Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1SC2C=CC(O)=CC=2N=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:39])[C:31]2=[O:40])=[CH:26][CH:25]=1.N1C2C(=CC=CC=2)C(=O)C1=O>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[C:8]([OH:11])=[CH:7][C:3]4[O:4][CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)[C:31]2=[O:40])=[CH:28][CH:29]=1
Reactant: O=C1C(=O)N(c2ccc(F)cc2)c2ccccc21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: Cc1nc2cc(O)ccc2s1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1N(c2ccc(F)cc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 1A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 2-methylbenzo[d]thiazol-5-ol, and 1-(4-fluorophenyl)indoline-2,3-dione (Coppola, G. M Journal of Heterocyclic Chemistry 1987, (24):1249) to replace isatin, 1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (23%) as a beige solid: mp 195-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.47-7.41 (m, 4H), 7.26 (s, 1H), 7.21-7.16 (m, 1H), 7.01-6.93 (m, 2H), 6.68 (d, J=7.8 Hz, 1H), 6.63 (s, 1H), 6.14 (s, 1H), 4.23-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 160.9 (d, 1JC-F=245 Hz), 147.1, 143.9, 142.6, 135.6, 132.0, 131.2 (d, 4JC-F=2.9 Hz), 128.6 (d, 3JC-F=8 Hz), 124.0, 122.4, 121.2, 116.4 (d, 2JC-F=22.8 Hz), 115.1, 108.2, 103.4, 74.4, 64.3, 63.7, 57.2; MS (ES+) m/z 390.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:24]=[CH:25][C:18]=12>C(OCC)(=O)C>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[C:18]2[CH:25]=[N:24]1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-amino-phenol (0.251 g, 2.3 mmol, 1.1 eq) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.13, 5.4 mmol, 2.7 eq). After 10 minutes 4-Chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.1 mmol, 1.0 eq.) was added and the reaction was allowed to warm up to room temperature. After stirring at room temperature for 1 hour the reaction mixture was diluted with ethyl acetate (50 ml) and Was washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, and (1×) brine. The organic layer was dried over sodium sulfate and the solvent removed to give 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine as a yellow solid (570 mg, 87%). 1H NMR (400 MHz, CDCl3): 8.56(s, 1H), 7.75 (s, 1H), 6.97 (d, 2H), 6.64 (d, 2H), 5.96 (dd, 1H), 5.21 (s, 2H), 3.96 (d, 1H), 3.72 (m, 1H), 2.42 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.57 (m, 2H); MS (ESI) for C16H17N5O2: 312 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(Nc2ccccc2)n1
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(Nc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (197 mg, 1.20 mmol) and 6-chloro-N4-phenyl-2,4-pyrimidinediamine (330 mg, 1.50 mmol) in a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (86 mg, 0.075 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (366 mg). LC-MS (ES) m/z=306 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:48]([O:50][C:51](=[O:55])[C@@H:52](O)[CH3:53])[CH3:49].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[CH2:48]([O:50][C:51](=[O:55])[CH:52]([O:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9])[CH3:53])[CH3:49]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.076 g, 0.18 mmol), triphenylphosphine (0.076 g, 0.29 mmol) and (2S)-2-hydroxy-propionic acid ethyl ester (0.036 g, 0.31 mmol) in tetrahydrofuran (1 mL) was added diethyl-azodicarboxylate (0.049 g, 0.29 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was concentrated in-vacuo. Chromatography on silica gel gave the title compound (0.078 g)
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23].C(OCC)(=O)C>O1CCCC1>[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: C/C=C/C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Reaction of the auxiliary (15) (0.416 g, 2.19 mmol) in solution in tetrahydrofuran (10 ml) at -78° C. with butyllithium (1.3M, 1.69 ml, 2.20 mmol) and crotonyl chloride (0.229 ml, 2.40 mmol) for 30 minutes and then at room temperature for 2 hours, with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (25) as a solid (0.564 g, 100%) ; mp 104° C.; νmax (CDCl3) 1687 and 1769 cm-1 ; [α]D24 (c 1 in CDCl3)=-82.6; (Found: C, 69.60; H, 6.64; N, 5.35. C15H17NO3 requires C, 69.48; H, 6.61; N, 5.40%); δH (CDCl3 ; 200 MHz) 0.99 (3H, s, C(CH3)2), 1.60 (3H, s, C(CH3)2), 1.93 (3H, d, J=5.4, CH3CHCH), 5.13 (1H, s, CHPh), 7.02-7.40 (7H, m, ArCH and CH3 CH=CH); δC (125 MHz; CDCl3) 18.39 (CH3), 23.60 (CH3), 28.81 (CH3), 67.09 (CH), 82.87 (C), 122.14 (CH), 126.08 (CH), 126.19 (CH), 128.71 (CH), 129.08 (CH), 136.61 (C), 147.31 (CH), 153.50 (CO), 165.07 (CO); m/z (CI+, NH3) 260 (M+ +1).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([OH:21])[CH:23]=3)[CH2:35][CH2:34]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1O
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1ccc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)cc1O
Yield: 69 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: BrCC1C=CC=C([C:9]2([C:12]([C:14]3([C:17]4[CH:18]=[C:19](CBr)[CH:20]=[CH:21][CH:22]=4)[CH2:16]C3)=[O:13])[CH2:11][CH2:10]2)C=1.[C-]#[N:26].[Na+]>CN(C)C=O>[CH:9]1([C:12]([C:14]2[CH:16]=[C:20]([CH2:21][C:22]#[N:26])[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: [C-]#N
Reactant: O=C(C1(c2cccc(CBr)c2)CC1)C1(c2cccc(CBr)c2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(C(=O)C2CC2)c1
Reaction time: 2 h

Procedure:
α-Bromo-m-tolylcyclopropyl ketone (10 g) in dry dimethylformamide (20 ml) was added dropwise during 1 hour to a stirred suspension of sodium cyanide (1.96 g) in dry dimethylformamide (40 ml). The mixture was cooled to 10° during the addition and for a further hour, then left to stand at 20° for a further 2 hours and poured onto ice (140 g). The mixture was extracted with ethyl acetate (3× 60 ml) and the extracts were combined, washed with water, dried over magnesium sulphate, filtered and evaporated to give a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C1COCC1.CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:8][CH:9]=1
Reactant: CC(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C#N)c1ccc(N)cc1
Reaction time: 0.5 h

Procedure:
To the flask was added THF/EtOH (1:1, 70 mL) followed by 2-(4-nitrophenyl)-propionitrile (13.2 g, 74.9 mmol) and 10% palladium carbon (1.07 g) at room temperature. The reaction mixture was hydrogenated and stirred for 30 minutes at 47 psi to 28 psi then filtered through celite bed, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/Br)=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4].[CH3:25][S-:26].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[S:26][CH3:25])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/SC
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (0.915 g, 2.196 mmol) was dissolved in DMSO (10 mL) and sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 min at ambient temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was diluted with petroleum ether to decrease the solubility of residual DMSO, washed with water thrice, filtered and concentrated. The product was purified by flash chromatography (hexane/ethyl acetate gradient) to provide the title compound (0.510 g, 60.5% yield) as a yellow solid: 1H NMR (CDCl3) δ 7.63 (dd, 1H), 7.19 (dd, 1H), 6.74 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=3)[CH:5]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Yield: 81.1 %

Procedure:
4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.291 g, 1.43 mmol) was treated with 4-chlorophenyl isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 75 (0.415 g, 1.16 mmol, 81%) as a white solid. LCMS m/z (%)=357 (M+H). 1H NMR (400 MHz, acetone-d6) δ: 8.21 (s, 1H), 8.07 (s, 1H), 7.58 (dd, J=2.8, 8.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.9 Hz, 1H), 6.20 (d, J=1.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([NH:25][CH3:26])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl.O>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([N:25]([CH3:26])[C:40]([C:34]4([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)C1(C)CCCCC1)[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C

Procedure:
To a solution of (2R)-1-[4-(1H-indol-4-yl)piperazin-1-yl]-N-methyl-3-pyridin-2-ylpropan-2-amine (349 mg.; 1 mmol, from Example 20) in dichloromethane (10 mL) at 0° C. is added a solution of potassium carbonate (690 mg.; 5 mmol) in water (1.6 mL), followed by a solution of 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol) in dichloromethane (1.6 mL). The reaction mixture is stirred while allowing to warm to ambient temperature over 1 hour, diluted with dichloromethane (20 mL), and the layers allowed to separate. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue is purified by flash chromatography on silica gel (10% methanol/ethyl acetate) to yield the free base of the title compound. The fumarate salt is prepared by treatment with an equimolar amount of fumaric acid in ethanol.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[C:32]([F:33])([F:34])[F:35])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: FC(F)(F)c1ccc(CBr)cc1Br
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(C(F)(F)F)c(Br)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 2-bromo-4-(bromomethyl)-1-(trifluoromethyl)benzene (53.5 mg, 0.168 mmol) following essentially the same procedure described in Step 1 of Example 7-9. The title compound was obtained as a yellow oil (91 mg) that was used without any further purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][C:3]=1[N+:16]([O-])=O.[CH3:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1>>[NH2:16][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:2]=1[N:25]1[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]1[CH3:19]
Reactant: COc1ccc(Cn2ncc([N+](=O)[O-])c2Cl)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: COc1ccc(Cn2ncc(N)c2N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)cc1

Procedure:
Following the procedure for Intermediate 33 starting with 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole and (R)-tert-butyl 3-methylpiperazine-1-carboxylate gave (R)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a red gum (325 mg, 81% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.16-7.11 (m, 3H), 6.82 (d, J=8.6 Hz, 2H), 5.16 (d, J=14.8 Hz, 1H), 5.05 (d, J=14.8 Hz, 1H), 4.10-3.80 (m, 2H), 3.78 (s, 3H), 3.26-3.19 (m, 1H), 3.01 (td, J=11.4, 3.0 Hz, 1H), 2.86 (t, J=13.2 Hz, 1H), 2.66 (s, 2H), 2.57 (s, 2H), 1.47 (s, 9H), 0.81 (d, J=6.3 Hz, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N:30]1[N:31]=[CH:32][N:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N:33]4[CH:34]=[N:30][N:31]=[CH:32]4)=[CH:40][CH:39]=3)[C:42](=[O:44])[CH3:43])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(-n2cnnc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (60 mg, 0.14 mmol) from Example 5 step 1 and N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide (30.6 mg, 0.15 mmol) were added in DMF (0.7 mL), then cesium carbonate (224 mg, 0.69 mmol) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+]>C(O)C.O>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH:9]([C:8]1[CH:20]=[CH:21][CH:22]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)[OH:10]
Reactant: Cc1cc(C)c(C(=O)c2cccc(-n3ccnc3)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(O)c2cccc(-n3ccnc3)c2)c(C)c1
Temperature: 56 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
To a suspension of 16 g of 3-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 90 ml of ethanol is added a solution of 3.4 g of sodium borohydride in 30 ml of water. After stirring at 56° C. for 20 hours, the reaction mixture is poured into ice-cold water. The precipitate is filtered off and recrystallized from a mixture of dioxane and water to give 13.6 g of α-(2,4,6-trimethylphenyl)-3-(1-imidazolyl)benzenemethanol as white crystals, melting at 191°-193° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.IC1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=C(O)C(C2C=CC=C([CH2:60][N:61]([CH3:63])[CH3:62])C=2)=CC=1>>[CH3:60][N:61]([CH2:63][C:26]1[CH:25]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][NH:9][CH:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=4)[C:14](=[O:22])[NH:13][C:12]3=[O:23])=[CH:7][C:2]=2[OH:1])[CH:29]=[CH:28][CH:27]=1)[CH3:62]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: CN(C)Cc1cccc(-c2ccc(CN)cc2O)c1
Agent: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Product: CN(C)Cc1cccc(-c2ccc(CNC=C3C(=O)NC(=O)c4ccc(I)cc43)cc2O)c1
Yield: 24 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) and 4-aminomethyl-3′-dimethylaminomethyl-biphenyl-2-ol (50 mg, 0.18 mmol) in 24% yield: MS (ESI): 554.0 (M+1)+1.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[O:30]>>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:23]2([OH:30])[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[NH:25][C:24]2=[O:29])=[C:3]([O:17][CH3:18])[CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 21.6 %

Procedure:
With 6.99 g of the compound obtained in Step 237-2 and 3.21 g of 5-chloroisatin as starting materials, 1.66 g of the title compound (colorless solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.[CH2:11]([NH2:14])[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[NH2:13][CH2:12][CH2:11][NH:14][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CCOC(=O)c1cccs1
Reactant: NCCN
Solvent: Cc1ccccc1
Product: NCCNC(=O)c1cccs1

Procedure:
A mixture of ethyl thiophene-2-carboxylate (12.0 g.) and ethylenediamine (15.4 ml.) was heated at 95°-100° C. for 48 hours. Excess ethylenediamine was removed under reduced pressure and the residue was dissolved in water (150 ml.). The insoluble material [bis(carboxamide)derivative] was removed by filtration. Evaporation of the filtrate gave a residue which was dissolved in toluene (50 ml.). The mixture was evaporated to give N-(2-aminoethyl)-thiophene-2-carboxamide as an oil (12.0 g.) essentially pure by TLC (Rf 0.90; SiO2 : 10% v/v methanol in chloroform as eluant) which was used without purification.
Reaction SMILES: N[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].[BrH:14]>O.CCCCCO>[Br:14][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: Br
Reactant: Nc1ncc([N+](=O)[O-])s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCO
Solvent: O
Product: O=[N+]([O-])c1cnc(Br)s1
Temperature: -10 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48% hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60% yield) of the 2-bromo-5-nitrothiazole as a yellow solid.