Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>COCCOC>[C:12]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DME (7 mL). Stir at ambient temperature for 17 h. Partition the reaction mixture between brine (15 mL) and diethyl ether (15 mL), separate the organic layer, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C.S([O-])(=O)(=O)C.[Na].[I-].[F:49][C:50]([F:54])([F:53])[CH2:51][O-].[Na+].FC(F)(F)CO.[H-].[Na+]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH2:51][C:50]([F:54])([F:53])[F:49])=[CH:4][CH:3]=1
Reactant: [O-]CC(F)(F)F
Reactant: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 18.85 g (59.2 mmol) 1-(4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl)-ethanone, prepared as in Part C, and 11.5 g (66.0 mmol) methanesulfonic anhydride in 300 ml anhydrous tetrahydrofuran, 13.06 ml (75 mmol) N,N-diisopropylethylamine is added at 10° C. over 20 minutes. The mixture is allowed to warm to 20° C. and stirred for 90 minutes at 20° C. When the mesylate formation is complete as monitored by 1H-NMR, 15 g (100 mmol) of solid sodium lodide is added. The conversion of the mesylate to the iodide is complete (as monitored by 1H-NMR) in about 2 hr. A solution of sodium 2,2,2-trifluoroethoxide, made from 21.8 ml (300 ml) 2,2,2-trifluoroethanol, 12 g (300 mmol) sodium hydride (60% disp. in mineral oil) in 280 ml anhydrous tetrahydrofuran, is added to reaction mixture. The resulting slurry is stirred at room temperature for 60 minutes, diluted with 500 mL ether, and extracted with water (3×200 mL). The water phase is extracted with methylene chloride (2×200 mL), and the organic phases are combined, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is then transferred to a silica gel packed column and purified using the following solvent mixtures: hexane-ethyl acetate (1:1), ethyl acetate (neat) then ethyl acetate-ethanol (9:1) to yield the title compound. 1H-NMR (CDCl3) d 1.88 (m, 2H), 2.10-2.20 (m, 2H), 2.16 (d, 3H), 2.91 (t, 1H), 3.12 (m, 1H), 3.28 (t, 1H), 3.93 (d, 1H), 4.00 (q, 2H), 4.57 (d, 1H), 4.71 (s, 2H), 7.19 (t, 2H), 7.65 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[S:28][C:27]([O:29][CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:31](=[O:32])[CH2:30][O:29][C:27]4[S:28][C:24]([Cl:23])=[CH:25][CH:26]=4)[C@@H:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one, EXAMPLE 78 and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24. 1H NMR (d6-DMSO, 300 MHz) δ9.78 (bs, 2H), 8.81 (s, 1H), 8.35 (d, 1H), 7.60 (m, 2H), 7.51 (s, 1H), 6.69 (m, 1H), 6.21 (d, 1H), 4.91 (AB, 2H), 4.72 (m, 2H), 3.84 (m, 1H), 3.52 (m, 2H), 3.23 (m, 1H), 1.80 (m, 2H), 1.24 (m, 2H), 0.82 (m, 3H). MS (ion spray), m/z, 474, 476, (M+H) (Cl pattern). Elemental analysis, cal C22H22ClN5O2S.C2HF3O2.1.15H2O % C=47.31, % H=4.52, % N=11.50; found % C=47.39, % H=4.140, % N=11.19.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]([CH3:14])C(O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C[CH2:23][O:24]CC>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][CH2:14][CH2:23][OH:24]
Reactant: CC(C(=O)O)C1Cc2ccccc2O1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCCCC1Cc2ccccc2O1

Procedure:
2-(2,3-Dihydrobenzofuranyl)-propanoic acid (10 g) was dissolved in ether (60 mls) added dropwise to a stirred suspension of lithium aluminum hydride (2.0 g) in ether (90 mls). The reaction temperature was maintained below 30° C. whilst under an atmosphere of nitrogen. After 3 hours water was added to destroy excess hydride. The mixture was filtered and the ether layer separated and dried over anhydrous magnesium sulphate. Removal of solvent gave an oil (8.0 g). M/e 178.0984 NMR (CDCl3) (60 MHz) δ1.65 (4H, m); 2.30-3.30 (2H, m); 3.50 (2H, t, J=6 Hz); 3.90 (1H, s), 4.65 (1H, m); 6.40-7.20 (4H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16](=[O:25])[C:15]([CH2:28][CH3:29])([CH2:26][CH3:27])[O:14][C:13]=2[N:30]=1.[C:31]([O:35][C:36]([NH:38][C@H:39]([C:41](O)=[O:42])[CH3:40])=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:37])[NH:38][C@H:39]([C:41](=[O:42])[NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16](=[O:25])[C:15]([CH2:28][CH3:29])([CH2:26][CH3:27])[O:14][C:13]=2[N:30]=1)[CH3:40])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCC1(CC)Oc2nc(N)ccc2N(c2ccc(Cl)cc2)C1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)Oc2nc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc2N(c2ccc(Cl)cc2)C1=O
Yield: 66.4 %

Procedure:
6-Amino-1-(4-chloro-phenyl)-3,3-diethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one trifluoroacetate salt (Example 5, product from Step 3) (235 mg, 0.53 mmol) was coupled with N-(tert-butoxycarbonyl)-L-alanine (255 mg, 1.32 mmol) by following procedures similar to those described in General Procedure 2 to give {(S)-1-[1-(4-chloro-phenyl)-3,3-diethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (177 mg) as a colourless gum. MS: [M+H]+503.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=1.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:22]3[CH:21]=[N:20][CH:19]=[C:18]([C:17]([F:27])([F:16])[F:26])[CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cncc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncc(C(F)(F)F)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.75 mmole), 3-(trifluoromethyl)-5-vinylpyridine (0.13 g, 0.75 mmole) and, tetra butyl ammonium chloride (2 mg, 0.0375 mmole) were charged in 5 ml, 50% aqueous NaOH. The reaction mixture at 100° C. for 8 hrs. The reaction mass was cool at RT, added 5 ml water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, concentrated and purified by Prep HPLC to get 2,8-dimethyl-5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][N:13]1[CH2:17][C@@H:16]([CH3:18])[C@@:15]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])([C:19](=[O:33])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([F:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:14]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:9])[F:10])[C:3]=1[CH2:12][N:13]1[CH2:17][C@@H:16]([CH3:18])[C@@:15]([CH2:34][C:35]([OH:37])=[O:36])([C:19](=[O:33])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([F:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:14]1
Reactant: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3C(F)(F)F)C[C@H]2C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)O)CN(Cc3c(Cl)cccc3C(F)(F)F)C[C@H]2C)CC1
Reaction time: 0.58 h
Yield: 88 %

Procedure:
A mixture of the chiral form of tert-butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 1l (153 mg, 0.252 mmol), trifluoroacetic acid (2 ml, 26.9 mmol) and dichloromethane (dehydrated) (2 ml) was stirred at mom temperature for two hours and 35 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title compound (122 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](Br)=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])[S:20]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:16][C@@H:17]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:18][N:19]([CH3:32])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4]
Reactant: CN(C[C@@H](N)c1cccc(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(Br)c2cccnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N[C@H](CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2cccc(F)c2)c2cccnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A reaction mixture of 5-Bromo-quinoline-8-carboxylic acid methyl ester (600.00 mg; 2.25 mmol; 1.00 eq.), N—[(S)-2-Amino-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide (876.48 mg; 2.48 mmol; 1.10 eq.), potassium phosphate, tribasic (957.26 mg; 4.51 mmol; 2.00 eq.), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (214.99 mg; 0.45 mmol; 0.20 eq.), palladium (+2) acetate (50.62 mg; 0.23 mmol; 0.10 eq.) and toluene (5 ml) in microwave tube were stirred at 100° C. overnight. The crude was purified by prep HPLC (Basic condition) to afford (S)-5-{1-(3-Fluoro-phenyl)-2-[methyl-(4-nitro-benzenesulfonyl)-amino]-ethylamino}-quinoline-8-carboxylic acid methyl ester (250 mg). LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CN1CCNCC1
Product: Cc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 93.4 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 93.4%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=1.[C-:10]#[N:11].[Na+]>C(#N)C.O>[NH2:9][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:10]#[N:11])[NH:8][N:7]=1
Reactant: [C-]#N
Reactant: Nc1cc(CCBr)[nH]n1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CCCc1cc(N)n[nH]1
Temperature: -70 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a solution of 5-(2-bromoethyl)-1H-pyrazol-3-amine (9.3 g, 48.9 mmol.) in acetonitrile (100 mL) was added a solution of NaCN (2.88 g, 58.6 mmol) in water (3 mL). The reaction mixture was stirred at −70° C. for 16 h and then concentrated in vacuo to remove the solvent. The residue was partitioned between DCM and brine. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The crude material was crystallized from MeOH-EtOAc to afford 4 g (60%) of 3-(3-amino-1H-pyrazol-5-yl)propanenitrile (87) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][C@@H:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Si:20]([O:21][C@@H:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: CC1(C)OB(c2cccc3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: N#Cc1cc(-c2nnc(Br)s2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Prepared using General Procedure 1: A 20 mL microwave vial was charged with 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (30 mg, 0.1 mmol), (S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (43.6 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol) and a 3:1 mixture of DME/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and mixture degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EA (10 mL), and washed with water and brine. The organic layer dried over MgSO4, concentrated, and purified by silica gel chromatography (EA/hexanes) to provide 25 mg (44%) of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C24H26FN3OSSi: 451.15; found 452.1 [M+H]+, tR=4.53 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.34-8.25 (m, 2H), 7.85 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.44-7.34 (m, 2H), 5.34 (t, J=7.1 Hz, 1H), 3.46 (ddd, J=16.8, 9.0, 2.8 Hz, 1H), 3.13 (dt, J=16.8, 8.3 Hz, 1H), 2.61-2.50 (m, 1H), 2.08-1.96 (m, 1H), 0.98-0.95 (m, 9H), 0.22-0.17 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([Br:12])[C:5]=2[O:4][CH2:3]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:12][C:11]1[C:5]2[O:4][CH2:3][C@H:2]([N:1]([CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]=2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Br)c2c1C[C@@H](N)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Br)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Temperature: 85 °C
Yield: 155.5 %

Procedure:
(R)-3-Amino-8-bromo-5-methoxy-3,4-dihydro-2H-1-benzopyran (11.5 g, 44 mmol) was dissolved in 400 mL anhydrous acetonitrile and to the reaction were benzyl bromide (13 mL, 110 mmol), anhydrous potassium carbonate (grounded) (16 g, 116 mmol), and a catalytic amount of KI added and then heated to 85° C. for 48 h. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted twice with ether. The combined ether portions were treated with brine, dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: CH2Cl2) gave 15 g (78% yield) of the title compound as a clear oil. [α]21D =-15.5° (C=0.1 CHCl3) GC-MS (70eV) M=437 (15%).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH3:9].[NH2:20][CH2:19][C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:10]([NH:9][CH2:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 153.7 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (5.70 g, 13.18 mmol) (Preparation 5) in ethanol (200 ml) saturated with ammonia gas was treated with Pearlman's catalyst (1.00 g), pressurised to 414 kPa (60 psi) with hydrogen in a sealed vessel and stirred at room temperature for 30 hours. The suspension was filtered through a pad of Arbocel (trade mark) and the solvent was removed under reduced pressure. The residue was twice azeotroped from dichloromethane and then purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound (4.34 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([CH3:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[C:21]=1[CH3:26]
Reactant: Cc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccn3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
[(S)-1-(6-Fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.29 g, 3.5 mmol) was dissolved in hydrochloric acid in dioxane (15 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to yield the title compound as an off-white solid (1.17 g, 100%). LCMS (Method C): RT=1.88 min, [M+H]+=271.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Product: CS(=O)(=O)n1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Yield: 92.1 %

Procedure:
Using the procedure of example 66, compound 13 (24 mg) and methanesulfonyl chloride (9.4 mg) were used to provide compound 67 (28 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, 1 H), 8.52 (d, 1 H), 8.32 (d, 1 H), 8.28 (s, 1 H), 7.40 (dd, 1 H); 6.85 (d, 1H), 5.12 (m, 1 H), 3.90 (m, 1 H), 3.65 (s, 3 H), 2.15 (m, 2 H), 1.85 (m, 2 H), 1.65 (m, 2 H), 1.50 (m, 2 H), 1.35 (m, 2 H). MS (ESI) m/z: 372 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:40][CH3:41])[C:32]([O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:52]>C(O)C>[Na+:52].[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([C:2]([F:49])([F:1])[F:50])[CH:44]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:40][CH3:41])[C:32]([O:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCN(C(=O)OCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C(=O)OCCC(=O)[O-])c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionate (114 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (5 ml), and the mixture is stirred at room temperature for 1 hour and 30 minutes. Thereto are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionic acid (81 mg). The resulting 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyloxy]-propionic acid (81 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (115 μl) and concentrated under reduced pressure to give 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylcarbamoyloxy]-propionic acid sodium salt (78 mg). MS (m/z): 722 [M−Na]−
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13](O)[C:14]2[S:19][CH:18]=[CH:17][C:15]=2[N:16]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[C:14]2[S:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[N:12]=1
Reactant: Oc1nc(-c2cnc3ccccc3n2)nc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2cnc3ccccc3n2)nc2ccsc12
Temperature: 25 °C

Procedure:
A solution of 2-(2-quinoxalinyl)thieno[3,2-d]pyrimidin-4-ol (150 mg, 0.54 mmol) in POCl3 (5 mL) was heated to reflux and maintained at reflux overnight. After cooling to rt, excess POCl3 was removed under reduced pressure to give the crude product which was used in the next step without further purification.