Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:7][C@H:8]([OH:18])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4]1.[Cl:19][C:20]1[C:21]([N:28]2[C:32]3=[N:33][CH:34]=[N:35][C:36](Cl)=[C:31]3[CH:30]=[N:29]2)=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[N:3]1([CH2:7][C@H:8]([O:18][C:36]2[N:35]=[CH:34][N:33]=[C:32]3[N:28]([C:21]4[C:22]([C:23]#[N:24])=[CH:25][CH:26]=[CH:27][C:20]=4[Cl:19])[N:29]=[CH:30][C:31]=23)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: O=C(Nc1ccccn1)[C@@H](O)CN1CCC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cccc(Cl)c1-n1ncc2c(O[C@@H](CN3CCC3)C(=O)Nc3ccccn3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
Sodium hydride (116 mg, 2.90 mmol) was added to (S)-3-(azetidin-1-yl)-2-hydroxy-N-(pyridin-2-yl)propanamide (Intermediate BC1) (232 mg, 1.05 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (280 mg, 0.97 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to ambient temperature for 2 hours. It was then cooled to 0° C., 20% Rochelle salt (20 mL) added and the mixture stirred for 10 minutes. It was extracted with EtOAc (50 mL), the organic phase was washed with water (10 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with EtOAc (10 mL), filtered and the filtrates evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in EtOAc and further purified by preparative HPLC (Phenomenex Luna C18 100A column, 5μ silica, 21 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents to afford the product (100 mg, 22%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][OH:16])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH2:15][OH:16])[CH2:29][CH2:30]1
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H](CO)NS(=O)(=O)c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, (S)-2-benzenesulfonylamino-3-hydroxy-propionic acid was coupled with 1-(2,5-dimethylphenyl)-piperazine to give N-{(S)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([O:10][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
1.1 3, 5-Dihydroxy-benzoic acid methyl ester (149 mmol), potassium carbonate (1 eq.) and 18-crown-6 (0.1 eq.) are dissolved in acetone (750 ml) and stirred for 1 hour at RT. Benzylbromide (0.8 eq.) is added and the reaction solution is heated to reflux for 8 hours. The solvent is removed in vacuo and 3-benzyloxy-5-hydroxy-benzoic acid methyl ester is isolated after column chromatography in a yield of 26%. The isolated compound is dissolved in acetone (180 ml), potassium carbonate (1.2 eq.) and isopropyl iodide (2. eq.) is added and the reaction solution is heated under reflux for 24 hours. The reaction is quenched with water and extracted with ethyl acetate. The combined organic layer is dried over Na2SO4 and the solvent removed in vacuo. 3-Benzyloxy-5-isopropoxy-benzoic acid methyl ester is obtained after column chromatography in a yield of 67%. The isolated compound is dissolved in methanol/TNF/water (90 ml, 1:1:1) and LiOH (4 eq.) is added. The reaction is stirred for 2 hours at RT and quenched with citric acid solution and the pH was adjusted to 7. The solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-benzoic acid is isolated as a brown powder in a yield of 93%; HPLC (Method 8): 3.43 min; LC-MS (Method B): 2.391 min, 287.15 (M+H+);
Reaction SMILES: CI.N1CCOC[CH2:4]1.[CH3:9][C:10]([CH3:20])=[CH:11][CH2:12][CH2:13][C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17].C(C(CC=C(C)C)C(OC)=O)(=O)C>>[CH3:4]/[C:14](/[CH2:13][CH2:12][CH:11]=[C:10]([CH3:20])[CH3:9])=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C#CCCC=C(C)C
Reactant: C1COCCN1
Agent: COC(=O)C(CC=C(C)C)C(C)=O
Solvent: CI
Product: COC(=O)/C=C(/C)CCC=C(C)C

Procedure:
The overall process can be illustrated by the manufacture of nerol, ((Z)-3,7-dimethylocta-2,6-dien-1-ol), which begins with the treatment of 2-butynoic acid with lithium 2,2,6,6-tetramethylpiperidide, followed by alkylation with 1-bromo-3-methyl-2-butene to yield 7-methyloct-6-en-2-ynoic acid as the major product. 2-Ethenylidene-5-methyl-4-hexenoic acid is produced as a minor product in the course of the alkylation. The acids are esterified conveniently with methyl iodide, and treated with morpholine, followed by acid workup, to give a mixture of a major amount of methyl 7-methyloct-6-en-2-ynoate and a minor amount of methyl 2-acetyl-5-methyl-4-hexenoate. The latter compounds are separated by chromatography on a silica gel column using ethyl acetate-n-hexane as eluant. Contacting of the isolated methyl 7-methyloct-6-en-2-ynoate with a mixture of lithium dimethyl cuprate and methyl copper at low temperatures gives methyl (Z)-3,7-dimethylocta-2,6-dienoate, which is reduced to nerol, (Z)-3,7-dimethylocta-2,6-dien-1-ol, for example, with aluminium hydride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: NCCSCc1nccs1
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1cccnc1

Procedure:
5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 g) was reacted with 2-(2-thiazolylmethylthio)-ethylamine (1.30 g) according to the procedure in Example 2. The reaction mixture was triturated in hot water to give 2-[2-(2-thiazolylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this product was treated with dilute hydrobromic acid to give the title compound, m.p. 229°-233.5° (ex. methanol-water).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
To a solution of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (2.5 g) in acetone (30 ml) was added 6 N hydrochloric acid (1 ml) and treated in a substantially similar manner to those of Example 2- 6) to give a viscous oil (2.10 g) of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:3]=1[NH2:19].S(Cl)(Cl)(=O)=O.[CH2:25]([C:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1)[CH:26]=[CH2:27]>N1C=CC=CC=1>[F:9][C:5]1[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[C:3]([NH:19][S:31]([C:28]2([CH2:25][CH:26]=[CH2:27])[CH2:30][CH2:29]2)(=[O:33])=[O:32])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred solution of the amine, i.e., 3,5,6-trifluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine, (1 eq) in anhydrous pyridine (5 ml/mmole) was added the sulfonyl chloride, i.e., 1-allyl-cyclopropanesulfonyl chloride, (1-5 eq). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was partitioned with water and EtOAc. The organic layer was washed with brine, dried (MGSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica. 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H), 6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d, 2H), 1.23 (m, 2H), 0.872 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:17])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CNc1ccc(CCO)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 67.1 %

Procedure:
To a solution of ethyl N-[4-(2-hydroxyethyl)phenyl]-aminoacetate (1.15 g) in N,N-dimethylformamide (10 ml) were added potassium carbonate (1.17 g) and methyl iodide (420 μl), and the mixture was stirred for 9 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by flash column chromatography on silica gel (eluent: dichloromethane/diethyl ether=10/1) gave ethyl N-[4-(2-hydroxyethyl)phenyl]-N-methylaminoacetate (820 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:11][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1ccc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(O)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 80 °C
Yield: 45.6 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)propan-1-ol (0.3 g, 1.38 mmol) in toluene (8 mL) and ethanol (4 mL) was added 4-cyano phenyl boronic acid (0.244 g, 1.6 mmol) and a 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, Pd(PPh3)4 (0.08 g, 0.069 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 80° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (100 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 15% ethyl acetate and hexane) to give 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.15 g, 45.45% yield). 1H NMR (400 MHz DMSO-d6): δ 8.78 (s, 1H), 7.89 (dd, 1H), 7.78 (d, 2H); 7.69 (d, 2H), 7.39 (d, 1H), 4.77 (t, 1H), 3.90 (s, 1H), 1.91-1.81 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(Cl)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[CH:10]([CH3:12])[CH3:11].FC(F)(F)S(OCC(F)(F)F)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)CBr
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CC(C)COc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 7 of EXAMPLE 7 using 3-fluorophenol and isobutyl bromide instead of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate.
Reaction SMILES: II.I[CH2:4]I.[CH2:6]=[C:7]1[CH2:16][CH2:15][C:10]2([O:14]CCO2)[CH2:9][CH2:8]1>C(OCC)C.[Cu].[Zn]>[CH2:14]1[C:10]2([CH2:9][CH2:8][C:7](=[O:6])[CH2:16][CH2:15]2)[CH2:4]1
Reactant: ICI
Reactant: C=C1CCC2(CC1)OCCO2
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CCC2(CC1)CC2
Temperature: 25 °C

Procedure:
A 250 mL round-bottom flask equipped with a reflux condenser was charged with zinc-copper couple (6.5 g, 0.05 mol) and ethyl ether (100 mL). Iodine (0.42 g, 0.00165 mol) was added and stirred until the brown color disappeared. Diiodomethane (26.56 g, 0.09915 mol) was added and heated at reflux for 2 h. 8-Methylene-1,4-dioxaspiro[4.5]decane (10 g, 0.06 mol), dissolved in ethyl ether (50 ml) was added and the mixture was heated at roflux overnight. An additional portion of diiodomethane (26.56 g, 0.09915 mol), zinc-copper couple (6.5 g, 0.05 mol) and iodine (0.42 g, 0.00165 mol) was added and the reaction was continued at reflux for overnight. The reaction mixture was cooled to room temperature, filtered, and the precipitate was rinsed with ethyl ether (100 mL). The combined ether solutions were placed in a 500 mL round-bottom flask and IN hydrochloric acid (200 mL) was added and stirred at room temperature for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl ether (2×200 mL). The combined organic layers were dried and concentrated under educed pressure. The residue was purified by flash chromatography to afford the desired product. (4.6 g 50%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-chloro-6-(trifluoromethyl)pyridine and 4-hydroxybenzaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 86 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl 3-amino-1-azetidinecarboxylate gave tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-azetidinecarboxylate in 86% yield: mp (CH2Cl2/hexanes) 201-203° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.50 and 8.45 (2d, J=6.3, 6.5 Hz, 1H), 8.01 and 7.93 (2d, J=8.2, 8.3 Hz, 1H), 7.83 and 7.44 (2t, JHF=53.1, 52.9 Hz, 1H), 7.44-7.37 (m, 1H), 6.96 and 6.95 (2d, J=8.1, 8.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.78 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 3.87-3.82 (m, 2H), 3.78 (m, 4H), 3.69, (m, 4H), 1 40 and 1.39 (2s, 9H); Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.0; 5.8; N, 21.0%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][CH:3]=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][OH:13])=[CH:17][CH:18]=2)=[N:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: OCCc1ccc(O)cc1
Reactant: FC(F)(F)c1nc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)n2)cc1
Temperature: 110 °C
Yield: 8.2 %

Procedure:
To the solution of 6-bromo-3-chloro-2-(trifluoromethyl)pyridine (2 g, 7.68 mmol) and 4-(2-hydroxyethyl)phenol (1.061 g, 7.68 mmol) in DMF (30 mL) was added K2CO3 (1.592 g, 11.52 mmol). The mixture was heated at 110° C. for 2 h. Purification via reverse phase flash chromatography afforded the title compound (200 mg, 8.2% yield) as brown solid. LCMS: rt=3.14 min, [M+H+]=318
Reaction SMILES: [NH2:1][CH:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1.Cl.[Cl-].[NH4+]>[CH2:24]([O:23][C:21](=[O:22])[NH:1][CH:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(N)Cn1ncc2ccc(O)cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopropyl)-indazol-6-ol (0.46 g, 2.4 mmol) in THF (10.0 mL) was added a saturated aqueous solution of sodium bicarbonate (2.0 mL) followed by benzyl chloroformate (0.40 mL) at room temperature. After stirring for 1 h, the solution was diluted with 1 N HCl (10 mL) and ammonium chloride (20 mL) followed by extraction with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give a residue which was used in the next step without further purification (0.75 g, 98%); MS (ES) m/z 326 (M+).
Reaction SMILES: [N:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH3:24])=[O:22])[NH:12]1.C(N1CCOCC1)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(O)=O.[Na+]>C1COCC1.O.C(Cl)(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([S:7]([N:12]2[CH:13]([C:21]([O:23][CH3:24])=[O:22])[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH2:2][CH2:3]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: COC(=O)C1Cc2ccccc2CN1
Agent: CCN1CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1Cc2ccccc2CN1S(=O)(=O)N1CCOCC1

Procedure:
With stirring, 4.2 g (0.025 mol) of morpholine-N-sulfonyl chloride in 20 ml of THF are added dropwise to a solution of 4.8 g (0.025 mol) of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate and 2.9 g (0.025 mol) of N-ethylmorpholine. The mixture is stirred at RT for 2 h and then heated under reflux for another 2 h so that the reaction goes to completion. CHCl3 is added to the reaction solution, which is then treated with 5% strength citric acid, 5% strength NaHCO3 solution and water. The organic phase is dried over Na2SO4 and evaporated to dryness. Yield of ester (26a): 7.5 g (92% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: CO
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-Amino-5-chloro-2-methoxy benzoic acid (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry cooled to 0° C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over the course of 20 minutes. The initially clear solution turned to a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The methanol was evaporated and the resulting slurry suspended in diethyl ether (1 L). The solid was filtered and rinsed thoroughly with diethyl ether to afford the title compound (50.9 g) as the hydrochloride salt. The salt was suspended in 1 N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and thorough rinsing with water afforded the title compound free base as a white solid, m.p. 136-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2=CC(O)=CCC2CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-(t-Butyloxycarbonyl)-7-hydroxy-tetrahydro-isoquinoline-3-carboxylic acid (0.5 g, 1.71 mmol) was dissolved in 10% MeOH/CHCl3 (70 mL). The solution was cooled to 0° C. and trimethylsilyldiazomethane (2 M in hexane) (1.88 mL, 3.76 mmol) was added dropwise via syringe. A yellow color persisted after addittion of 1.2 mL of this reagent. The cooling bath was removed and the solution was stirred at 25° C. for 0.75 hr. The reaction was cooled to 0° C. and acetic acid was added dropwise until the yellow color disappeared. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and evaporation in the title compound which was used without further purification.