Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:15]=[C:16]([OH:22])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:24]2)[CH:15]=[C:16]([O:22][CH2:4][CH2:3][CH2:2][Br:1])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:10])=[O:11]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1,3-Dibromopropane (0.105 mL, 1.0 mol) was added to a solution of trans-2-[3-(2-hydroxypropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (102 mg, 0.20 mmol) in DMF (1 mL) containing potassium carbonate (105 mg, 0.76 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 2 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue (143 mg). Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound as a colorless foam; Rf 0.5; NMR (CDCl3) δ 1.26 (d, CH2CHOHCH3), 3.66 (t, CH2Br).
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CCC>CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4]([CH:5]([CH3:7])[CH3:6])=[N:25][N:24]=[C:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: CCSC(=Nc1ccc(Br)cc1)C(C)C
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccc(Br)cc1
Temperature: 130 °C
Yield: 28 %

Procedure:
In a 300 mL recovery flask were put 13 g (44 mmol) of N-[1-(ethylsulfanyl)isobutylidene]-4-bromoaniline, 3.9 g (29 mmol) of benzoylhydrazine, and 40 mL of 1-butanol, and the mixture was heated and refluxed at 130° C. for 10 hours. After that, 1-butanol was distilled off to give a solid. A methanol suspension of this solid was irradiated with ultrasonic waves, and a white solid was collected by gravity filtration, so that 2.8 g of white powder of 4-(4-bromophenyl)-5-isopropyl-3-phenyl-4H-1,2,4-triazole was obtained in a yield of 28%. The reaction scheme of Step 4 is shown in (b-4) below.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:2]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][CH:17]=2)([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(Br)cc1)(Cc1ccc(Br)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Ethyl acetoacetate (0.632 mL, 5 mmol) was added to a solution containing NaH (0.493 g, 11.25 mmol) in DMF (5 mL), and the resulting mixture was stirred at 0° C. for 30 minutes. 1-bromo-4-(bromomethyl)benzene (2.788 g, 11.15 mmol) was added to the mixed liquid, and the resulting mixture was stirred at room temperature for 12 hours. The mixed liquid was then poured into a saturated aqueous solution of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried using MgSO4, and then concentrated under reduced pressure, yielding the title compound (4k) in a yield of 90%.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[CH3:16].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:16][C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(=O)c1cc(C)c(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C)c(C#C[Si](C)(C)C)s1
Reaction time: 3 h

Procedure:
Trimethylsilylacetylene (16 ml) is added to a solution of 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (16.9 q, example 1, step A), Pd(PPh3)2Cl2 (3.78 g), CuI (1.46 g) and triethylamine (16 ml) in DMF (15 ml). After 3 hours at room temperature, the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by filtration over a plug of silica gel eluting with dichloromethane to yield 1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g) as yellow solid. The compound is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[C:37]([CH2:39][C:40](O)=O)#[N:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:37]#[N:38])[NH:1][C:2]=6[CH:3]=5)[CH:7]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC#N)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 40 mg (0.46 mmol) cyanoacetic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.00 mmol) TEA in 2.00 mL DMF were stirred for 4 h at RT. Then 2.00 mL glacial acetic acid was added and the mixture was stirred overnight at RT. The reaction mixture was also stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[CH:10]=[O:11].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18])[CH2:6][N:5]1[CH:10]=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C=O
Yield: 96.4 %

Procedure:
To a solution of (2S,4R)-1-formyl-4-hydroxyproline methyl ester (3.46 g, 20.0 mmol) in N,N-dimethylformamide (10 ml) and methylene chloride (20 ml) were successively added tert-butylchlorodimethylsilane (3.20 g, 21.2 mmol) and imidazole (1.47 g, 21.6 mmol) under a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 4 h. Then, the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=1:1) to give the title compound (5.54 g, yield: 96.3%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Br)c3)CC2)c(OC)nc1C
Yield: 65 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1>>[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([I:11])=[N:6]2)[CH2:15][CH2:14]1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: OC1CCC(F)(F)CC1
Product: Fc1ccc2c(c1)c(I)nn2C1CCC(F)(F)CC1
Yield: 17 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 4,4-difluorocyclohexanol in 17% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.94-2.17 (4H, m), 2.34-2.52 (4H, m), 4.67-4.73 (1H, m), 7.02 (1H, dd, J=2.4, 8.4 Hz), 7.11 (1H, td, J=2.4, 9.2 Hz), 7.67 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].CN(C=O)C>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.COCCOC>[NH2:26][C:27]1[CH:28]=[C:29]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)cc1N

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-amino-4-methylphenylboronic acid (51.2 mg, 0.339 mmol) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Amino-4-methyl-phenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[CH:7][CH:6]=3)[CH2:9]2)[CH3:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@H]2CN([C@H](C)c3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (7.9 g, 28 mmol) and triethylamine (8.5 g, 84 mmol) in tetrahydrofuran (180 ml) was added acetyl chloride (4.4 g, 56 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)-acetamide (6.47 g, 71%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:18][Li].O>O1CCCC1>[CH3:18][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
The title compound of Step A (9.0 g, 38 mmol) was dissolved in 50 mL of tetrahydrofuran and treated with methyl lithium (1.4 M in ether, 34 mL, 47 mmol) at a temperature of −70° C. The reaction mixture exothermed to −35° C. The mixture was stirred at −30° C. for 1.5 h and then treated with 1 mL of water and dichlorodicyanoquinone (9.44 g, 42 mmol). The mixture was stirred at 25° C. for 30 minutes and then partitioned twice between 100 mL of water and 100 mL of dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography using hexanes/ethyl acetate (95:5) as eluent to give 9.02 g of the title compound of Step B as a white solid melting at 128-131° C. 1H NMR (CDCl3): δ2.31 (s, 3H), 2.56 (s, 3H), 7.71 (d, 2H), 8.49 (d, 2H), 8.53 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:8]=[C:9]([C:15]#[C:16][CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH3:6])[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36](O)=[O:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH:1]1([N:4]([CH:5]([C:7]2[CH:12]=[N:11][C:10]([O:13][CH3:14])=[C:9]([C:15]#[C:16][CH2:17][NH:18][C:19]([O:20][CH3:21])=[O:22])[CH:8]=2)[CH3:6])[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31]2)=[O:37])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COC(=O)NCC#Cc1cc(C(C)NC2CC2)cnc1OC
Product: COC(=O)NCC#Cc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC

Procedure:
Methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-4)] as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Br:37]N1C(=O)CCC1=O>C1COCC1>[Br:37][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:3]1[CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (121 mg, 0.22 mmol) [prepared in Example 25] and N-bromosuccinimide (52 mg, 0.290 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=622 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[CH3:21]N>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][CH3:21])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: CN
Reactant: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1
Product: CNC(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Forty milliliters of ethanolic methylamine solution were added to 0.42 gm of 8-(2'-methoxy-4'-chlorocarbonylphenyl)-purine hydrochloride (see Example 43), with cooling, and the mixture was refluxed for 30 minutes. It was then concentrated by evaporation, and the product was purified by column chromatography on silica gel [eluant: methylene chloride/ethanol (8:2)].
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][C@@H:23]([CH2:25][OH:26])[CH3:24]>>[OH:26][CH2:25][C@H:23]([NH:22][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:24]
Reactant: C[C@@H](N)CO
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)N[C@H](C)CO)[nH]n1
Yield: 90 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using D-alaninol instead of L-alaninol, to the title compound (103 mg, 90%) which was obtained as a colorless oil.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:13]=[C:12]([O:26][C@@H:27]2[CH2:31][O:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]2)[CH:11]=1>>[N:1]1([S:5]([NH:8][C:10]2[N:15]=[C:14]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[N:13]=[C:12]([O:26][C@@H:27]3[CH2:31][O:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]3)[CH:11]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)CO1

Procedure:
The subtitle compound was prepared from azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.22 g) and 1,1-Dimethylethyl (S)-4-[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]pyrimidin-4-yloxy]-isoxazolidine-2-carboxylate (the product of step i) (0.13 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.14 g
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[CH2:13]=[C:14](B(O)O)[CH3:15].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:14]([CH3:15])=[CH2:13])[CH:3]=1
Reactant: C=C(C)B(O)O
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3-dibromo-5-(trifluoromethyl)benzene (3.03 g, 10 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol), prop-1-en-2-ylboronic acid (1.0 g, 12 mmol), K2CO3 (2.8 g, 20 mmol) and water (1 mL) under N2. The mixture was stirred at 90° C. overnight, concentrated and purified by CC (hexane) to afford compound P28a (1.9 g, 71%) as an oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)=[CH:13][C:12]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([OH:39])=[C:33]([Cl:40])[CH:32]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].O.Cl>C1COCC1>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([O:37][CH3:38])[C:34]([OH:39])=[C:33]([Cl:40])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-butyryl-6-(3-chloro-4-hydroxy-5-methoxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (36 mg, 0.063 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was triturated with diethyl ether. The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (22 mg, 75%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.96 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.7, 2.0 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 2H), 4.24-4.18 (m, 1H), 3.98 (s, 3H), 3.11-3.00 (m, 3H), 2.37 (d, J=12.9 Hz, 2H), 2.10 (d, J=12.2 Hz, 2H), 1.84-1.74 (m, J=7.4 Hz, 2H), 1.71-1.65 (m, J=12.6 Hz, 2H), 1.49-1.43 (m, 2H), 1.04 (t, J=7.4 Hz, 3H). ESI MS m/z 468 [C26H30ClN3O3+H]+; HPLC>99% (AUC), tR=10.17 min.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:4].Br[CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16]>>[C:8]([C:7]1[CH:6]=[C:5]([CH:3]([N:2]([CH3:1])[C@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH3:4])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: COC(=O)C(C)Br
Reactant: CNC(C)c1cccc(C#N)c1
Product: COC(=O)[C@H](C)N(C)C(C)c1cccc(C#N)c1

Procedure:
Compound was prepared following the general procedure 11 starting from 3-[1-(methylamino)ethyl]benzonitrile and methyl 2-bromopropionate, affording the title compound as a colorless oil. HPLC (Method A) Rt 1.54 min (Purity: 74%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(O)C.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by stirring a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 4-nitrobenzaldehyde (96 mg, 0.633 mmol), ethanol (5 ml) and saturated NaOH (50 ul) at room temperature for 4 h. The mixture was diluted with ethyl acetate (100 ml), washed with water and saturated NaCl. The crude was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (4:1, 3:1) to give a yellow solid (33 mg, 12%). 1H NMR (CDCl3): 8.26 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.72 (d, J=16.2 Hz, 1H), 7.61 (d, J=15.6 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.49-4.35 (m, 4H).