Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B1C2CCCC1CCC2.[CH2:18]([O:25][C:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][C:31](I)=[CH:32][CH:33]=2)[O:28][C:27]=1[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:18]([O:25][C:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][C:31]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:32][CH:33]=2)[O:28][C:27]=1[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCCCCCC
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 60.7 %

Procedure:
To a stirring solution of 1-octene (0.148 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 2.7 ml, 1.4 mmol, 1.5 eq). The reaction was allowed to warm to room temperature and stirred for 9 hours then 34 (0.504 g, 0.9 mmol) (produced as described in Example 2) in tetrahydrofuran (5 ml), 3M NaOH solution (1.1 ml) and dichloropalladium (dppf) (0.031 g, 0.04 mmol, 0.04 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine dried (MgSO4) and concentrated in vacuo to give a orange oil. Column chromatography (silica gel, DCM) yielded 39f (0.290 g, 59%) as a colourless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>CCO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1CCC(=NO)CC1

Procedure:
4-Methylcyclohexanone (2.0 g, 17.8 mmol) was mixed with hydroxylamine hydrochloride (1.86 g, 26.8 mmol) and sodium acetate (2.63 g, 32.0 mmol) in a mixture of EtOH (20 mL) and water (12 mL). The mixture was refluxed for 5 h. All solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)=[CH:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:23]=4)[C:32]#[N:33])=[CH:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1ccc(-c2cnc(-c3cccc4c3CC[C@@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2cnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.1 mmol) in 1,4-dioxane (5 mL) was added 4N HCl solution in 1,4-dioxane (5 mL). The reaction mixture was stirred at 55° C. for 2.5 h. Upon cooling to 0° C., the reaction mixture was diluted with diethyl ether (50 mL) and the resulting solid was filtered, washed with ether (20 mL), and dried to afford 0.86 g (100%) of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 71. LCMS-ESI (m/z) calculated for C22H21N3OS: 375.1; found 376.2 (M+H). tR=2.45 min. 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=3.6 Hz, 2H), 8.30 (d, J=2.3 Hz, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 8.21 (s, 1H), 7.70 (dd, J=7.6, 2.6 Hz, 2H), 7.45 (dd, J=8.4, 5.4 Hz, 2H), 4.91 (dt, J=12.2, 6.1 Hz, 1H), 4.85-4.58 (m, 1H), 3.36-3.21 (m, 1H), 3.21-3.04 (m, 1H), 2.63-2.51 (m, 1H), 2.09 (td, J=8.3, 2.8 Hz, 1H), 1.43-1.28 (m, 6H). 13C NMR (101 MHz, DMSO) δ 166.61, 166.11, 161.50, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.20, 102.53, 72.43, 54.75, 31.48, 30.12, 21.74. Chiral HPLC: (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride was eluted in 8% EtOH/hexanes: >99.9% ee, tR=67.15 min (Chiral Method 1).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][CH2:28][C@@H:29]([OH:42])[C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=4)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[N:7]=1.Cl>CO.[OH-].[Na+]>[OH:42][C@@H:29]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:31]=1)[CH2:28][NH:27][CH2:26][CH:23]1[CH2:22][CH2:21][N:20]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:43])=[O:2])[O:10][N:9]=3)=[CH:12][CH:13]=2)(=[O:18])=[O:19])[CH2:25][CH2:24]1
Reactant: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(CNC[C@@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-c4noc(CCC(=O)O)n4)cc3)CC2)ccc1O
Yield: 58.8 %

Procedure:
A solution of 3-(3-{4-[(4-{[((2S)-2-hydroxy-2-{4-hydroxy-3-[(methyl-sulfonyl)-amino]-phenyl}ethyl)amino]methyl}-1-piperidinyl)sulfonyl]-phenyl}-1,2,4-oxadiazol-5-yl)propanoic acid methyl ester (0.150 g, 0.24 mmol) in 15 ml of methanol and 0.470 ml of 1N NaOH was heated at reflux for 14 hours. To the reaction mixture was added 0.470 ml of 1N HCl . The solvent was removed in vacuo and the resulting solid was triturated with water, then with ethyl acetate to give the final product (0.088 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:30]#[N:31])[C:7]=1[C:8]1[CH:13]=[C:12]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]([OH:26])([CH3:25])[CH3:24])=[N:22][C:17]3=[N:16][CH:15]=2)[C:11]([O:27]C)=[CH:10][C:9]=1[F:29].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:30]#[N:31])[C:7]=1[C:8]1[CH:13]=[C:12]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]([OH:26])([CH3:24])[CH3:25])=[N:22][C:17]3=[N:16][CH:15]=2)[C:11]([OH:27])=[CH:10][C:9]=1[F:29]
Reactant: COc1cc(F)c(-c2c(F)cccc2C#N)cc1-c1cnc2nc(C(C)(C)O)cnn12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(O)c1cnn2c(-c3cc(-c4c(F)cccc4C#N)c(F)cc3O)cnc2n1
Temperature: -60 °C
Yield: 16 %

Procedure:
A solution of 6,2′-difluoro-5′-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]-4′-methoxybiphenyl-2-carbonitrile (0.18 g, 0.43 mmol) dissolved in anhydrous dichloromethane (10 ml) was cooled to −60° C. under nitrogen. Boron tribromide (2 M solution in dichloromethane, 1.28 ml, 2.57 mmol) was added with stirring. After 0.5 h the cooling bath was removed and the mixture was allowed to stir at room temperature for 4 h. Methanol (2 ml) was added and the mixture was shaken with 2 N NaOH (10 ml). Following neutralisation of the aqueous layer with 3 N HCl the solution was extracted with EtOAc (3×50 ml), dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, EtOAc) and crystallised from dichloromethane to give 28 mg (16%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 1.70 (6H, s), 3.38 (1H, br s), 3.96 (3H, s), 7.38–7.49 (3H, m), 7.59–7.61 (1H, dd, J 0.9, 7.4), 8.10 (1H, d, J 8.0) 8.52 (1H, s), 8.71 (1H, s), 8.90 (1H, s); MS (ES+) m/z 408 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][CH:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:7]2)(=O)[CH3:2].[H][H]>>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:1][CH3:2])[CH2:7][CH:8]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:9]2)[CH3:14]
Reactant: CCc1cc2c(cc1C(C)=O)CC(NC(=O)C(F)(F)F)C2
Reactant: [H][H]
Product: CCc1cc2c(cc1CC)CC(NC(=O)C(F)(F)F)C2

Procedure:
Preferably in Step (v), N-(5-acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide is treated with hydrogen gas to form N-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide having Formula (XIII)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]=[C:12](NC=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Cl.[OH-:23].[Na+].O>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:23]
Reactant: [OH-]
Reactant: COc1cccc(C=C(NC=O)c2ccncc2)c1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(CC(=O)c2ccncc2)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of N-[2-(2,3-dimethoxyphenyl)-1-(4-pyridinyl)vinyl]formamide (45.2 g, 0.16 mol) in methanol (400 ml), cooled to 0° C., was added, dropwise, concentrated HCl (120 ml). After complete addition, the temperature was raised to between 35-40° C. for 2 h. The reaction was allowed to stand at ambient temperature for 1 h, and after cooling it in an ice bath, 50% aqueous NaOH was added dropwise until the mixture was basic. Water was added and the resulting white precipitate was collected to yield the desired ketone which was removed and recrystallized twice from isopropanol to afford the titled compound as a white solid, mp 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 22. (−)-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 83% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 8), 242 (78), 227 (31), 157 (36), 71 (bp).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CC1C=COC=1C.CCOCC>[N:20]([CH2:6][CH:7]1[CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)=[N+:21]=[N-:22]
Reactant: CS(=O)(=O)OCC1CC2CC2N1c1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccoc1C
Agent: [Na+]
Solvent: CCOCC
Product: [N-]=[N+]=NCC1CC2CC2N1c1cncc(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a stirred solution of methane sulfonate (as obtained in Step (i) of Example 1) (215 mg, 0.62 mmol) in dry dimethylfuran (2 mL) was added sodium azide (180 mg, 2.77 mmol). The reaction mixture was gradually heated to 90° C. and stirred for 16 hours. Upon completion of the reaction, it was diluted with ether, washed with water, brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography to obtain the title compound as gummy liquid of 164 mg. Yield: 90%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][C:28]#[N:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCC#N)c2ccccc12
Yield: 98.3 %

Procedure:
N-tertbutyloxycarbonyl-4-amino-1-naphthol (1.0 g, 3.86 mmol), potassium carbonate (1.06 g, 7.7 mmol) and bromoacetonitrile (0.4 ml, 5.8 mmol) in anhydrous dimethylformamide (10 ml) are stirred at room temperature for 5 hours. The mixture is poured into ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness to give (4-cyanomethoxynaphthalen-1-yl)-carbamic acid tert-butyl ester as a red brown solid (1.132 g). 1H NMR 300 MHz (CDCl3) 8.2(d, 1H, J=11.5 Hz), 7.85(d, 1H, J=11.5 Hz), 7.55-7.75(m, 3H), 6.9(d, 1H, J=14 Hz), 6.62(s, 1H), 4.95(s, 2H), 1.5(s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]CC2C=CC=CC=2)=[C:4]([O:11]CC2C=CC=CC=2)[CH:5]=[C:6]([CH:10]=1)[CH:7]1[O:9][CH2:8]1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[C:3]([OH:19])=[C:4]([OH:11])[CH:5]=[C:6]([CH:10]=1)[CH:7]([OH:9])[CH2:8][NH:31][CH2:30][CH:27]1[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: Clc1cc(C2CO2)cc(OCc2ccccc2)c1OCc1ccccc1
Product: Oc1cc(C(O)CNCC2CC2)cc(Cl)c1O

Procedure:
By reacting 5-chloro-3,4-dibenzyloxystyrene oxide with cyclopropylmethylamine followed by hydrogenation there is obtained 5-chloro-α-(cyclopropylmethylaminomethyl)-3,4-dihydroxybenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc2c(I)n[nH]c2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
6-Fluoro-3-iodo-1H-indazole (300 mg, 1.1 mmol) in 30 mL of dry THF was cooled to −20° C. under nitrogen atmosphere, then isopropylmagnesium chloride (1.2 mL, 2.42 mmol) was added and mixture stirred for 15 mins at −20° C. Tributylchlorostannane (0.4 mL, 1.32 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated ammonium chloride, product extracted with ethyl acetate (3×50 mL), dried with sodium sulphate, filtered and concentrated to give 6-fluoro-3-(tributylstannyl)-1H-indazole (500 mg, crude) as a colorless oil which was used directly in the next step without further purification.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=23)=[C:11]([F:27])[CH:10]=1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[F:27][C:11]1[CH:10]=[C:9]([NH2:8])[CH:14]=[C:13]([F:15])[C:12]=1[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=12
Reactant: Cc1c[nH]c2nccc(Nc3c(F)cc(N(Cc4ccccc4)Cc4ccccc4)cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(N)cc3F)c12

Procedure:
66 mg of 10% palladium-on-carbon are added to a solution of 280 mg (0.62 mmol) of N4,N4-dibenzyl-2,6-difluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine in 20 ml of ethanol and 1.85 ml (1.85 mmol) of 1 M hydrochloric acid, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through Celite, the Celite is washed with methanol and the filtrate is then concentrated under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)[CH2:2]1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[N:11]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:10]=3)[CH2:4]2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]
Reactant: O=C(CNc1nn(Cc2ccccc2)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(Cc4ccccc4)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-benzyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([CH2:23]O)=[CH:18][N:17]=2)([O-:7])=[O:6].CN(C=O)C>C(Cl)Cl>[Cl:3][CH2:23][C:19]1[CH:20]=[C:21]2[N:22]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N+:5]([O-:7])=[O:6])[S:15][C:16]2=[N:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CO)cnc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (3.1 mol, 227 mL) was slowly added to a room temperature suspension of (2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methanol (0.62 mol, 180 g) in CH2Cl2 (1.8 L). DMF (5 mL) was added and the reaction became homogeneous. The reaction was stirred for 1 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was chased with hexane (200 mL×3)) and dried under vacuum for 16 h to give 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a tan solid (180 g, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=1.COC1C=CC(O)=C([N+]([O-])=O)C=1.[C:37](Cl)(=[O:42])[CH2:38][C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:13][CH:12]=3)[C:37](=[O:42])[CH2:38][C:39](=[O:40])[NH:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: O=C(Cl)CC(=O)Cl
Agent: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
tert-Butyl 4-(2-amino-4-methoxyphenylamino)phenylcarbamate (500 mg, 1.52 mmol) synthesized in the same manner as that of Example 1 by using 4-methoxy-2-nitrophenol as the starting material was dissolved in anhydrous tetrahydrofuran (30 mL), and the solution was added dropwise with malonyl chloride (0.178 mL, 1.82 mmol) on an ice bath. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate, the aqueous layer was extracted with chloroform, the organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (230 mg, yield 38%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.[CH3:22]I>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[O:14][CH3:22])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Reactant: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of the compound from Example 12, Step B (188 mg, 0.6 mmol) in anhydrous DMF (6 mL) was added Nail (60% in mineral oil; 26 mg, 0.66 mmol). The mixture was stirred at room temperature for 0.5 h and then cooled. MeI (45 μL) was added at 0° C. and the reaction mixture allowed to warm to 15° C. in 5 h. Then the mixture was poured into ice-water (20 mL) and extracted with CH2Cl2 (100+50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried (Na2SO4). The evaporated residue was purified on a silica gel column with a solvent system of CH2Cl2/MeOH: 30/1. Appropriate fractions were pooled and evaporated to yield the title compound (50 mg) as a colorless glass.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=1[CH:9]=[O:10]>C(O)C>[F:17][C:4]([F:3])([F:16])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Cl)ccc1OCC(F)(F)F
Reaction time: 1 h

Procedure:
Sodium borohydride (200 mg, 5.3 mmol) was added to a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzaldehyde (2 g, 8.4 mmol) in ethanol at room temperature. After stirring for 1 hr, the solvent was removed under reduced pressure. Aqueous ammonium chloride was added to the residue to destroy excess hydride following which the mixture was extracted with ethyl acetate. The organic extracts were washed with brine and then dried over sodium sulfate. Concentration yielded the title compound as an oil: 1H NMR (CDCl3) δ7.41 (d, J=2.4 Hz, 1H), 7.25 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.73 (d, J=4.6 Hz, 2H), 4.40 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=[O:15].[Cl:16][C:17]1[CH:18]=[C:19]([SH:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH:14]=[O:15])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution containing 175 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 142 mg of 3,5-dichlorothiophenol and 132 mg of potassium carbonate in 5 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 60° C. for 2 h. The mixture was diluted with 10 ml of water and extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 164 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde as a yellow oil.