Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH3:27])=[C:22]([CH:24]4[CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[O:28])=[CH:20][N:19]3[C:21]=2[CH3:27])[CH2:26][CH2:25]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cn12
Agent: [Pd]
Solvent: CO
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (127 mg) in MeOH (8 ml) was added Pd/C (10%, 25 mg), and the mixture was stirred under H2 atmosphere at room temperature for 4 h. The solid was then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([CH2:38][C:39]([NH2:44])([CH3:43])[C:40](O)=[O:41])(OC(C)(C)C)=O>>[NH2:44][C:39]([CH3:43])([CH3:38])[C:40]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:41]
Reactant: CC(C)(C)OC(=O)CC(C)(N)C(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Agent: Cl
Product: CC(C)(N)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-2-aminoisobutyric Acid via General Procedure B followed by Boc removal with TFA to generate 28.8 mg of 103 after purification. MS (Q1) 498.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[O:12])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCOCC3)cc2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
The compound 4 (2.0 g, 4.6 mmol) was dissolved in CH2Cl2 (25 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.94 mL, 6.76 mmol) and BOP reagent (2.19 g, 4.96 mmol) were added and the reaction mixture was stirred for 15 min. Morpholine (0.79 mL, 9.02 mmol) was added and the resulting solution was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (60 mL). The organic layer was extracted with 1.0 N NaOH (1×10 mL), water (2×20 mL) and brine (1×20 mL). Drying and concentration of the organic layer gave the desired amide 13 (1.7 g, ˜74%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.56 (m, 1H), 3.58 (s, 3H), 3.24-3.54 (m, 8H), 2.74-2.87 (m, 4H), 2.62 (t, J=6.0 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=[O:8])C1C=CC=CC=1.[CH3:19][C:20]1[CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24]2)[CH2:22][CH:21]=1.[OH-].[Na+]>C(#N)C.CO.O>[CH3:19][C:20]1[C@@H:25]([OH:8])[CH2:24][C@H:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH:21]=1
Reactant: CC1=CCC2CC1C2(C)C
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: C=C(C)[C@@H]1CC=C(C)[C@@H](O)C1
Yield: 61 %

Procedure:
A well stirred solution of benzoyl peroxide (24.0 g), cuprous chloride (0.2 g), cupric benzoate (1.5 g) and alpha-pinene (28.0 g) in acetonitrile (150 ml) is heated on an oil bath at 65° ± 5° for 24 hours. The acetonitrile is removed by evaporation under vacuum (water pressure) at 40°. Excess alpha-pinene is recovered by continuing the evaporation at 75° (3 mm). The resulting blue-green slurry is dissolved in 100 ml ether and the solution filtered to remove the cupric benzoate. The filtrate is washed with 2N HCl (2 × 30 ml), distilled water (3 × 30 ml) and then the ether removed by evaporation. This gives a straw colored oil which is dissolved in a solution of methanol (200 ml), water (50 ml), NaOH (10 g), and hydroylzed by refluxing 1 hour. Removal of the methanol affords an aqueous suspension which is diluted with water (100 ml) and steam distilled. The distillate is extracted with ether (4 × 20 ml). This organic solution is dried over magnesium sulphate and evaporated to yield crude trans-carveol (9.2 g). Distillation affords pure material, b.p. 106°-110°C (10 mm).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=O)=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.[CH3:21][NH:22][NH2:23]>C(O)CCC>[CH3:21][N:22]1[C:2]2=[C:3]3[CH:20]=[CH:19][NH:18][C:4]3=[N:5][CH:6]=[C:7]2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:23]1
Reactant: CSc1ccc(C(=O)c2cnc3[nH]ccc3c2Cl)cc1
Reactant: CNN
Solvent: CCCCO
Product: CSc1ccc(-c2nn(C)c3c2cnc2[nH]ccc23)cc1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
To (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-(methylthio)phenyl)methanone (0.20 g, 0.66 mmol, prepared using S from 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [Preparation #1, Step B] and AV) in BuOH (4 mL) was added methylhydrazine (0.052 mL, 0.991 mmol). The mixture was stirred for about 1.5 h at about 95° C. and then cooled to rt. The resulting precipitate was collected by filtration, washed with EtOAc (2 mL) and dried in a vacuum oven at about 70° C. for about 2 h to give 1-methyl-3-(4-(methylthio)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.15 g, 77%): LC/MS (Table 2, Method a) Rt=2.23 min.; MS m/z: 295 (M+H)+. Syk IC50=A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ncc(Br)cc1N
Product: CCc1ncc(Br)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 87.4 %

Procedure:
5-Bromo-2-ethyl-3-pyridinamine (285 mg, 1.42 mmol, prepared according to WO 2008157191 A2 20081224) was treated with 4-methoxybenzene-1-sulfonyl chloride (323 mg, 1.56 mmol) according to the method described In Preparation 15b to give 461 mg (75% yield) of the title compound as an oil. Purity 85%.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][NH:8][C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1>ClC(Cl)C>[CH3:7][N:8]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CNc1cnn(-c2cccnc2)c1
Reactant: CC(C)C(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)C(=O)N(C)c1cnn(-c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A solution of isobutyryl chloride (0.138 g, 1.3 mmol) in dichloroethane (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-(1-pyridin-3-yl-1H-pyrazol-4-yl)-amine (0.15 g, 0.86 mmol) in dichloroethane (5 mL), stirred for 10 minutes and then treated at a dropwise rate with a solution of 4-N,N-dimethylaminopyridine (0.11 g, 0.9 mmol) in dichloroethane (1.5 mL). The cooling bath was removed after 30 minutes, stirred under nitrogen at room temperature for 14 hours, diluted with dichloroethane (40 mL), washed with water (30 mL), brine (10 mL), dried over MgSO4 and purified by reversed phase column chromatography to give a yellowish gum (0.114 g, 54%) 1H NMR (300 MHz, CDCl3) δ 9.01-8.93 (m, 1H), 8.67 (s, 0.4H), 8.61 (d, J=4.2 Hz, 0.6H), 8.54 (d, 0.4H), 8.08-8.02 (m, 1H), 7.96 (s, 0.6H), 7.80 (s, 0.4H), 7.70 (s, 0.6H), 7.47-7.37 (m, 1H), 3.49 (s, 1.2H), 3.26 (s, 2.8H), 3.06-2.98 (m, 0.4H), 2.86-2.70 (m, 0.6H), 1.25 (d, J=6.1 Hz, 2.4H), 1.09 (d, J=6.6 Hz, 3.6H). ESIMS m/z 245 ([M+1]).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[O:24]1CCCC1>C(C(C)=O)C>[C:9]1(=[O:24])[CH2:23][CH2:22][CH2:12][CH2:11][CH2:10]1.[C:1]([C:3]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[C:4]([C:5]#[N:6])[C:7]#[N:8])#[N:2]
Reactant: C1CCOC1
Agent: CCCCN(CCCC)c1ccc(C(C#N)=C(C#N)C#N)cc1
Solvent: CCC(C)=O
Product: O=C1CCCCC1

Procedure:
A dye solution containing 3.37 wt-% dibutyl magenta dye (4-tricyanovinyl-N,N-dibutylaniline), 0.84 wt-% butyl magenta (structure shown below), 3.94 wt-% GEON® 178 (polyvinyl chloride, B.F. Goodrich Co., Cleveland, Ohio), 0.28 wt-% VITEL™ PE-200 (polyester resin from Goodyear Chemicals Co., Akron, Ohio), 1.57 wt-% TROYSOL™ CD 1 dispersing agent (CAS registry No.: 64742-88-7, purchased from Troy Chemical, Newark, N.J.), 13.5 wt-% tetrahydrofuran, 36.0 wt-% methyl ethyl ketone, and 40.5 wt-% cyclohexanone was prepared. The individual components were first dissolved in an appropriate solvent and then mixed. ##STR1## This dye solution was coated onto the antistatic layer using a No. 9 Mayer bar and dried at 85° C. for five minutes to give an antistatic thermal dye transfer donor film. The static decay time for the antistatic thermal dye transfer donor film was 0.04 second. In comparison, the dye solution was applied to unprimed and untreated 5.7 micron Teijin F22G polyester film using a No. 9 Mayer bar and dried at 85° C. for 5 minutes to give a non-antistatic thermal dye transfer film. The non-antistatic film did not exhibit decay of a triboelectrically generated charge and could not be charged by the Electro-tech Static Decay Meter.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([O:23][CH2:24][CH2:25]CCCCCCCCCCCC)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C=CC(C(OCCCCCCCCCCCCCC)=O)=CC=1>>[CH3:40][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:38][CH:39]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: CCCCCCCCCCCCCCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
n-Tetradecyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate-Using n-tetradecyl 4-hydroxybenzoate, the title compound was synthesized as a colorless oil. PMR (CDCl3): δ 0.83-0.94 (3H, m), 1.15-1.50 (34H, m), 1.70-1.85 (6H, m), 4.34 (2H, t, J~6.7 Hz), 7.29 (2H, d, J~8.7 Hz), 7.46 (1H, d, J~8.4 Hz), 7.95 (1H, dd, J~8.4 Hz, 1.8 Hz), 8.14 (2H, d, J~8.7 Hz), 8.16 (1H, d, J~1.8 Hz).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1([C:41]1[S:45][C:44]2[C:46]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=3)=[CH:47][CH:48]=[CH:49][C:43]=2[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:10]1[C:41]1[S:45][C:44]2[C:46]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([CH3:57])=[CH:55][CH:56]=3)=[CH:47][CH:48]=[CH:49][C:43]=2[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2cccc3cc(C4(O)O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)sc23)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(Cc2cccc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)sc23)cc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-1-[7-(4-methylbenzyl)benzo[b]thiophen-2-yl]-D-glucopyranose (1.2 g) and triethylsilane (0.49 mL), in acetonitrile (15 μL) was added boron trifluoride diethyl ether complex (2.0 mL) at −20° C., and the mixture was stirred for 1 hour. A saturated potassium carbonate aqueous solution was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (0.95 g).
Reaction SMILES: C(C1C2NC3C(=CC=CC=3)N(CC)C=2C=CC=1)(O)=O.CC1C=C2C(N(CC)C3C=CC=C(C(O)=O)C=3N2)=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.NC1C(C)=CC=CC=1.Br[C:56]1[C:64]([N+:65]([O-:67])=[O:66])=[CH:63][CH:62]=[CH:61][C:57]=1[C:58]([OH:60])=[O:59].C(N1CCOCC1)C>CC(O)C(O)C.[NH4+].[OH-].Cl[Cu]>[C:41]1([NH:40][C:56]2[C:57](=[CH:61][CH:62]=[CH:63][C:64]=2[N+:65]([O-:67])=[O:66])[C:58]([OH:60])=[O:59])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: Cl[Cu]
Agent: CC(O)C(C)O
Agent: CCN1CCOCC1
Solvent: Cc1ccccc1N
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1ccccc1

Procedure:
Reaction scheme 7 illustrates the synthesis of a 1-carboxy N-ethyl phenazine (29a) and 8-methyl 1-carboxy N-ethyl phenazine (29b) derivative. A mixture of aniline (or ortho toluidine) and 2-bromo-3-nitrobenzoic acid is reacted in the presence of CuCl, Cu powder and N-ethylmorpholine in butane-2,3-diol at 70 to 80° C. for 8 to 24 hours. This reaction mixture is diluted with 0.1 M NH4OH solution and filtered through a bed of celite. The resulting solution is slowly poured over into 2N HCl to give N-phenyl-3-nitro anthranilic acid (25a) or the methyl substituted derivative (25b). Intermediates (25a) or (25b) are reacted with sodium borohydride in 2N NaOH solution under reflux conditions to effect ring closure and provide the sodium salt of a phenazine, which, upon acidification, provides (26a) or (26b). The acid chloride of the phenazine 1-carboxy derivative (or 8-methyl 1-carboxyphenazine) is prepared by the reaction with thionyl chloride and the resulting acid chloride is converted to methyl ester by the reaction with methanol in HCl. The resulting phenazine methyl ester (27a) or (27b) is alkylated with diethyl sulfate and potassium carbonate to give corresponding N-ethyl phenazine derivatives (28a) or (28b). Finally, the methyl ester group of phenazines (28a) or (28b) is hydrolyzed with dilute hydrochloric acid to give (29a) or (29b).
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][C:5]=1[O:14][C:15]([F:18])([F:17])[F:16]>C1COCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[O:14][C:15]([F:16])([F:18])[F:17]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 70 °C
Yield: 95.5 %

Procedure:
To a solution of lithium borohydride (1.16 g, 53.4 mmol) in THF (100 mL) was added methyl 4-bromo-3-(trifluoromethoxy)benzoate (10.6 g, 35.6 mmol) at 0° C., and the resulting solution was heated at 70° C. for 3 h under nitrogen atmosphere. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to afford the crude title product (9.17 g, 34 mmol). MS (ESI) m/z 270.1 M+, 272.1 [M+2]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])(C)[CH3:2].C([Mg]Cl)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35](NOC)=[O:36])[C:30]=1C>C1COCC1>[C:4]([SiH:1]([CH3:2])[O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15]([C:35]([C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[CH:33][N:32]=2)=[O:36])=[CH:14]1)([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CONC(=O)c1nccc(Cl)c1C
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[SiH](OCC(C)(C)n1cc(C(=O)c2cc(Cl)ccn2)c2cnccc21)C(C)(C)C
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 60.8 %

Procedure:
1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 65, 3.99 g, 9.06 mmol) was dissolved in THF (75 mL) and the solution was degassed and cooled to −5° C. 2M iPrMgCl in THF (5.44 mL, 10.9 mmol) was added dropwise and the resulting yellow solution stirred at this temperature for 45 minutes. A solution of 4-chloro-N-methoxy-M-methylpicolinamide (2.18 g, 10.9 mmol) in THF (20 mL) was added dropwise and the reaction allowed to warm to room temperature for 4.5 hours. The reaction was partitioned between saturated aqueous ammonium chloride solution (30 mL) and EtOAc (50 mL), the organic layer was collected, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-90% EtOAc in DCM to afford the title compound as an orange oil (2.37 g, 59%). Taken on to the next step directly.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]([O:24][CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])(=[O:3])[CH3:2].C(Cl)Cl.[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:22]([O:24][CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C(C)O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Yield: 86.5 %

Procedure:
To a solution of methyl 8-acetyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.15 g, 3.33 mmol) in MeOH (20 mL)/DCM (10 mL) was added sodium tetrahydroborate (0.139 g, 3.66 mmol) at −10° C. The reaction mixture was quenched with water (50 mL) 15 min later. The volatiles were removed and the aqueous layer was extracted twice with DCM. Combined organics phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with MTBE/DCM (9/1) and collected by filtration to give methyl 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.0 g, 86%) as a grey solid, which was used in the next step without further purification. Mass Spectrum: M+H+ 348.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][NH:21][CH3:22])[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].C(=O)([O-])O.[Na+]>ClCCl>[C:36]([N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23])[CH3:22])(=[O:38])[CH3:37]
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CN(C)C(C)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (207 mg, 0.5 mmol) is dissolved in dichloromethane (10 ml) and treated with pyridine (0.07 ml, 0.85 mmol) and acetyl chloride (0.05 ml, 0.7 mmol) and stirred for 16 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate (10 ml) is added, the layers are separated and the aqueous phase extracted twice with each 10 ml dichloromethane. The combined organic phases are dried with magnesium sulfate and evaporated. Recrystallization from ethyl acetate afforded the title compound as light-yellow solid (80% yield), mp 228-230° C. MS: m/e=456 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:33]1[CH:37]=[N:36][C:35]([CH:38]=O)=[N:34]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[CH2:38][C:35]3[N:36]=[CH:37][NH:33][N:34]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=Cc1nc[nH]n1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nc[nH]n3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (256.8 mg) obtained in Example 122-4 was dissolved in methanol (7.7 ml) and added with 1H-[1,2,4]-triazol-3-carboxaldehyde (115.0 mg) and sodium cyanoborohydride (74.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (337.9 mg) of the subject compound as a white solid.