylpropionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-dichloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].[OH:18][CH2:19][C@H:20]([NH:27][C:28]1[S:29][CH2:30][C:31](=[O:33])[N:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:30]3/[C:31](=[O:33])[N:32]=[C:28]([NH:27][C@H:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][OH:18])[S:29]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(N[C@@H](CO)c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 1g was used, starting from 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e) and 2-((R)-2-hydroxy-1-phenyl-ethylamino)-thiazol-4-one (example 3a) to give 4-ethoxy-6-[2-((R)-2-hydroxy-1-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 445 (MH+).
Reaction SMILES: [H-].[Na+].C(OP(OCC)([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:19])=O)C.[C:23]([C:26]1[CH:27]=[CH:28][C:29]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31][C:30]=2[CH:38]=1)(=O)[CH3:24]>CN(C)C=O>[CH3:36][C:33]1([CH3:37])[CH2:32][CH2:31][C:30]2[CH:38]=[C:26](/[C:23](/[CH3:24])=[CH:19]/[C:9]3[CH:8]=[CH:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=3)[CH:27]=[CH:28][C:29]=2[CH2:35][CH2:34]1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)CC2
Reactant: CCOC(=O)c1ccc(C)c(P(=O)(OCC)OCC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)CCC(C)(C)CC3)cc1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
770 mg of sodium hydride (50% in mineral oil) are treated at room temperature under an argon atmosphere with 5.30 g of ethyl o-(diethoxyphosphinyl)-p-toluate. After stirring for 2 hours 2.55 g of 2-acetyl-6,7,8,9-tetra-hydro-7 7-dimethyl-5H benzocycloheptene, dissolved in small amount of dimethylformamide, are added dropwise. After 2 hours, the reaction mixture is poured on to ice and extracted with diethyl ether. The ethereal extract is washed with water, dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling)/ ethyl acetate (9:1), there are obtained 3.40 g of ethyl p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclo-hepten-2-yl)propenyl]benzoate of m.p. 87-°88° (from hexane).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[O:21])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:29]=1)=[O:21]
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.10 g, 7.0 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.83 g, 7.0 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-Amino-2'-fluoro benzophenone (1.00 g, 4.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (1.23 g, 75%); mp 141°-142° C. 1H-NMR (300 MHz, d6-DMSO): 1.60 (s, 3H, CH3) 7.35-7.42 (m, 2H, aromatic) 7.53-7.59 (m, 2H, aromatic+OH) 7.65-7.68 (m, 1H, aromatic) 7.75 (d, 2H, J=8.5 Hz, aromatic) 7,96 (dd, 2H, J=8.6, 1.7 Hz, aromatic) 10.37 (s, 1H, NH). MS (CI, CH4): 356 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]([CH3:55])=[CH:53][N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][C:52]([CH3:55])=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1cnc(N)s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-thiazol-2-yl)-propionamide (201 mg, 78%) as a orange foam: [α]23589=−72.7° (c=0.055, chloroform); EI-HRMS m/e calcd for C19H23ClN2O3S2(M+) 426.0838, found 426.0837.