Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[OH:13][CH2:14][C:15]([CH3:19])([CH2:17]O)[CH3:16].C(OCC)(OCC)OCC>CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:7]([CH:8]2[O:13][CH2:14][C:15]([CH3:19])([CH3:17])[CH2:16][O:9]2)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: COc1ccc(Br)c(C=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Br)c(C2OCC(C)(C)CO2)c1O
Temperature: 110 °C
Yield: 99.9 %

Procedure:
A mixture of 6-bromo-2-hydroxy-3-methoxy-benzaldehyde (2.31 g, 10.0 mmol), neopentyl glycol (1.14 g, 11.0 mmol), TsOH (9.5 mg) and triethyl orthoformate (1.93 g, 13.0 mmol) were heated at 110° C. for 30 min and then partitioned between NaHCO3 (300 mL) solution and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3×30 mL) and the combined extracts were washed with brine and dried through Na2SO4. Evaporation of solvent afforded the title compound (3.17 g, 100%). 1H NMR (CDCl3) δ 0.85 (s, 3H), 1.27 (s, 3H), 3.70 (s, 2H), 3.82 (s, 2H), 3.85 (s, 3H), 5.90 (s, 1H), 6.72 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)[CH:20]=[CH2:19]
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Reactant: C=CCBr
Product: C=CCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and allylbromide, the title compound was recovered by the procedure described in Example 2: MS m/z (rel. intensity, 70 eV)) 310 (M+, 91), 214 (73), 96 (86), 69 (80), 56 (bp).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC[C@@H](CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 67 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and acetyl chloride as the starting materials in 67% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z=505.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C@@H:5]([C:6]([O:8]C(C)(C)C)=[O:7])[CH2:4][C@H:3]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O1CCOCC1>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([C@@H:3]1[CH2:4][C@H:5]([C:6]([OH:8])=[O:7])[C:2]1([CH3:23])[CH3:1])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)[C@@H](C(=O)O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of (1R,3S)-1-benzyl 3-tert-butyl 2,2-dimethylcyclobutane-1,3-dicarboxylate (step 3, 1.0 g) dioxane-HCl (10 ml) was added at about 0° C. under nitrogen atmosphere. The reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude product, which upon column chromatography to afford the title compound (800 mg, 97.2% Yield). 1H NMR (300 MHz, CDCl3): δ 7.35 (5H, s), 5.12 (2H, d, J=2.7 Hz), 2.84 (2H, m), 2.63 (1H, m), 2.0 (1H, m), 1.35 (3H, s), 0.99 (3H, s); Mass: [M+H]+ 263.1 (20%), 285.1 [M+Na]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29](Cl)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:29]([NH:1][CH:2]3[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3]3)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reactant: NC1CCS(=O)(=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NC2CCS(=O)(=O)C2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a suspension of 3-amino-1,1-dioxotetrahydrothiophene (345 mg, 2.01 mmol) in methanol (5 mL) was added DIPEA (350 μL) followed by 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (200 mg, 0.67 mmol). The mixture was allowed to stir for 16 h. The resulting mixture was poured into ice-water and the resulting solids were collected by filtration. The solids were washed with ethyl acetate and hexanes and were dried. This afforded 147 mg (0.37 mmol, 55% yield) of the titled product as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.78 (d, 1H), 8.65 (s, 1H), 7.65 (m, 2H), 7.18 (m, 2H), 4.87 (m, 1H), 3.52 (m, 1H), 3.35–3.04 (m, 3H), 2.50, M, 1H), 2.22 (m, 1H); MS (EI) m/z 395.05 (M−H)−.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CO[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C1(C)C=CC=CC=1>[CH3:15][C:11]1[O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=2[C:12]=1[CH3:13]
Reactant: Oc1cccc(O)c1
Reactant: COC(C)C(C)=O
Solvent: Cc1ccccc1
Product: Cc1oc2cc(O)ccc2c1C
Temperature: 90 °C
Reaction time: 10 h
Yield: 60.7 %

Procedure:
A mixture of 1.9 g of resorcinol, 1.8 g of 3-methoxy-2-butanone, 0.2 g of Amberlyst-15 and 2 ml of toluene was stirred at 90° C. for 10 hours. After cooling, the catalyst was separated, and the filtrate was concentrated. The residue was purified by column chromatography to give 1.7 g of 2,3-dimethyl-6-hydroxybenzofuran as pale yellow crystals. The crystals were dissolved in 20 ml of acetic acid, and 0.2 g of 5% palladium-carbon was added. The mixture was stirred at room temperature for 12 hours in an atmosphere of hydrogen. The crude product was purified by column chromatography to give 1.5 g (yield 54%) of the desired product as a brown liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: COc1cc(-n2cncn2)ccc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-n3cncn3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (80 mg, 0.38 mmol), 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline (72 mg, 0.38 mmol) and p-toluene sulphonic acid (72 mg, 0.38 mmol) in dioxane (2 mL) was heated at 100° C. for 1 h. The mixture was cooled and filtered. The solid was partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL) and the product was extracted into dichloromethane (3×10 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded a residue that was triturated with methanol/diethyl ether yielding N2-(2-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a white solid (34.5 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=366 at 3.13 min. 1H NMR (400 MHz, DMSO): δ 9.29 (s, 1H); 8.33 (d, J=8.7, 1H); 8.24-8.15 (m, 3H); 7.53 (d, J=2.4, 1H); 7.45 (dd, J=8.7, 2.4, 1H); 7.23 (d, J=5.2, 1H); 3.97 (s, 3H); 2.92 (d, J=4.4, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)#[N:2].Cl.[NH2:20][OH:21].CCN(C(C)C)C(C)C>CCO>[OH:21][NH:20][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=N)NO)cc2C1
Yield: 99.7 %

Procedure:
A product of Step C (0.22 g; 0.904 mmol), HCl×NH2OH (0.16 g; 2.3 mmol) and DIPEA (0.48 ml; 5 mmol) in anhydrous EtOH (3.5 ml) was refluxed for 2 h under N2. The solvents were removed under reduced pressure and the residue was diluted to 30 ml with EtOAc, washed with H2O (2×5 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.25 g; 100%) as colourless foam, which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1(N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NN1CCCCC1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCCC4)n3)cc2s1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol) and piperidin-1-amine (0.03 g, 0.3 mmol) in DMSO (0.03 g, 0.3 mmol) was heated under microwave (CEM) at 80° C. and 130 W (Powermax® off) for 20 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (20 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 354, (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[N+:15]([O-])=O.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:8]=1
Reactant: [H][H]
Reactant: COc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1nc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 4-(6-methoxy-5-nitropyridin-2-yl)morpholine (Preparation 81, 280 mg, 1.170 mmol) in EtOAc/EtOH (1:1, 10 ml) was added palladium on charcoal (10%, 100 mg). The flask was charged with hydrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (245 mg, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12][CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])([OH:3])=O.N#N>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:12][C:13]3([C:1](=[O:3])[C:4]=2[CH:9]=1)[CH2:18][CH2:17][O:16][C:14]3=[O:15])[CH3:11]
Reactant: CCc1ccc(SC2CCOC2=O)c(C(=O)O)c1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc2c(c1)C(=O)C1(CCOC1=O)S2

Procedure:
A mixture of α-[(2-carboxy-4-ethylphenyl)thio]-γ-butyrolactone (1.0 g) in acetic anhydride (30 ml) and triethylamine (6 ml) was heated at 130° C. for 30 minutes under a stream of N2 gas with stirring. The mixture was evaporated in vacuo. The resulting residue was submitted to column chromatography on silica gel (20 g) and charcoal (5 g) eluting with CHCl3 to give 5-ethyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as colorless oil. Anal. Calcd. for C13H12O3S: C, 62.88; H, 4.87. Found: C, 62.83; H, 4.83.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Cl)ccc1O
Product: O=c1cc(N2CCN(Cc3cc(Cl)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chlorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.60-2.64 (m, 4H), 3.58-3.65 (m, 4H), 3.70 (s, 2H), 5.40 (s, 1H), 6.76-6.78 (m, 1H), 6.96-6.99 (m, 1H), 7.13-7.15 (m, 1H), 7.85 (s, 1H), 10.60 (br s, 1H), 12.65 (br s, 1H). Mass spectrum (ES) MH+=321.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23](Cl)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1.N1C=CC=CC=1>ClCCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23]([O:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Oc2cccnc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
A solution of (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.050 g, 0.13 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to a 50° C. solution of pyridine-3-ol (0.053 g, 0.26 mmol) and pyridine (1 mL) in 1,2-dichloroethane (20 mL). The resulting solution was stirred for 6 h at 50° C. and then concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1-20% methanol-dichloromethane) and then by preparative-HPLC (conditions: Column, SunFire™Prep C18OBD™, 19×150 nm; Mobile phase, A: 0.05% ammonium carbonate, B: acetonitrile; Detector, 220 and 254 nm) to afford (S)-pyridin-3-yl 4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.026 mg, 46%) as a white solid. 1H NMR (300 MHz, CD3OD) 1.17 (d, J=6.60 Hz, 3H), 2.27 (s, 3H), 3.50-3.79 (m, 1H), 4.35-4.45 (m, 1H), 5.02-5.25 (m, 5H), 5.55-5.65 (m, 1H), 7.39-7.49 (m, 2H), 7.51-7.57 (m, 1H), 7.78-7.83 (m, 1H), 7.97 (s, 1H), 8.10-8.19 (m, 2H), 8.47-8.50 (m, 1H), 8.52-8.56 (m, 1H). MS (ESI, pos. ion) m/z 434 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([OH:17])([C:13](F)(F)F)=[O:12]>>[S:9]1[C:10]2[C:2]([CH2:13][C:11]([OH:17])=[O:12])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[CH:8]1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1cccc2ncsc12
Product: O=C(O)Cc1cccc2ncsc12

Procedure:
The title compound (20 mg) was prepared from 7-bromobenzo[d]thiazole according to protocol P. LCMS (0.05% TFA): [M+1]+ 194.1. 1H-NMR (CDCl3, 400 MHz): δ9.05 (s, 1H), 8.10 (d, 1H, J=6.8 Hz), 7.53 (m, 1H), 7.39 (d, 1H, J=6.8 Hz), 3.96 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH:14]1([O:20][C:21](N2C=CC=CC2=O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O.C1COCC1>[CH:14]1([O:20][C:21]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(OC1CCCCC1)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OC1CCCCC1)C(=O)O
Yield: 97.9 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing cyclohexyl-2-pyridyl-carbonate and cyclohexyl-2-oxopyridine 1-carboxylate (0.418 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.3 g, 97%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 246 [M−H]+; (ESI) m/z: 244 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.2 Hz, 3H), 1.16-1.43 (m, 5H), 1.49 (s, 1H), 1.69 (s, 2H), 1.80 (s, 2H), 3.93 (dd, J=2.9, 8.8 Hz, 1H), 3.99-4.12 (m, 1H), 4.44-4.61 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 12.32 (br s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
To a solution comprising about 1.3 g of compound 9a (m=6) in 50 ml of CH2Cl2 was added 7.0 ml of boron tribromide (BBr3, 1M solution in CH2Cl2) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2.5 h and quenched by adding about 30 ml of 1N HCl. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×30 ml). The combined organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: EtOAc, 1:1) affording the phenol 10a (1.1 g, 88%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:18])=O>CN(C=O)C>[Cl:18][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc2ccccc12
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(Cl)c2ccccc2n1
Yield: 61 %

Procedure:
To a mixture of 2-(trifluoromethyl)quinazolin-4(3H)-one (12 g) and phosphorous oxychloride (100 ml) was added DMF (0.5 ml) and the mixture was refluxed under nitrogen for 16 h. The excess phosphorous oxychloride was distilled off and the residue was diluted with ethyl acetate (200 ml). The ethyl acetate layer was washed with 10% solution of sodium bicarbonate, water and brine. The solvent was dried and evaporated. The residue was purified by chromatography (silica gel: 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 8 g (61%) of the titled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]#[N:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1>[Ni].N.CO>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([CH2:17][NH2:18])[CH:3]=1
Reactant: Cc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc(CN)c2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (120 mg, 0.5 mmol) in a solution of NH3/MeOH (7 N, 10 mL) was added Raney nickel (50 mg). The mixture was stirred under hydrogen at RT for 2 hours. It was filtered with Celite, and the filtrate was concentrated in vacuo to afford (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanamine (113) as brown solid (120 mg, ˜100%). MS (ESI): m/z=246.3 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)cc1

Procedure:
The substituted aniline compounds of formula (I) wherein W is oxygen can be prepared by the reaction of nitrophenol with a substituted pyridylalkyl halide to obtain the corresponding substituted nitrobenzene which is reduced to the desired substituted aniline of formula (I). For example, the reaction of 4-nitrophenol and 6-chloro-3-pyridylmethyl bromide gives 4-(2-chloro-5-pyridylmethyloxy)nitrobenzene which is then reduced to 4-(2-chloro-5-pyridylmethyloxy)aniline of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitrobenzene with a substituted pyridylalkyl alcohol or substituted pyridylalkyl thiol followed by reduction of the nitro group. For example, the reaction of 4-fluoronitrobenzene and 5-bromo-2-pyridine methanol gives 4-(5-bromo-2-pyridylmethyloxy)nitrobenzene which is then reduced using, for example, iron powder to give 4-(5-bromo-2-pyridylmethyloxy)aniline.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:23][C:22]([C:32]([F:35])([F:34])[F:33])=[N:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][C:7](OC)=[O:8].[BH4-].[Na+]>CO>[OH:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][OH:2])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:23][C:22]([C:32]([F:33])([F:35])[F:34])=[N:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COC(=O)CN(CC(=O)OC)S(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)cc1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of methyl N-(2-methoxy-2-oxoethyl)-N-({4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate prepared as in example 2.A. (0.330 g, 0.628 mmol) in anhydrous methanol (50 mL), was added NaBH4 (0.4 g, 10.6 mmol) and the mixture was allowed to stand at room temperature for 2 hours. Additional NaBH4 (0.4 g, 10.6 mmol) was then added and after 1 hour, the solvent was removed in vacuo. The residue was dissolved in water (100 mL), saturated with NaCl and the pH was adjusted to 2 with 1N HCl. The solution was extracted with ethyl acetate (200 mL). The organic solution was washed with sat. NaCl (50 mL), dried over MgSO4, filtered and concentrated under vacuum to afford 0.285 g (97% yield) of the product as a white powder: mp, 79.1° C.; 1H NMR (dmso-d6/300 MHz) δ 7.87 (d, 2H, J=8.7 Hz), 7.54 (d, 2H, J=8.7 Hz), 7.23-7.16 (m, 5H), 4.81 (exchangeable with D2O, t, 2H, J=5.4 Hz), 3.52-3.46 (m, 4H), 3.20 (t, 4H, J=6.0 Hz), 2.30 (s, 3H); HRMS (M+H)+ calcd. for C21H23F3N3O4S: 470.1361; found 470.1330.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[S:22][CH:23]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:18][C:19]3[N:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[S:22][CH:23]=3)=[N:6][C:5]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: CC(=O)Nc1nc(CCl)cs1
Product: CC(=O)Nc1nc(CSc2nc(N[C@H](C)CO)c3sc(N)nc3n2)cs1

Procedure:
The titled compound was prepared from the product of example 4, step (b), and N-[4-(chloromethyl)-2-thiazolyl]-acetamide, using the method of example 4, step (c)