Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@:19]2([CH2:30][F:31])[CH2:24][C@@H:23]([C:25]([F:28])([F:27])[F:26])[O:22][C:21]([NH2:29])=[N:20]2)[C:15]([F:18])=[N:16][CH:17]=1>>[NH2:29][C:21]1[O:22][C@H:23]([C:25]([F:26])([F:28])[F:27])[CH2:24][C@:19]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:17]=[N:16][C:15]=2[F:18])([CH2:30][F:31])[N:20]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-chloropicolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (12k, as described in Example 138, method S). MS m/z=449.9 [M+H]+. Calculated for C17H13ClF5N5O2: 449.8
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]>C1C=CC=CC=1>[CH2:4]([NH:5][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])[C:3]#[CH:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: C#CCNC=C1C(=O)c2cc(OC)c(OC)cc2N(C(=O)OCC)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.6 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester in 15 ml. of benzene is added 275 mg. of proparglyamine, and the resulting solution allowed to stir overnight at room temperature. The reaction mixture is concentrated in vacuo to about 2 g. and is then dissolved in 50 ml. of chloroform. The resulting solution is washed with 50 ml. of a 1N aqueous sodium hydroxide solution and subsequently dried over magnesium sulfate. Removal of the chloroform solvent leaves 1.9 g. of the desired product as a yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:25][CH2:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[NH2:31][C:27]1([CH2:26][NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][O:29][CH2:28]1
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Reactant: NCC1(N)COC1
Product: NC1(CNc2cc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 3-aminomethyloxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 443, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J=2.02 Hz, 1 H), 7.77 (d, J=7.83 Hz, 1 H), 7.71 (d, J=8.59 Hz, 1 H), 7.52-7.34 (m, 4 H), 6.22 (s, 1 H), 5.25 (d, J=15.92 Hz, 2 H), 4.78 (brs, 2 H), 4.65-4.52 (m, 4 H), 3.66 (s, 2 H), 3.47-3.38 (m, 2 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[C:6]([Cl:12])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]>>[ClH:12].[CH3:8][C:7]([CH3:10])([CH3:9])[C:6](=[O:11])[S:5][CH2:4][CH2:3][NH2:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCS
Agent: Cl
Product: CC(C)(C)C(=O)SCCN
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of cysteamine hydrochloride (30.81 mmol) in pivaloyl chloride (10 mL) was heated to 100° C. during 15 minutes. The reaction mixture was allowed to cool down to room temperature and was triturated in Et2O. The mixture was filtered. The solid was washed with Et2O and then dissolved in DMF (50 mL and 5 drops of HCl) upon heating. After cooled down to room temperature, the mixture was precipitated with Et2O, filtered and washed with Et2O to give after drying under vacuum the expected compound as a white solid in 94% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.19 (s, 9H), 2.88 (t, J=7.08 Hz, 2H), 3.05-3.08 (m, 2H), 8.30 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[N:6]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:5]2[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26]>CN(C)C=O>[C:28]([CH2:29][N:8]1[C:7](=[O:9])[N:6]2[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1])([O:27][CH2:25][CH3:26])=[O:31]
Reactant: CCOC(=O)CBr
Reactant: CSc1nc2cc(-c3ccccc3)nn2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(SC)nc2cc(-c3ccccc3)nn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 260 mg of 2-methylthio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one and 140 mg of anhydrous potassium carbonate in 5 ml dry dimethylformamide is stirred at room temperature for 15 min while 0.14 ml ethylbromacetate is added dropwise. The mixture is stirred at room temperature overnight, filtered, and the filter cake washed with dimethylformamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 98.9 %

Procedure:
To a solution of (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (1.62 g, 3.16 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (10 mL). The resultant solution was maintained at ambient temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL). The aqueous layer was extracted with dichloromethane (50 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (1.29 g, 99%) as a yellow solid which was used in the subsequent step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][Si@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:21])[CH2:18][CH2:19]1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CC(C)CC[Si@H]1CC[C@H](C(=O)Oc2ccc(C#N)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using (4-cyanophenol and 4-(3-methylbutyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>CO>[CH3:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Cc1ncccc1C(=O)O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Temperature: 80 °C
Yield: 78 %

Procedure:
To 2-Methylnicotinic acid (1.00 g, 7.29 mmol) was added BH3.THF (1.0 m in THF, 18 mL, 18 mmol) and the resultant mixture was heated to 80° C. for 20 hours. MeOH (6 mL) was added and the mixture was heated to 80° C. for an additional 2 hours before being cooled to room temperature and concentrated under reduced pressure. The resultant crude syrup was repeatedly dissolved in MeOH (5 mL) and concentrated (3×). Purification by column chromatography on silica gel (4:1-EtOAc:Hexanes) afforded the desired alcohol (700 mg, 80%) as a white solid. 1H NMR (CDCl3) δ 1.96 (t, 1H, J=5.4 Hz), 2.73 (s, 3H), 4.81 (d, 2H, J=5.4 Hz), 7.32 (dd, 1H, J=7.8, 6.3 Hz), 8.03 (d, 1H, J=7.8 Hz), 8.73 (d, 1H, J=5.7 Hz).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]([NH:16][C@@H:17]([CH2:20][C:21]1[NH:25][CH:24]=[N:23][CH:22]=1)[CH2:18][OH:19])=[O:15])=O)C1C=CC=CC=1>[Pd].CO.O>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][C@@H:17]([CH2:20][C:21]1[NH:25][CH:24]=[N:23][CH:22]=1)[CH2:18][OH:19])=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)N[C@H](CO)Cc1cnc[nH]1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCC(=O)N[C@H](CO)Cc1cnc[nH]1
Temperature: 40 °C
Yield: 56.5 %

Procedure:
A round-bottom flask under inert atmosphere is loaded with 26 g of the oily product from Example 3, and 100 g of a 1:1 methanol/water mixture. The mixture is stirred to complete dissolution, then added with 2.6 g of 10% Pd/C. A washing cycle is carried out under nitrogen-vacuum, then the mixture is heated to 40° C. and hydrogen is slowly bubbled therein until complete disappearance of the starting product. The mixture is cooled to 30° C. and the catalyst is filtered off through a celite pad, washing twice with a methanol-water mixture. The solvent is evaporated off and the residue is repeatedly taken up with isobutanol and evaporated to obtain 9 g of a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cccs4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (270 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (657 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:30][S:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][CH:17]=[C:16]2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:21][CH:22]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OS(C)(=O)=O)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2cccc(C(=O)N3CCNCC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step F (560 mg, 1.20 mmol) in dichloromethane (40 mL) at 0° C. was added trifluoroacetic acid (10 mL). The solution was stirred for 2 hours and then concentrated in vacuo to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1>[Pt].CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:21])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=1
Reactant: Cc1nsc(NC(=O)Cc2ccc(O)c([N+](=O)[O-])c2)c1Cl
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)Cc2ccc(O)c(N)c2)c1Cl
Temperature: 35 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
N-(4-Chloro-3-methyl-5-isothiazolyl)-4-hydroxy-3-nitrophenylacetamide (50 g, 0.15 mol), 1% w/w platinum on carbon (15 g) and N,N-dimethylformamide (400 ml) were charged to a 600 ml stainless steel hydrogenation vessel. Once purged the vessel was pressurised to 35 bar with hydrogen, stirring was started and the reaction was heated to 35° C. After 6 hours the uptake of hydrogen had stopped; the stirring and heating were turned off and the mixture was allowed to cool to ambient temperature. The vessel was vented, purged with nitrogen and was heated to 50° C. to ensure complete solution. The reaction mixture was filtered to remove the catalyst and the liquors concentrated under high vacuum to remove the N,N-dimethylformamide. The resultant residue was slurried in dichloromethane (300 ml), filtered, washed with dichlorometane (200 ml) and dried to give give N-(4-chloro-3-methyl-5-isothiazolyl)-3-amino-4-hydroxy-phenylacetamide (43.9 g) as a buff solid, m.p. 239-243° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:12]([O:11][CH:4]([O:3][CH2:1][C:2]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-diethoxypropionate (20.0 g, 0.1051 mole), benzyl alcohol (22.7 g, 0.2102 mole), p-toluenesulfonic acid monohydrate (0.5 g, 0.0026 mole) and benzene (350 mL). Heating the mixture at 80° C., the solvent was distilled from the reaction mixture in 1.5 h period. The resulting residue was dissolved in ether (@ 300 mL) and washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to give ethyl 3,3-dibenzyloxypropionate (9) as a colorless oil (32.9 g, 99.5% yield): 1H NMR (CDCl3) d 1.22 (t, 3H, J=7.2 Hz), 2.79 (d, 2H, J=5.9 Hz), 4.12 (q, 2H, J=7.2 Hz), 4.60 (d, 2H, J=11.6 Hz), 4.70 (d, 2H, J=11.6 Hz), 5.22 (t, 1H, J=6 Hz), 7.27-7.36 (m, 10H); IR (Neat) 3100, 3080, 3040, 2990, 2940, 2920, 2885, 1740, 1630, 1458, 1375, 1315, 1190, 1120, 1050, 1030, 740, 700. ##STR8##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Yield: 139.5 %

Procedure:
To a stirred suspension of [1-(1H-indazol-5-ylamino)-cyclobutyl]-methanol (0.690 g, 3.18 mmol) in DCM (100 mL) at ambient temperature and under nitrogen was added Et3N (2.66 mL, 19.1 mmol) followed by methanesulfonyl chloride (0.74 mL, 9.54 mmol). After 5 minutes the mixture was washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to give methanesulfonic acid 1-(1H-indazol-5-ylamino)-cyclobutylmethyl ester (1.31 g) as a gum that was used directly in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](CCC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:55][CH2:56][C:57](Cl)=[O:58]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:57](=[O:58])[CH2:56][Cl:55])[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (372 mg, 0.63 mmol, example 8A) and diisopropylethylamine (230 uL, 1.32 mmol) were dissolved in methylene chloride (4 mL) and cooled to ice temperature. Chloroacetyl chloride (100 uL, 1.26 mmol) in methylene chloride (1 mL) was added dropwise and this mixture was stirred for 30 min at ice temperature. The reaction was diluted with methylene chloride and washed with water. The organic layers were dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated. Purification of the crude material by flash chromatography using ethyl acetate and hexanes gave 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-chloro-ethanone (193 mg, 0.29 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][CH:12]([N:14]1[C:18]([C:19]2[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[CH:12]([N:14]1[C:18]([C:19]2[C:24]([O:25][CH2:2][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[CH:5]=[O:6])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)([CH3:13])[CH3:11]
Reactant: CC(C)n1nccc1-c1ncccc1O
Reactant: O=Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)n1nccc1-c1ncccc1OCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH3CN (25 mL). 2-[1-(Propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and KI (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H2O, and then it was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; 1HNMR (300 MHz, CDCl3, ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88 (m, 1H), 7.86 (m, 1H), 7.61-7.79 (m, 6H), 6.61 (d, J=2.1 Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46 (d, J=6.6 Hz, 6H); (ES, m/z): 322 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH:17]([N:30]1[CH2:33][CH:32](OS(C)(=O)=O)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:18]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:30]2[CH2:33][CH:32]([O:1][C:2]3[C:7]4[CH:8]=[C:9]([CH3:11])[O:10][C:6]=4[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=3)[CH2:31]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2cc(C)oc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.70 g, 7.72 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (193a) (2.95 g, 9.29 mmol) and Cs2CO3 (6.29 g, 19.3 mmol) in DMF (10 mL) was stirred for 4 hours at 100° C. The reaction was cooled to room temperature, diluted with EtOAc and washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (10/90 to 40/60) to give the desired compound (2.15 g, 63%) as a white solid after evaporation of the solvent. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.49 (m, 3 H) 2.42-2.57 (m, 3 H) 3.10-3.29 (m, 2 H) 3.75-3.94 (m, 2 H) 4.27-4.42 (m, 2 H) 4.43-4.52 (m, 1 H) 4.91-5.10 (m, 1 H) 6.50 (s, 1 H) 7.05 (s, 1 H) 7.15-7.25 (m, 2 H) 7.24-7.35 (m, 4 H) 7.39-7.54 (m, 4 H) 7.74 (s, 1 H); MS (ESI, pos): 442.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:42])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)(=[O:29])=[O:28].[Cl:43][C:44]1[C:45]([C:54]([F:57])([F:56])[F:55])=[N:46][N:47]([CH2:50][C:51](O)=[O:52])[C:48]=1[CH3:49]>>[Cl:43][C:44]1[C:45]([C:54]([F:56])([F:55])[F:57])=[N:46][N:47]([CH2:50][C:51]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:32]=[CH:31][C:30]([S:27]([N:26]([CH3:42])[CH3:25])(=[O:28])=[O:29])=[CH:35][CH:34]=3)[CH2:37][CH2:38]2)=[O:52])[C:48]=1[CH3:49]
Reactant: CN(C)S(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(S(=O)(=O)N(C)C)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein N,N-Dimethyl-4-piperazin-1-yl-benzenesulfonamide and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.54 (d, 2H), 7.08 (d, 2H), 5.38 (s, 2H), 3.62 (m, 4H), 3.48 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=494.1, found=494.0.
Reaction SMILES: CO[C:3]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:4].[C:24](OCC)(=[O:26])C>[Pd]>[CH3:24][O:26][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]([C:14]([OH:16])=[O:15])[C:5](=[C:3]=[O:4])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1c(C(=O)OCc2ccccc2)oc2ccccc12
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COc1ccc2c(c1)C(=C=O)C(C(=O)O)O2
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of benzyl methoxy-carbonylbenzofuran-2-carboxylate (0.144 g, 0.409 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (0.072 g, 50% w/w). After stirring under a hydrogen atmosphere for 2 h, the mixture was filtered through Celite. The filtrate was concentrated to yield the title compound as a white solid (0.098 g, 91%): 1H NMR: