Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC[C@@H]1Cc1cn(C(=O)c2ccccc2)c2ccc(OC3CCCCC3)cc12
Reaction time: 15 h
Yield: 20.1 %

Procedure:
Benzoyl chloride (0.10 mL, 0.86 mmol) was added to a solution of (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3g, ~75 mg, 0.24 mmol), triethylamine (0.20 mL, 1.4 mmol) and DMAP (23 mg, 0.19 mmol) in dichloromethane (2.5 mL). The mixture was stirred for 15 h. prior to quenching with water (25 mL) and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform (1.5-3.3%) yielded (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-benzoylindole (20.1 mg, 20%, HRMS-FAB+ for C27H32N2O2 : calculated MH+ :417.25421; found MH+ :417.25475).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[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.CCO.COCCOC.O>[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Reactant: Nc1ccncc1B(O)O
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
Solvent: O
Solvent: CCO
Product: Nc1ccncc1-c1ccnc2c1cnn2-c1cccc(S(N)(=O)=O)c1
Temperature: 105 °C
Yield: 33.1 %

Procedure:
Example 79 was prepared according to the general procedure in Example 2, except heating at 105° C. for 2.25 h, and using the following materials: Intermediate 1A (50 mg, 0.084 mmol), 4-aminopyridin-3-ylboronic acid (81 mg, 0.59 mmol), sodium carbonate (31 mg, 0.292 mmol), EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (9.65 mg, 8.35 μmol). Example 79 was isolated as a yellow solid (10.2 mg, 32.3%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 5% Solvent B to 85% Solvent B over 12 min, ret. T=5.7 min. 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.93-9.00 (1 H, m), 8.71-8.79 (1 H, m), 8.60-8.67 (1 H, m), 8.22-8.27 (1 H, m), 8.18 (1 H, s), 8.09-8.14 (1 H, m), 7.84-7.93 (1 H, m), 7.69-7.80 (1 H, m), 7.37-7.47 (1 H, m), 6.79-6.92 (1 H, m) LC/MS (Condition B): ret. T=1.75 min, (M+H)+ 366.98. Analytical HPLC: (Condition A): >97%, ret. T=13.51 min, (Condition B): >97%, ret. T=15.81 min, (Condition C): >99%, ret. T=4.54 min, (Condition D): >97%, ret. T=4.87 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=O)[CH:5]=[CH:6][N:7]=1.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li]>>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[S:2][CH3:1])[CH:9]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cccc(-n2ccnc2SC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(2-methylsulfanyl-imidazol-1-yl)-benzoate [prepared by esterification of 3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoic acid [CAS-No. 108035-46-7] with conc. H2SO4 in EtOH, followed by treatment methyl iodide and NaH in THF/DMF] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light brown oil (4.41 g).
Reaction SMILES: C1COCC1.Br[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1.C([Li])CCC.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21](Cl)[N:20]=1>CCOC(C)=O.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:23]1[CH:24]=[C:19]([Cl:18])[N:20]=[C:21]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][N:11]=2)[CH:22]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: Cc1cnc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(-c2cc(Cl)cc(Cl)n2)s1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
A dry 25 mL schlenk flask equipped with a stir bar and placed under N2 atmosphere was charged with THF (7 mL) and 2-bromo-5-methylthiazole (610 mg, 3.43 mmol). The solution was cooled to −78° C. To the solution was added n-butyllithium in hexanes (1.37 mL, 3.43 mmol) upon which the solution immediately turned dark/golden. The solution was stirred for 5 minutes. To the solution was added zinc(II) chloride in THF (6.85 mL, 3.43 mmol) upon which the solution lightened to a golden color. The solution was immediately warmed to r.t. with a water bath, with stirring for 30 minutes. To the reaction solution was added 2,4,6-trichloropyridine (250 mg, 1.37 mmol) and Pd(dppf)Cl2 (100 mg, 0.137 mmol). The flask was sealed and then was placed in a 60° C. oil bath with stirring for 16 h. The reaction solution was transfered to a 500 mL reparatory funnel and was diluted with EtOAc (100 mL), then washed with brine (50 mL). The organic phase was dried over MgSO4; filtered; then concentrated in vacuo to afford a dark amber solid. This material was subjected to silica gel chromatography to afford 2-(4,6-dichloropyridin-2-yl)-5-methylthiazole as a white solid (33 mg, 8%): 1H-NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.7 Hz, 1H), 7.59 (d, J=1.1 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 2.55 (d, J=1.1 Hz, 3H); and 2,2′-(4-chloropyridine-2,6-diyl)bis(5-methylthiazole) as a white solid (160 mg, 48%): 1H-NMR (500 MHz, CDCl3) 8.10 (s, 2H), 7.60 (d, J=1.3 Hz, 2H), 2.59-2.55 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.CN(C)C=O.[C:16]([NH:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:18])[CH3:17]>O>[C:16]([NH:19][C:20]1[CH:25]=[C:24]([S:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc(Sc2ccc(C)cc2)ccc1[N+](=O)[O-]

Procedure:
0.84 G. of 57% sodium hydride is added to 3.0 g. p-methylthiophenol in 20 ml. dimethylformamide, 4.3 G. 2-acetamido-4-chloro-1-nitrobenzene is added and the mixture heated at 140°-145°C for 5 hours, cooled and treated with water. The crude product is filtered off, washed with water and pentane. Recrystallization from methanol gives 2-acetamido-4-(p-methylthiophenoxy)-1-nitrobenzene.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]>C(O)(=O)C.O.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[O:1]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC1CCC(C(C)C)C(C(=O)NCC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
A 20 mL round bottom flask equipped with a stir bar was charge with 2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide (100 mg, 0.33 mmol) and acetic acid (1 mL). A solution of CrO3 (36 mg, 0.363 mmoles, 1.1 eq) in acetic acid (500 μl) and water (100 μl) was slowly added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 15 min and diluted with ethyl acetate (30 mL) and saturated NaHCO3 (aq.) (30 mL). The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with sat NaHCO3 (3×10 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% to 50% ethyl acetate/hexane for elution) provided the title compounds as white solid (92 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([C:22](OC)=[O:23])[C:15](=[CH:20][CH:21]=2)[C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:23][CH2:22][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([CH3:1])[CH:3]=2)[CH:21]=[CH:20][C:15]=1[CH2:16][OH:17]
Reactant: COC(=O)c1ccc(CCCc2ccc(O)c(C)c2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCCc2ccc(CO)c(CO)c2)ccc1O

Procedure:
In a manner similar to Example 3a, by reacting 1 g (2.9 mmol) of dimethyl 4-[3-(3-methyl-4-hydroxyphenyl)propyl]phthalate (Example 2e) with 260 mg (7 mmol) of lithium aluminum hydride. A white solid is obtained (m=740 mg, m.p.=92° C., y=89%).
Reaction SMILES: C(OC([N:8]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH3:56])[CH:50]=1)[CH2:9][C@@H:10]([OH:47])[C@@H:11]([NH:21][C:22](=[O:46])[CH:23]([CH2:35][S:36]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])(=[O:38])=[O:37])[NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)=O)(C)(C)C.[ClH:57]>O1CCOCC1>[ClH:57].[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][C@H:11]([NH:21][C:22](=[O:46])[CH:23]([CH2:35][S:36]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])(=[O:37])=[O:38])[NH:24][C:25](=[O:34])[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C@H:10]([OH:47])[CH2:9][NH:8][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH3:56])[CH:50]=1
Reactant: CCCC(CCC)S(=O)(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN(Cc1cccc(CC)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(CCC)S(=O)(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(CC)c1
Reaction time: 0.17 h

Procedure:
N1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)-amino]-2-hydroxypropyl}-N2-(4-methoxybenzoyl)-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide, (LXXXVIII, 114 mg, 0.14 mmole) in hydrochloric acid (4 N, 1 ml) in dioxane. After stirring for 10 minutes at 20–25°, the solvent is removed under reduced pressure to give N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N2-(4-methoxybenzoyl)-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide hydrochloride,
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[C:13]1([S:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[C:13]1([S:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:25]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1Cc1ccc(Sc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.230 g, 1 mmol), 4-phenylsulfanyl-benzylamine (0.215 g, 1 mmol), and K2CO3 (0.230 g, 1.67 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-phenylsulfanyl-benzyl)-2,3-dihydro-isoindol-1-one (0.175 g, 53%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.27 (s, 2H), 4.77 (s, 2H) 7.22-7.49 (m, 12H), 7.88 (d, 1H). GC-MS: m/z 331 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[N:5]=[C:4]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[N:18]=2)[N:3]=1>CCO.[Pd]>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[N:18]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(5-methyl-1-(3-nitrobenzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (100 mg, 0.231 mmol) and Pd/C (10% w, 10 mg) in EtOH (10 mL) was stirred at RT for 2 h under hydrogen atmosphere. The reaction mixture was then filtered and concentrated under reduced pressure, and the residue was purified by prep-HPLC (Mobile phase: A=0.1% formic acid/H2O, B=MeCN; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C19H13ClF3N5O4S requires: 416. found: 417 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31-8.28 (m, 2H), 7.34 (m, 2H), 7.26 (s, 1H), 7.14 (m, 1H), 6.63 (m, 1H), 6.51 (m, 1H), 5.36 (s, 2H), 2.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>CCCCCC.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OCc2ccccc2)cc1-c1ccccc1
Yield: 82 %

Procedure:
The compound prepared in Example 975A was hydrolyzed with 1N aqueous NaOH and the carboxylic acid was coupled with (L)-methionine methyl ester by using coupling reagents. After flash column chromatography (1.5:1 =hexane/ethyl acetate), the desired compound was obtained (82% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:15])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(Cl)nc(N)nc21
Reaction time: 0.75 h
Yield: 77 %

Procedure:
The 2-amino-6-chloropurine (1.08 g, 6.4 mmol) was suspended in dry DMF (75 ml) and treated with sodium hydride, 60% dispersion (0.28 g, 7 mmol). The suspension was stirred for 15 min before iodomethane (0.44 ml, 7.06 mmol) was added and the resulting yellow solution stirred for 1 hr 45 min. The solid was filtered and the filtrate evaporated before addition of water for 10 min. The resulting solid was filtered and dried overnight to give the product as a mixture of N-7 and N-9 alkylation products. The residual liquor was left overnight and more crystals were collected the next day and dried. Yield=77%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([C:50]([F:53])([F:52])[F:51])[CH:37]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.O.CN(C=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[C:38]([C:50]([F:53])([F:51])[F:52])[CH:37]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(C(O)c2ccccn2)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (500 mg) was added a solution of [4-amino-2-(trifluoromethyl)phenyl](2-pyridyl)methanol (366 mg) and 1-hydroxybenzotriazole monohydrate (210 mg) in. DMF (15 ml), and catalytic amount of 4-(N,N-dimethylamino)pyridine and then, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (263 mg) was added to the mixture, and the mixture was stirred overnight under nitrogen atmosphere. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (400 mg) as colorless amorphous.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[O:18][CH3:17])[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COc1ccccc1C(=O)O
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: COc1ccccc1C(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2-methoxybenzoic acid
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].F[B-](F)(F)F.[CH3:17][O+](C)C>>[CH3:17][O:3][C:2]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: C[O+](C)C
Reactant: O=C1CCc2ccccc2N1
Agent: F[B-](F)(F)F
Product: COC1=Nc2ccccc2CC1

Procedure:
A sample of 3,4-dihydrocarbostyril (Apin Chemicals Ltd., 736 mg, 5.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (924 mg, 6.2 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 130 mg (16%) of the title material.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:8]([C:40]#[C:41][Si](C)(C)C)=[C:9]([F:39])[C:10]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(C)(C)C)=[C:18]([F:29])[CH:17]=3)=[CH:13][C:12](=[O:30])[C:11]=2[C:31]=1[NH:32]C(=O)C(C)(C)C>>[NH2:32][C:31]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:39])=[C:8]([C:40]#[CH:41])[C:7]=1[F:6]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(C#C[Si](C)(C)C)c(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: C#Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
3 mL of concentrated sulfuric acid was added to 37 mg (0.065 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-7-(2-trimethylsilylethynyl)-4H-1-benzopyran-4-one and the mixture was stirred at 50° C. for 10 minutes. The reaction solution was poured into ice water and the mixture was extracted once with ethyl acetate. The organic layer was washed once with 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (chloroform:acetonitrile=9:1) to give 15 mg of Compound 112 (yield: 70%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC(=O)O1
Reactant: NCc1ccnc(Nc2ccccc2)n1
Product: O=C(O)CCCC(=O)NCc1ccnc(Nc2ccccc2)n1
Yield: 51.4 %

Procedure:
By an analogous process to Method 13, 2-anilino-4-aminomethylpyrimidine (Method 12)(4.8 g, 24 mmol) was treated with glutaric anhydride (2.74 g, 24 mmol) to give the title compound (3.88 g, 51.7%) as a pale brown solid. NMR: 1.75 (m, 2H), 2.25 (t, 4H), 4.23 (d, 2H), 6.68 (d, 1H), 6.93 (t, 1H), 7.27 (t, 2H), 7.76 (d, 2H), 8.4 (d, 2H), 9.53 (s, 1H): m/z 315.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C2CCOCC2)C3)cc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0714 g, 0.174 mmol) in dry N,N-Dimethylformamide (0.850 mL, 11.0 mmol) at 0° C. was added Tetrahydro-4H-pyran-4-one (0.0160 mL, 0.174 mmol). The reaction mixture was stirred at 50° C. for 10 minutes then cooled at 0° C. and added Sodium triacetoxyborohydride (0.0788 g, 0.372 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was filtered through a disc filtered, concentrated, chromatographed through silica gel (40 g, 0-10% MeOH in dichloromethane), and purified by HPLC. LC/MS-m/z+495.3 (M+H)+