Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (275 mg, 3.31 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (35 mL) and the colorless solution was cooled to −50° C. Then, n-butyllithium (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise which afforded a dark reddish-brown viscous solution. The mixture was stirred between −20 to −10° C. for 30 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (700 mg, 1.44 mmol in 4 mL THF, Intermediate 47: step f) was introduced at 0° C. The reaction mixture became a dark brown color and was allowed to warm gradually to room temperature. The mixture was stirred for 60 minutes at room temperature then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc, 3×50 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (1% MeOH-DCM increasing to 5% MeOH-DCM) provided the product as a light brown solid. MS m/e 586.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (d, J=1.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.37 (d, J=7.9 Hz, 3H), 6.93 (q, J=8.1 Hz, 2H), 6.80 (s, 1H), 5.51 (s, 1H), 4.36-4.22 (m, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H). Racemic (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol was separated into its individual enantiomers using the following conditions: Chiralcel OD, 20 uM (Diacel) using ethanol with 242 nM detection to give the first eluting enantiomer Example 77B: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H); and the second eluting enantiomer Example 77C: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[CH:22]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([CH3:18])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)([CH3:24])[CH3:23]
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(C)c3nn2C(C)C)cc1
Yield: 7.1 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.01 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[NH2:14][CH:15]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:16]([CH:15]([NH:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)#[N:17]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CON1CCC(CC(N)C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CON1CCC(CC(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Reaction time: 0.5 h

Procedure:
At room temperature, (2,4,6-trimethyl-phenyl)-acetyl chloride (10.6 g, 54 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionitrile (6.6 g, 36 mmol) and K2CO3 (9.9 g, 72 mmol) in 100 ml of THF. After the addition, the mixture was stirred for 0.5 h. The reaction mixture was diluted with 50 ml of water and extracted with EtOAc five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel Yield: 10.6 g of N-[1-cyano-2-(1-methoxy-piperidin-4-yl)-ethyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:50]1[C:62]2[CH:61]([CH2:63]OC(ON3C(=O)CCC3=O)=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[CH:50]1[C:62]2[CH:61]([CH2:63][O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:10][C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:16]=3)=[O:7])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)CCCCCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCCCc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (S)-6-(4-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)hexanoate (Compound SP426) (5.65 g, 11.24 mmol) was dissolved in DCM (30.0 ml), trifluoroacetic acid (15.0 ml, 195 mmol) was added and the mixture was stirred for 30 minutes at room temperature, after which the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in dioxane (40 ml) and a 10% aqueous sodium carbonate solution (80 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (3.68 g, 10.90 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding a 5 N aqueous HCl solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound SP427 (6.39 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)[C:3]=1[N+:20]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CC(C)O)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(N)c(Nc2ccc(CC(C)O)cc2)n1

Procedure:
A mixture of 1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol (step 2, 500 mg, 1.66 mmol), iron powder (440 mg, 7.88 mmol), ammonium chloride (80 mg, 1.5 mmol) in ethanol/water (v/v, 31:8, 39 mL) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with dichloromethane (200 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4), and concentrated. Removal of solvent gave 450 mg (quant.) of the title compound as brown solids: TLC Rf 0.10 (hexane/ethyl acetate=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[CH3:30][CH:31]([CH3:35])[C:32](O)=[O:33].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CC(C)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)C(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
The title compound was prepared in analogy to Example 2-17 by using 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-methylpropanoic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH3:12][CH:13]([C@H:15]([NH:26]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C:16](ON1C(=O)CCC1=O)=[O:17])[CH3:14].CCN(C(C)C)C(C)C>ClCCl>[NH2:26][C@@H:15]([CH:13]([CH3:14])[CH3:12])[C:16]([NH:9][C@@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the alanine-O-tert-butyl ester hydrogen chloride salt (98) (500 mg, 2.76 mmol) in dichloromethane (5 mL) was added Fmoc-val-OSu (99) (1.09 g, 2.51 mmol). DIPEA (0.96 ml, 5.5 mmol) was added and the reaction mixture was allowed to stir at an ambient temperature for 16 h. The mixture was poured into dichloromethane (100 mL) and washed with 1N HCl (50 mL) and water (50 mL) before being dried over magnesium sulfate. The material was chromatographed on a 2 mm radial chromatotron plate eluting with 1 to 5% methanol/dichloromethane gradient and product containing fractions were combined and concentrated. The resulting residue was dissolved in dichloromethane (16 mL) and piperidine (4 mL) was added. The mixture was stirred for 10 min before being concentrated under reduced pressure. The resulting residue was chromatographed on a 2 mm plate eluting first with ammonia-saturated dichloromethane followed by 5% methanol in ammonia-saturated dichloromethane to give 494 mg (2.02 mmol, 81% for two steps) of 97: 1H-NMR (400 MHz, CDCl3) δ 7.78 (bs, 1H), 4.47 (m, 1H), 3.30 (d, 1H), 2.30 (m, 1H), 1.38 (d, 3H), 1.47 (s, 9H), 1.00 (d, J=7.0 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:30]([C:33]4[C:34]([CH3:39])=[N:35][O:36][C:37]=4[CH3:38])(=[O:32])=[O:31])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH:19]2[CH2:20][C:21]3[CH:22]=[C:23]([O:29][S:30]([C:33]4[C:34]([CH3:39])=[N:35][O:36][C:37]=4[CH3:38])(=[O:32])=[O:31])[CH:24]=[CH:25][C:26]=3[CH2:27][CH2:28]2)[CH2:10][CH2:9]1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 4-({[7-(3,5-dimethyl-isoxazole-4-sulfonyloxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.16 g, 2.1 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (847 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CS(C)=O.O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(C)nc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(N2CCNCC2)c1
Yield: 51.6 %

Procedure:
A solution of 2-chloro-4,6-dimethyl-pyridine (1 g, 7.09 mmol) and piperazine (2 g, 23.2 mmol) in DMSO was heated at 140° C. for 24 h. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel (60-120 mesh), eluting with 5% methanol/chloroform to afford 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (0.7 g, 52%).
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[C:7]1([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:5][C:4]1[N:3]=[C:1]([NH2:2])[C:15]2[CH2:14][CH:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17][C:16]=2[N:6]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(c2ccccc2)CC1
Product: Nc1nc(N)c2c(n1)CCC(c1ccccc1)C2

Procedure:
This compound was prepared in a manner analogous to that of Example 1, using 4.2 grams (0.05 mole) of cyanoguanidine and 13.1 grams (0.08 mole) of 4-phenylcyclohexanone. The crude product was recrystallized from ethanol, yielding 2,4-diamino-6-phenyl-5,6,7,8-tetrahydroquinazoline, mp 223°-226° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([CH3:19])([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)[CH3:7].[BH4-].[Na+]>C(O)C>[CH3:19][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)([CH3:7])[CH2:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CCC(C)(C)n1cnc(-c2cccnc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CCCO)n1cnc(-c2cccnc2)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, a solution of the residue in dichloromethane was washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated to give 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentan-1-ol (68%). MH+(246).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH3:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]([OH:20])([CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
n-BuLi (2.5 M in hexanes, 17.0 mL, 42.5 mmol) was added dropwise to a solution of 1,4-dibromobenzene (10.04 g, 42.5 mmol) in THF (100 mL) at −78° C. under nitrogen. After stirring at −78° C. for 1 hour, 2-hexanone (4.5 g, 44.9 mmol) was added dropwise, and the solution was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and the organic layer was separated. Next, the organic phase was washed with water, dried over Na2SO4, and concentrated on a rotary evaporator to give a crude oil. The crude was purified by column chromatography (silica gel, chloroform) to give 6 as a colorless oil (10.0 g, 91% yield). 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 1.79-1.75 (m, 2H), 1.68 (s, 1H), 1.54 (s, 3H), 1.24-1.28 (m, 4H), 0.85 (t, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:36])([F:38])[F:37])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.28 g, 54%). MS (ISP) 523.1 [(M−H)−]; mp 247° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH:13](OCC)=[O:14].Cl>>[CH:13]([NH:8][CH2:7][CH2:6][C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[O:1][CH:5]=1)=[O:14]
Reactant: NCCc1coc2ccccc12
Reactant: CCOC=O
Agent: Cl
Product: O=CNCCc1coc2ccccc12

Procedure:
A solution of 2.35 g (0.015 mole) of 2-(3-benzo[b]furanyl)ethylamine and 5 mL of ethyl formate was heated at 60° C. for 3 hours, poured into 2 N HCl and washed with methylene chloride which in turn was washed with 5% sodium hydroxide (w/v), dried (MgSO4), filtered and concentrated to give 2.70 g of product.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]([OH:38])([CH3:37])[CH2:34][CH2:35][OH:36].[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:36][CH2:35][CH2:34][C:33]([OH:38])([CH3:37])[CH3:32])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)CCO
Reactant: COC(=O)c1ccc(NC(c2cc(-c3ccc(F)nc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCCC(C)(C)O)nc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 15.1 %

Procedure:
Methyl 4-({cyclohexyl[5-(6-fluoropyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoate (1.7 g) and 3-methyl-1,3-butanediol (2.1 g) were dissolved in tetrahydrofuran (10 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 10 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.3 g, 16%) as an amorphous compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl(O)(=O)(=O)=O>CN(C)C=O>[Si:12]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCO
Agent: [O-][Cl+3]([O-])([O-])O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 2 °C

Procedure:
A mixture of 186 ml of dimethylformamide, 93.5 g of 5-hydroxy-1-pentyne and 185.5 g of imidazole at room temperature (20-30° C.) is added with 185.5 g of t-butyldimethylsilyl chloride, in portions and under stirring, keeping this temperature with cooling bath. The resulting pale-yellow, dense suspension is cooled to 2° C., kept under stirring and monitored by TLC (eluent 7/3 diethyl ether/petroleum ether, developer: hot perchloric acid; Rf of the starting product=0.33, Rf of the final product=0.95); the reaction is complete after two hours. The reaction mixture is slowly added with 375 ml of water and 150 ml of toluene, and stirring is continued for 10 minutes, controlling the temperature with cooling bath. The organic phase is separated, the aqueous one is extracted with 100 ml of toluene, then combined organic phases are filtered under reduced pressure through Celite, washing the cake with 50 ml of toluene. The solution is concentrated under reduced pressure to obtain a pale-yellow oily residue which is distilled at a temperature-ranging from 23 to 34° C. at about 13 mbars and subsequently at 7.5 mbars at a temperature ranging from 35 to 60° C. The two resulting fractions are discarded. Continuing the distillation at 7.5 mbars, the fractions which distil above 60° C. are collected. The first fraction, which distils between 60 and 75° C. (89 g) is in turn discarded whereas the second one, which distils at 75° C., consists of 101 g of 5-(t-butyldimethylsilyloxy)pent-1-yne identical to the product of preparation I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1.C(OCC)(=O)C.O.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1)#[N:36]
Reactant: O=C(NCc1ccc(Oc2cccc(Br)c2)s1)c1ccc2ncccc2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3ccc4ncccc4c3)s2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Next, to a solution of the mixture of quinoline-6-carboxylic acid (5-(3-bromophenoxy)-thiophene-2ylmethyl)-amide and debrominated compound (130 mg, 0.303 mmol) in N,N-dimethylformamide (5.0 mL) were added zinc cyanide (71 mg, 0.605 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol) under nitrogen atmosphere, the solution was stirred at 100° C. for 1 hour, and the solution was stirred at 140° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and title compound (25 mg, 21%) was obtained as a colorless oil.