Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].P([O-])([O-])([O-])=O.[OH-].[Na+]>C(O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][C@:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)(CCN1C(=O)c2ccccc2C1=O)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@](C)(CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
In a 1 L round bottom flask, diethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl](methyl)propanedioate (Banerjee, S.; Wiggins, W. J.; Geoghegan, J. L.; Anthony, C. T.; Woltering, E. A.; Masterson, D. S. Org. Biomol. Chem., 2013, 11, 6307-6319) (9.56 g, 27.5 mmol) was suspended into a 0.1 M phosphate buffer at pH 7.4 (784 mL) and ethanol (16 mL). Pig liver esterase (0.90 mL, technical grade, 2.8 kilounits/mL) was then added and the reaction was stirred rapidly at room temperature for 17 h. The mixture was sonicated, additional pig liver esterase was added (0.1 mL) and the pH was adjusted to −7-8 with 1.0 M aqueous NaOH and stirring was continued for 7 h. Additional pig liver esterase (0.05 mL) was added, the pH was adjusted to −7-8 with 1.0 M aqueous NaOH and stirring was continued for 16 h. The mixture was transferred to a separatory funnel and extracted with tert-butylmethylether (2×300 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and extracted with tert-butylmethylether (3×300 mL) and EtOAc (3×300 mL). The combined organic phases were dried over MgSO4, filtered, washed with brine, dried again over MgSO4, filtered and concentrated. The crude product was purified via silica gel chromatography eluting with 15-50% EtOAc/heptanes to give the title compound (6.29 g, 72%) as a white solid whose spectroscopic properties were identical to previous reports.
Reaction SMILES: C(OC([N:8]1[C:12]2([CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[N:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:9]1=[S:33])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][C:12]32[NH:8][C:9](=[S:33])[N:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:11]3=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C(=S)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=S)NC12CCCC2c1ccc(Br)cc1
Yield: 60.4 %

Procedure:
6-(4-Bromophenyl)-3-(3,5-dichlorophenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (42 mg, 74 μmol) (Preparation 10) was added to a TFA/DCM/H2O (1/1/0.1) solution (1 ml) at RT. After 30 min the reaction mixture was concentrated to give a beige solid which was washed with pentane to yield 6-(4-Bromophenyl)-3-(3,5-dichlorophenyl)-2-thioxo-1,3-diazaspiro[4.4]nonan-4-one (21 mg, beige solid). 1H NMR (CDCl3): 8.39 (1H, s), 7.51 (2H, d, J=8.4 Hz), 7.35 (1H, m), 7.19 (2H, d, J=8.4 Hz), 6.44 (2H, m), 3.36 (1 H, dd, J1=12.9 Hz, J2=6.1 Hz), 2.45-2.65 (2H, m), 1.8-2.25 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:36])=[CH:33][C:32]=2[C:40]([F:41])([F:43])[F:42])[CH2:26][CH2:25]1
Reactant: CN1CCC(=Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(C=C3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (Patent Document 1) and 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethylbenzoyl chloride hydrochloride (Reference Example 7) were used.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:29]=3)[O:16][C:17]3[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=3)=[CH:10][CH:9]=2)=[N:3]1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:29]=[C:28]([CH:27]=[C:15]([O:16][C:17]4[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][N:18]=4)[CH:14]=3)[O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])=[CH:10][CH:9]=2)=[N:3]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)=N[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulfonyl)pyrazine (513 mg, 1.02 mmol) synthesized in Example (109d) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.50 mL, 1.50 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 2 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=4%-5%) to afford the desired compound (390 mg, yield 79%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1ccc(C)c(O)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Yield: 84.8 %

Procedure:
2,5-Dimethylphenol (6.99 g, 57.20 mmol) and 4-chloro-3-nitrobenzonitrile (8.00 g, 43.96 mmol) were combined with K2CO3 (30.40 g, 220.00 mmol) in THF (100 mL). The reaction mixture was heated to reflux for 48 hrs and then the solid was filtered through a bed of Celite. After rinsing the residue with copious amounts of EtOAc, the filtrate was washed sequentially with NaHCO3, water, and brine, dried over anhydrous MgSO4, and filtrated. The filtrate was concentrated in vacuo to produce compound 30 as a white powder (10.00 g, 85.0% yield, 99.1% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.65 (d, J=2 Hz, 1H), 8.03 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=9 Hz, 1H), 2.28 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.C1N=CN([C:13](N2C=NC=C2)=[S:14])C=1>O1CCCC1>[CH3:7][C:6]1[C:2]([N:1]=[C:13]=[S:14])=[CH:3][S:4][CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cscc1N
Solvent: C1CCOC1
Product: Cc1cscc1N=C=S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
is obtained by reacting equimolar amounts of 3-amino-4-methylthiophene and N,N′-thiocarbonyldiimidazole in anhydrous tetrahydrofuran (THF) by stirring the reaction mixture at room temperature for 5 hours and then allowing the mixture to stand at room temperature overnight. 4-Methyl-3-thienyl isothiocyanate is isolated by distillative removal of the solvent under reduced pressure using a rotary evaporator, dissolving the residue in ethyl acetate and washing the organic phase repeatedly with water. The organic phase is dried over sodium sulfate and the organic solvent is then distilled off under reduced pressure using a rotary evaporator, giving 4-methyl-3-thienyl isothiocyanate as a brown oily residue. 4-Methyl-3-thienyl isothiocyanate can be used without further purification.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][CH2:8][CH2:9]C[N+](CCCC)(CCCC)CCCC.[F-].CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C>C1COCC1>[C:1]([O:6][CH2:9][CH:8]=[CH2:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C=C(C)C(=O)[O-]
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of MTS (5.5 x 10-3 g) in dry THF (10.0 ml) was added (D2.1) (3.0 g), AM (0.11 ml) and TBAF (2 μl of 1M THF solution). The mixture warmed up and was stirred overnight at room temperature. 50 ppm Irganox 1010 antioxidant was added to the very viscous clear solution, which was cast into a polyester tray in a stream of nitrogen. The last traces of THF were removed by heating in a vacuum oven at 60° for 4 hours.
Reaction SMILES: II.C[Si](Cl)(C)C.[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:25]I)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].I[C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[CH:32][C:33]=1[CH3:34].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.[Zn]>[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:25][C:32]1[CH:31]=[C:30]([OH:35])[CH:29]=[CH:28][C:33]=1[CH3:34])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(O)cc1I
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc(O)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Following the General Procedure of Description 15 (Part A), zinc dust (Zn) (392 mg, 6.0 mmol) is activated with elemental iodine (I2) (38 mg, 0.15 mmol, 15 mol-%) and trimethyl silylchloride (MeSiCl, TMSCl) (19 μL, 16 mg, 0.15 mmol, 15 mol-%) in degassed anhydrous N,N-dimethylformamide (DMF) (3 mL). The zinc insertion product is prepared from tert-butyl(3S)-3-(tert-butoxycarbonylamino)-4-iodo-butanoate (6c) (385 mg, 1.0 mmol) in the presence of additional I2 (38 mg, 0.15 mmol, 15 mol-%) and TMSCl (19 μL, 16 mg, 0.15 mmol, 15 mol-%). Following the General Procedure of Description 15 (Part B), the zinc insertion product of (6c) is used in situ to cross couple with commercial 3-iodo-4-methyl-phenol (234 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography furnish the title compound (19a).
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16].[NH3:37]>>[NH2:37][C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: N
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O
Product: Cc1ccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)cc1Nc1c(N)c(=O)c1=O

Procedure:
EXAMPLE 45 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]4-methylphenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 44) and ammonia instead of dimethylamine. MS (ES+): m/z 483.9 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (75 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (19 μL, 0.24 mmol) and triethylamine (37 □L, 0.26 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then loaded directly onto a pre-wetted Biotage 25M column and purified by flash chromatography (0-5% MeOH/CH2Cl2) to give the title compound as a white solid, 77 mg, 83%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.58-8.67 (2 H, m), 7.59-7.69 (2 H, m), 6.97-7.13 (4 H, m), 6.49 (1 H, s), 4.84-4.98 (1 H, m), 4.45 (2 H, dd, J=8.97, 6.44 Hz), 4.05 (2 H, t, J=8.34 Hz), 4.01 (2 H, s,) 3.05 (3 H, s); m/z (APCI+) for C19H19N4O2SF 387.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]1([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:39]([CH:40]=O)=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][CH2:40][C:39]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:29][CH2:28]2)=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3,5-Bis(trifluoromethyl) benzylamine (0.305 g, 1.25 mmol) was added to a solution of 2-(4-cyclohexylmethyl-piperazin-1-yl)-quinoline-3-carbaldehyde (0.4 g, 1.23 mmol) in methanol followed by acetic acid (0.15 mL) at ambient temperature under nitrogen atmosphere. After stirring 1 h, sodium cyanoborohydride (0.237 g, 3.77 mmol) was added carefully, and the reaction was stirred at RT for overnight. The reaction mixture was evaporated to dryness, and water (30 mL) and ethyl acetate (30 mL) were added to the residue, and this was then extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to afford a pale yellow crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol/dichloromethane afforded the title compound (0.468 g, yield: 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([N:20]=[CH:21][C:22]3[S:26][CH:25]=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[S:26][CH:25]=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(N=Cc3cncs3)c2CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3cncs3)c2CC1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
Dissolve 3-(t-butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyleneamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (228 mg, 0.58 mmol) in methanol (10 mL), add sodium borohydride (263 mg, 7 mmol) and reflux for 28 h. Cool to ambient temperature, dilute with EtOAc and add slowly water. Separate the organic layer, extract the aqueous layer three times with EtOAc. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to give the desired intermediate as a colorless oil (134 mg, 58%). MS (ES+) m/z: 394 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][CH2:36]Cl.COCNC(C1C(N(COC)S(C2C=CC(Cl)=C(C(F)(F)F)C=2)(=O)=O)=CC(Cl)=CN=1)=O>C1COCC1>[CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:34][O:35][CH3:36])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: COCNC(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 1.05 g (2.48 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide, 1.71 g of potassium carbonate and 566 μL of methoxymethyl chloride in 7 mL THF using procedure used in the preparation of Intermediate 12. Yield: 420 mg of a white solid. LC-MSD, m/z for C17H17ClF3N3O5S [M+Na]+=490.0, 491.9; HPLC retention time: 2.5 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:22]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:20][CH2:21]3)[C:9]2=[O:12])=[CH:4][C:3]=1[OH:22]
Reactant: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C1CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2cc(Cl)c(O)cc2CCN1c1cnccc1C1CC1
Yield: 95.3 %

Procedure:
7-Chloro-6-methoxy-2-(4-cyclopropylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (89A: 200 mg, 0.6 mmol) in DCM (5 mL) was demethylated with BBr3 (1.8 mL) at 0° C. for 2 hours to afford 180 mg of the product (94.7% yield).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:20])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19])([CH3:5])[CH2:3]O.[K].CC(C)([O-])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:5])[CH2:3][N:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH3:19])[C:7](=[O:20])[NH:6]1
Reactant: COC(=O)c1ccc(NC(=O)NC(C)(C)CO)c(C)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N2CC(C)(C)NC2=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7.00 g (25.0 mmol) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]-ureido)-3-methyl-benzoate are dissolved in 400 ml THF at 0° C. and combined with 6.73 g (60.0 mmol) potassium-tert.-butoxide. After stirring for 15 minutes at 0° C. a solution of 5.72 g (30.0 mmol) p-toluenesulphonic acid in 50 ml THF is added dropwise. After another 10 minutes stirring at 0° C. 300 ml of water are added, the mixture is neutralised with 1-molar hydrochloric acid and the THF is removed i. vac. The residue is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=100:0->97:3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Temperature: 0 °C
Yield: 55.5 %

Procedure:
To the suspension of 0.25 g (0.88 mmol) 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester in 5 mL tetrahydrofuran, 0.15 g (1.05 mmol) 1-isopropyl-piperidin-4-ol (commercially available) and 0.28 g (1.07 mmol) tributylphosphine were added. The suspension was cooled to 0° C., 0.244 g (1.06 mmol) di-tert-butyl azodicarboxylate was added and the reaction was allowed to reach room temperature. After 48 hours the suspension was filtered and the filtrate was evaporated. The residue was flash-chromatographed on silica gel with a gradient of dichloromethane:methanol (100:0 to 60:40 v/v) to give 0.20 g (55%) of the product as a light yellow foam.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[N+:9]([O-:24])[CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(-c2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(Cl)Cl
Product: O=C(O)c1cc(-c2ccccc2)c[n+]([O-])c1
Reaction time: 15 h
Yield: 37 %

Procedure:
Preparation H10, Step 1: 5-Phenylnicotinic acid (50 mg) was dissolved in dichloroethane (2 ml) prior to the addition of 77% mCPBA (250 mg). The reaction was stirred for 15 h and then it was concentrated, filtered, and purified by reverse phase HPLC (gradient elution, water/acetonitrile/TFA) to afford 5-phenylnicotinic acid N-oxide (20 mg). MS found: (M+H)+=216.1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of methyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (600 mg, 2.21 mmol) and lithium hydroxide monohydrate (186 mg, 4.42 mmol) in tetrahydrofurane (10 ml) and water (2.0 ml) is stirred for 3 hours at 25° C. The solvent is evaporated, the residue diluted with water (ca 10 ml) and acidified with 2N aqueous hydrochloric acid (2.2 ml), the precipitated red solid is collected by filtration, washed with water and dried affording 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (497 mg. 87.4%) as a pink solid. Mp.: >250° C. MS: m/z=329.2 (M−H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:21])[NH:11][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][OH:14])[CH3:9])(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][OH:14])=[O:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC(CO)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)NC(CO)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 154.9 %

Procedure:
To a solution of [(S)-1-(2-Hydroxy-1-pyridin-2-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (556 mg, 1.79 mmol) in dioxane (1 mL) was added 4 N HCl in dioxane (2.24 m, 8.95 mmol). The reaction was stirred at room temperature for 1 h. Removal of solvents in vacuo provided the title compound (S)-2-Amino-N-(2-hydroxy-1-pyridin-2-yl-ethyl)-propionamide (580 mg) as a HCl salt. m/z 210.96 [M+1]+