Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[N:18]=[CH:17][N:16]([CH3:19])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:19][N:16]1[CH:17]=[N:18][C:14]([C:10]2[CH:9]=[C:8]([C:28]3[C:29]([C:31]([F:33])([F:34])[F:32])=[N:30][C:25]4[N:26]([CH:22]=[CH:23][N:24]=4)[N:27]=3)[CH:13]=[CH:12][CH:11]=2)=[N:15]1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: Cn1cnc(-c2cccc(B3OCC(C)(C)CO3)c2)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: COCCOC
Product: Cn1cnc(-c2cccc(-c3nn4ccnc4nc3C(F)(F)F)c2)n1
Yield: 57.9 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 3-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-1-methyl-1H-[1,2,4]triazole (515 mg, 1.9 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.461 g, 1.73 mmol), 2 M Na2CO3 (1.9 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) in 1,2-dimethoxyethane (4 ml). The crude residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (346 mg, 58%). 1H NMR (360 MHz, CDCl3) δ 4.02 (3H, s), 7.64 (1H, t, J 7.9 Hz), 8.11 (1H, s), 8.16 (1H, dt, J 8.2, 1.6 Hz), 8.21 (1H, dt, J 8.2, 1.6 Hz), 8.71 (1H, s), 8.81 (1H, t, J 1.4 Hz), 8.84 (1H, s); MS (ES+) m/z 346 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH2:25][CH2:26][NH:27][S:28]([C:31]3[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=3)(=[O:30])=[O:29])[CH:18]=2)[CH2:11][N:10]([C:12](OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:8]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:18]=2)[O:24][CH2:25][CH2:26][NH:27][S:28]([C:31]2[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=2)(=[O:29])=[O:30])[CH2:11][N:10]([CH3:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CC(Cc2ccccc2)(c2ccc(F)c(OCCNS(=O)(=O)c3cn(C)cn3)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC(Cc2ccccc2)(c2ccc(F)c(OCCNS(=O)(=O)c3cn(C)cn3)c2)C1
Temperature: 25 °C

Procedure:
To ethyl 3-benzyl-3-(4-fluoro-3-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)phenyl)azetidine-1-carboxylate (20.8 mg, 0.040 mmol) in tetrahydrofuran (1 ml) was added a 1M lithium aluminium hydride solution in tetrahydrofuran (0.121 ml, 0.121 mmol) and refluxed for 2 h. Cooled down to room temperature and 2N NaOH was slowly added and extracted twice with dichloromethane, washed with sodium bicarbonate and brine, dried over MgSO4, filtered, evaporated and purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% MeOH in dichloromethane affording 8.9 mg of the titled compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]([CH2:24][CH3:25])=[CH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:24]([C:16]1[S:15][C:14]([NH:13][C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=1)[CH3:25]
Reactant: CSc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(CC)sc1N
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(SC)cc1[N+](=O)[O-]

Procedure:
4-Fluoro-3-nitro-thioanisole and ethyl 2-amino-5-ethyl-thiophene-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: COc1ccccc1I
Product: COc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-2-methoxybenzene: ESMS m/e: 257.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#N)cc1Nc1ccccc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of [(S)-1-(4-cyano-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester (750 mg, 1.97 mmol) in AcOH (3 mL) was stirred for 18 h at 80° C. After cooling to RT, volatiles were evaporated under reduced pressure affording [(S)-1-(6-cyano-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.97 mmol) which was used without any further purification in the following step. LCMS: RT 3.55 min [M+H]+ 363.2.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH2:33][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCN(Cc5ccc(Cl)cc5Cl)CC4)cc3)n2)cc1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
To a 1 ml vial was added N-(4-{2-[(4-piperazin-1-ylphenyl)amino]pyrimidin-4-yl}-phenyl)acetamide (38.85 mg, 0.1 mmol), 2,4-dichlorobenzaldehyde (350 mg, 2.0 mmol, 20 eq, source: Aldrich) and 1 ml of DMF. To this mixture was added sodium triacetoxyborohydride (106 mg, 0.5 mmol, 5 eq). The mixture was stirred over night at room temperature. Upon completion of the reaction as determined by LC/MS, 0.1 ml of 2M HCl was added. The residue was purified via reverse phase HPLC (ammonium acetate/ACN) to yield N-(4-{2-[(4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1-yl}phenyl)amino]pyrimidin-4-yl}phenyl)acetamide 180 (20.2 mg, 37%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.[Zn]>[NH2:19][C:11]1[CH:10]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=1
Reactant: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cc(C(=O)N2CCOCC2)cc(C(F)(F)F)c1
Reaction time: 0.12 h

Procedure:
Dissolve the morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (830 mg, 2.7 mmol) in MeOH (40 mL) at room temperature. Add ammonium chloride (3 g, 56 mmol) and stir at for 10 minutes before adding Zn powder (5 g, 76 mmol) with stirring for another 5-10 minutes. Filter and wash with MeOH. Concentrate to a white solid of 2 g material, containing excess ammonium chloride. LCMS (ES), m/z 275 (M+1). Use in the next step without further purification.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[N+:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:21]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Agent: Cl
Product: O=[N+]([O-])c1ccnc(OC2CCNCC2)c1
Reaction time: 4 h
Yield: 100 %

Procedure:
Add 8 mL of a 4 M solution of HCl in Et20 to 1.2 g of 4-(4-Nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester and stir the suspension for 4 hours. Evaporate the solvent and triturate the remaining solid with Et2O to afford 1.1 g of 4-nitro-2-(piperidin-4-yloxy)-pyridine dihydrochloride as a pale yellow solid (100% yield) (ES+(Q/z)=224 [M+H].
Reaction SMILES: [Cl:1]C1C=[C:4]([N:12]2CCN(C[C@@H](O)CC(O)=O)[C:14](=[O:25])[C@@H:13]2C)[CH:5]=[CH:6][C:7]=1[C:8](F)(F)F.C1C2(CCNC[C@H]2O)C1>>[ClH:1].[CH2:7]1[C:6]2([CH2:5][CH2:4][NH:12][CH2:13][C@H:14]2[OH:25])[CH2:8]1
Reactant: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)O)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Agent: O[C@@H]1CNCCC12CC2
Product: Cl

Procedure:
In analogy to example 15, (S)-4-[(S)-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-3-hydroxy-butyric acid (61% ds) (intermediate 44) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after flash chromatography (SiO2, dichloromethane/methanol 2%) and precipitation (dichloromethane/n-pentane) the titled compound in 61% yield (80% ds) as white powder. MS: 504.19 (MH+, 1Cl).
Reaction SMILES: C(O)=O.C([O:6][CH:7](OCC)[C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[CH2:11][CH2:12][N:13]1[CH2:31][CH2:30][C:16]2([O:21][CH2:20][CH2:19][N:18]([C:22]([C:24]3[S:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:23])[CH2:17]2)[CH2:15][CH2:14]1)C>O1CCCC1.O>[CH3:29][C:26]1[S:25][C:24]([C:22]([N:18]2[CH2:17][C:16]3([CH2:30][CH2:31][N:13]([CH2:12][CH2:11][C:10]4[CH:9]=[C:8]([CH:34]=[CH:33][CH:32]=4)[CH:7]=[O:6])[CH2:14][CH2:15]3)[O:21][CH2:20][CH2:19]2)=[O:23])=[CH:28][CH:27]=1
Reactant: CCOC(OCC)c1cccc(CCN2CCC3(CC2)CN(C(=O)c2ccc(C)s2)CCO3)c1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(CCc4cccc(C=O)c4)CC3)C2)s1
Reaction time: 0.17 h

Procedure:
Formic acid (2 mL) was added to stirred solution of (9-(3-(diethoxymethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 20, step e) (0.20 g) in tetrahydrofuran (3 mL) and water (1 mL) cooled in an ice bath. After 10 min, the reaction mixture was evaporated in vacuo, toluene was added and the reaction mixture was evaporated in vacuo. The residue was dissolved in acetonitrile and then evaporated in vacuo, and this process was repeated to give the subtitled compound as an oil that was used directly. Yield 0.16 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Yield: 105.1 %

Procedure:
tert-Butyl [3-(3-amino-4-nitrophenoxy)phenyl]carbamate (5.51 g, 15.6 mmol) and 10% palladium-carbon (875 mg) were dissolved in tetrahydrofuran (20 mL) and methanol (100 mL), and the mixture was stirred at room temperature for 18 hr under a hydrogen atmosphere (3 atm). Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.17 g) as a purple amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[C:16](OCC)(OCC)(OCC)[CH2:17][CH3:18]>>[Cl:1][C:2]1[C:11]2[N:10]([C:16]([CH2:17][CH3:18])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2
Reactant: COc1ccc2nc(Cl)c(NN)nc2c1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(Cl)nc3ccc(OC)cc3n12
Temperature: 25 °C
Reaction time: 60 h
Yield: 35 %

Procedure:
2-Chloro-3-hydrazino-6-methoxyquinoxaline (1.3 g., 0.0058 mole) and 25 ml. of triethyl orthopropionate were heated at 100° C. for 4 hours and stirred at room temperature for 60 hours. The precipitate was removed by filtration and washed with ethanol. Recrystallization from ethanol then afforded 530 mg. (35% yield) of pure 4-chloro-1-ethyl-8-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 196°-198° C. (decomp.).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: c1ccc(-c2cccs2)cc1
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
2-Phenylthiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound. APCI-Mass m/Z 343/345 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[S:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1>C1(C)C=CC=CC=1.ClCCl>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:34]([C:32]1[N:31]=[CH:30][S:29][CH:33]=1)[OH:35]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: O=Cc1cscn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cscn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 89.7 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (200 mg, 0.7 mmol) in anhydrous toluene (8 mL), TMEDA (110 uL, 0.7 mmol) was added followed by nBuLi (0.47 mL, 0.75 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and a solution of thiazole-4-carbaldehyde (0.32 g, 2.8 mmol) in dichloromethane (1 mL) was added. The mixture was stirred for 16 hrs during which the temperature reached room temperature. The reaction was quenched with water, the resulting mixture was basified by the addition of NH4OH and extracted with EtOAc. The combined organic layers were concentrated and subjected to mass triggered preparative HPLC to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (Compound 14-1) (200 mg). MH+=318.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21](O)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36].O>C(O)CCC>[ClH:36].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=[C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 30 g (0.059 mole) of 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone, 400 ml of 37% HCl, 200 ml of water and 100 ml of n-butanol was refluxed for one and one-half hours after which the solvent and excess acid were removed. The remaining residue was recrystallized from toluene to give the desired product, M.P. 223.5°-225.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([O:17][C:18]([C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(c2cccc(O)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one (0.1 g), 4-ethoxycarbonyl-4-(3-hydroxyphenyl)tetrahydropyran (0.098 g), potassium carbonate (0.057 g) and DMF (2 ml) was stirred at ambient temperature for 16 hours. The mixture was partitioned between diethyl ether and 0.5N aqueous hydrochloric acid. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and acetone as eluent. There was thus obtained an oil which was triturated in pentane to give 4-ethoxycarbonyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran (0.099 g, 60%), m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1([CH3:31])[CH3:30])(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[C:25]([CH3:31])([CH3:30])[CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)CNCCN1S(C)(=O)=O
Agent: Cl
Product: CC1(C)CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-2,2-dimethyl-piperazine hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [CH:1]1([N:6]2[C:14]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])=[N:13][C:12]3[C:7]2=[N:8][C:9]([NH:25][C:26]2[CH:27]=[N:28][C:29]([O:32]C)=[CH:30][CH:31]=2)=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>Br.C(O)(=O)C>[CH:1]1([N:6]2[C:14]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])=[N:13][C:12]3[C:7]2=[N:8][C:9]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[N:28][CH:27]=2)=[N:10][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(Nc2ncc3nc(Nc4c(F)cc(F)cc4F)n(C4CCCC4)c3n2)cn1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Nc2ncc3nc(Nc4c(F)cc(F)cc4F)n(C4CCCC4)c3n2)cn1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
9-Cyclopentyl-N2-(6-methoxypyridin-3-yl)-N8-(2,4,6-trifluorophenyl)-9H-purine-2,8-diamine (0.350 g., 0.769 mmol) was dissolved in 30% HBr/acetic acid in a sealed tube and heated to 80° C. for 16 hours. Product confirmed by LC-MS. The solution was partitioned between 1.75 M potassium carbonate and ethyl acetate (3×). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The resultant solid was purified via preparative HPLC (5-55% acetonitrile/water, 20 mL/min.) to afford the title compound (0.212 g, 34%). ES-MS (m/z) 442 [M+1]+. Melting point 257-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH2:28])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C.[Br:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH:28][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][Br:42])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCBr)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Reaction time: 0.5 h

Procedure:
5-(6-Aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (52.5 mg, 0.117 mmol) is dissolved in DCM (5 mL) at 0° C. DIEA (0.025 mL, 0.143 mmol) is added followed by 4-bromo-butyryl chloride (0.020 mL, 0.172 mmol). The reaction is stirred for 30 min before being diluted with ethyl acetate and washed with water. The organic layer is removed, dried, and concentrated to provide the title compound. MS (ESI) m/z 595.6 (M+1). 110-B. 5-[6-(2-Oxo-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]1)=[O:41])[CH3:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:16]=[CH:17][C:2]([O:1][CH:45]2[CH2:46][CH2:47][CH:42]([C:40]([O:39][CH2:37][CH3:38])=[O:41])[CH2:43][CH2:44]2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a solution of benzyl 4-hydroxybenzoate (50 g, 0.22 mol) and triphenylphosphine (63.2 g, 0.241 mol) dissolved in THF (800 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (35.3 mL, 0.22 mol). The reaction mixture was cooled on an ice bath and DEAD (38 ml, 0.241 mol) was added dropwise maintaining the temperature at 0° C. The resulting mixture was allowed slowly to reach room temperature and stirred for 16 hrs. at this temperature. The volume was reduced to app. 250 mL by evaporation and to the resulting mixture was added water (500 mL) followed by extraction with DCM (3×400 mL). The combined organic phases were washed with brine (400 mL), dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Crude product ˜80 g was purified on column chromatography (Flash 75) using first heptane (7.5 L) followed by a mixture of EtOAc-heptane (1:10) (5 L) and finally a mixture of EtOAc-heptane (1:6) (8 L). Combined fractions were evaporated in vacuo affording 18.1 g (22%) of 4-(4-ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester as an oil.