Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].[Li]CCCC.[CH2:11]([N:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](N(OC)C)=[O:26])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:31]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25](=[O:26])[C:5]#[C:4][CH2:3][O:2][CH3:1])[CH2:23][CH2:24]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: C#CCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC#CC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methoxyprop-1-yne (0.207 ml, 2.456 mmol) in THF (2 mL) was treated with BuLi (1.535 ml, 2.456 mmol) dropwise at −78° C. After stirring for 15 min, 13D (300 mg, 0.819 mmol) in THF (2 mL) was added and reaction mixture was warmed to room temperature over 30 min. The reaction was quenched with aq. HOAc and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by Isco silica column (12 g), eluted with ethyl acetate:hexane, 0-70%. Concentration of the appropriate fractions provided 13E (300 mg, 98% yield). This material was taken without characterization to the next step.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].C(N(CC)CC)C.[C:15]([C:18]([CH2:25][C:26](=[O:28])[O-:27])([CH2:20][N+:21]([CH3:24])([CH3:23])[CH3:22])[OH:19])(=[O:17])[CH3:16].[Cl-].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=O)CCCCC1>O1CCCC1.O>[C:15]([C:18]([CH2:25][C:26](=[O:27])[O-:28])([CH2:20][N+:21]([CH3:22])([CH3:24])[CH3:23])[OH:19])(=[O:17])[CH3:16].[F:2][C:3]([F:7])([F:6])[CH2:4][NH-:5]
Reactant: NCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [NH-]CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoroethylamine hydrochloride (2.7 grams; 0.02 moles) in tetrahydrofuran (150 ml) and triethylamine (2.8 ml; 0.02 moles) was added acetyl carnitine chloride (4.8 grams; 0.02 moles) in water (10 ml) and lastly N,N'-dicyclohexylcarbodiimide (4.2 grams; 0.02 moles) dissolved in tetrahydrofuran (50 ml). The reaction mixture was kept for a whole day under stirring at room temperature. A precipitate formed. The precipitate consisting of dicyclohexyl urea was filtered and the filtrate was concentrated until complete removal of tetrahydrofuran. The residual aqueous solution was washed with CHCl3 (2×50 ml), then evaporated to dryness. The raw solid was taken up with CH3CN (30 ml), and the resulting mixture was kept at 0° C.-5° C. for 2 hours. After filtering off the unreacted acetyl carnitine, if any, upon addition of ethyl acetate-ethyl ether to the filtrate a product crystallized as a very hygroscopic solid which was stored in a nitrogen atmosphere in anhydrous conditions.
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[CH2:9][CH:8]2[C:12](OCC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.P([O-])([O-])(O)=O.[Na+].[Na+]>CO>[C:1]1([N:7]2[CH:8]([CH2:12][OH:13])[CH2:9][C:10]2=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CC(=O)N1c1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1CC(CO)N1c1ccccc1
Temperature: 0 °C
Yield: 76 %

Procedure:
To a dilution of 106.5 g. (0.486 moles) of ethyl 1-phenyl-4-oxo-2-azetidine-carboxylate prepared according to Example 24 in 700 ml. of methanol 18.74 g. (0.493 moles) of sodium tetrahydrido-borate(III) are added with outer cooling with ice water and stirring. The mixture is acidified with dilute hydrochloric acid and it is then neutralized with disodium hydrogenphosphate. Methanol is distilled off in vacuo. 65 g. (76%) of the named compound are obtained, melting at 100° to 102° C. (ethyl acetate/petroleum ether).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7].[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([NH:9][C:10](=[O:11])[N:18]([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:8])[CH3:7]
Reactant: CNc1ccccc1
Reactant: CC(C)(N=C=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CN(C(=O)NC(C)(C)c1cccc(C(F)(F)F)c1)c1ccccc1
Yield: 77 %

Procedure:
A solution of 2.3 g of m-trifluoromethyl-α,α-dimethylbenzyl isocyanate in 5 ml of benzene was added to 1.1 g of N-methylaniline in 5 ml of benzene and the mixture was heated under reflux for 2 hours. After allowing the reaction mixture to cool, the mixture was washed successively with 2N aqueous sodium hydroxide, 2N hydrochloric acid and water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation and the resulting crystals were recrystallized from n-hexane to obtain 2.6 g of the title compound.
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: Brc1ccc[se]1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 26.0 g (0.12 mol) of 2-bromoselenophene, 20.5 g (0.13 mol) of 4-propylphenylboronic acid, 7.0 g (6.1 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 140 ml of 2 N sodium carbonate soln. in 300 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. A further 7.0 g (6.06 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is refluxed again for 3 h. After cooling, water is added, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). 2-(4-Propylphenyl)selenophene is obtained as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:19]([N:18]1[C:14]([NH:13][C:2]2[C:3](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:15][CH:16]=[N:17]1)[CH3:20]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1Nc1ccc(OC)cc1C(=O)O
Yield: 69 %

Procedure:
A mixture of 2-bromo-5-methoxybenzoic acid (141.5 g, 0.61 mol), 5-amino-1-ethylpyrazole (68 g, 0.61 mol), K2CO3 (84.2 g, 0.61 mol), DMF (500 mL) and Cu(OAc)2 (3 g) was refluxed for about 2 days. The reaction mixture was cooled and then was poured into water (1500 mL). The mixture was acidified with acetic acid and the resulting solid was collected by filtration and dried to afford 110 g of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Mg]Cl)=[CH:12][CH:11]=1)=[CH2:9].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1)=[CH2:9]
Reactant: C=Cc1ccc([Mg]Cl)cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccccc2)cc1

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 0.0674 g (0.3 mmol) of palladium (II) acetate and 6 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.314 g (0.6 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 19° C. for 30 minutes. 4.710 g (30 mmol) of bromobenzene was added, followed by stirring at 19° C. for 30 minutes. 40 ml (50 mmol) of 1.25M tetrahydrofuran solution of 4-vinylphenylmagnesium chloride was added dropwise at 19° C. over a period of 2 hours, followed by stirring at 30° C. for 2 hours. After the completion of the reaction, 10 ml of saturated aqueous ammonium chloride solution was added, followed by separation. The organic phase was purified by column chromatography to afford 4.450 g of 4-vinylbiphenyl (yield: 82 mol % based on bromobenzene). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])[CH:6]=[N:7][OH:8].[O-]Cl.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])[C:6]#[N+:7][O-:8]
Reactant: COc1cc(C=NO)ccc1OCCN1CCNC1=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C#[N+][O-])ccc1OCCN1CCNC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 3-methoxy-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde oxime (21.7 g, 0.078 mol) in CH2Cl2 (950 mL) at −3° C., is added dropwise an aqueous NaOCl solution in water (Aldrich, >4% of active chlorine) (161 mL) over 10 minutes. The reaction medium is then stirred for 20 minutes at 0° C. The organic phase is separated and the aqueous phase is extracted with CH2Cl2 (4 times 100 mL). The combined organic phases are washed with water (3 times 100 mL), dried over Na2SO4 and then concentrated under reduced pressure (Tbath 22° C.) to 200-220 mL. The precipitate obtained is filtered, washed with CH2Cl2 (twice 10 mL) and dried under atmospheric pressure at room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of example 67a (16 g; 70 mmol) in dioxane (25 ml) was added drop wise at 5-10° C. to (toluene washed) 55% NaH (3.84 g; 80 mmol) suspended in dioxane (25 ml) over a period of 30 min. in an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 h, cooled to 0° C. and treated to a drop wise addition of ethyl 2-bromoacetate (8.9 ml; 80 58 mmol) over a period of 15-20 min. It was poured over crushed ice, and extracted with EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5-10% CH3CN in chloroform). Yield, 18.5 g (84.55%), oil; MS (ESI): 344 (M++Na), 322 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 40 (0.105 g, 0.345 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added in one portion. The mixture was stirred at room temperature for 2 h, and then concentrated under vacuum to dryness. The crude residue was used directly without further purification. 1H NMR (300 MHz, CD3OD): δ 1.60-1.75 (m, 4H), 2.65 (t, 2H), 2.92 (t, 2H), 4.38 (s, 2H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (APCI): 205 [C12H16N2O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 621.0 [(M−H)−]; mp 265° C.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:32]CC>>[CH2:16]([O:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[CH:4]([OH:32])[CH3:3])[N:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1cccc2nc(OCc3ccccc3)ccc12
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1cccc2nc(OCc3ccccc3)ccc12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
(2-Benzyloxy-quinolin-5-yl)-acetic acid methyl ester (0.198 g, 0.64 mmol) was dissolved in 10 mL of anhydrous ether, and cooled to −10° C. Lithium aluminum hydride (1.0M solution in ether, 0.5 mL, 0.5 mmol) was added and stirred at −10° C. for 1 h. The reaction was quenched with 0.5 mL water, then 0.5 mL 15% NaOH, then 1.5 mL water. A solution of Na, K tartrate was added to help solublized the salts. Ethyl acetate was added and the layers were separated. The aqueous layer was washed with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and rotovapped. (2-Benzyloxy-quinolin-5-yl)-ethanol (0.140 g, 78%) was used without further purification. MS m/z 280 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH2:11]([NH:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:12]([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][N:15]([CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)CN(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
A solution of 3,5-dichlorobenzaldehyde (0.79 g, 4.5 mmol, 3 eq) in 1,2-dichloroethane (2 ml) is added to a solution of tert-butyl (2S)-2-[(isobutylamino)methyl]pyrrolidine-1-carboxylate (0.38 g, 1.5 mmol, 1 eq) in 1,2-dichloroethane (8 ml) followed by a solution of sodium triacetoxyborohydride (0.95 g, 4.5 mmol, 3 eq) in DMF (2 ml). After 16 hrs water (5 ml) followed by 2N aqueous sodium hydroxide (5 ml) is added. The biphasic mixture is passed through a hydrophobic frit to separate the organic layer. Methanol is added to the organic layer and the solution is loaded onto a SCX-2 (10 g) column. The column is washed with methanol (50 ml) and then the basic material is eluted with 2M ammonia in methanol (50 ml). The solvent is removed in vacuo to give the tert-butyl (2S)-2-{[(3,5-dichlorobenzyl)(isobutyl)amino]methyl}pyrrolidine-1-carboxylate (0.61 g, 98%). LCMS: Rt=4.17 (6 min method) [M+H]=415.4.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[CH:8][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Bromopropane (701 μl) was added to a suspension of 2-bromo-5-hydroxypyridine (1.0 g) and potassium carbonate (2.38 g) in N,N-dimethylformamide (19 ml), and stirred at 80° C. for four hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (1.05 g) as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH:16]1[CH2:18][CH2:17]1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].[O:19]1[CH2:25][CH:24]([OH:26])[CH2:23][NH:22][CH2:21][CH2:20]1>CC#N>[CH:16]1([O:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[S:2]([N:22]2[CH2:23][CH:24]([OH:26])[CH2:25][O:19][CH2:20][CH2:21]2)(=[O:4])=[O:3])[CH2:18][CH2:17]1
Reactant: OC1CNCCOC1
Reactant: COC(=O)c1ccc(OC2CC2)c(S(=O)(=O)Cl)c1
Solvent: CC#N
Product: COC(=O)c1ccc(OC2CC2)c(S(=O)(=O)N2CCOCC(O)C2)c1
Temperature: 28 °C
Yield: 57.8 %

Procedure:
To a solution of methyl 3-chlorosulfonyl-4-(cyclopropoxy)benzoate (840.00 mg, crude, 2.89 mmol, 1.00 eq) in MeCN (10.00 mL) were added 1,4-oxazepan-6-ol (338.49 mg, 2.89 mmol, 1.00 eq) and TEA (584.88 mg, 5.78 mmol, 2.00 eq). The resulting mixture was stirred at 28° C. until the starting material was consumed. The solvent was removed and the residue was purified by chromatography (silica gel, eluting with PE:EA=3:1) to give desired compound methyl 4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoate (620.00 mg, 1.67 mmol, 57.76% yield) as white solid. LCMS: 372 [M+1].
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[C:16]([F:26])[CH:15]=2)=[CH:4][CH:3]=1.[CH:28](B(O)O)=[CH:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[F:26][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=1)[C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:3][CH:4]=1)=[O:27]
Reactant: CCCCC=CB(O)O
Reactant: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCC=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Yield: 107.6 %

Procedure:
N-(4-Bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide (2.5 g, 5.8 mmol), 1-hexenyl boronic acid (1.06 g, 8.3 mmol), cesium carbonate (3.04 g, 9.34 mmol) and tetrakis triphenylphosphine palladium(0) (100 mg) in dioxane (22 ml) are heated to 100° C. under nitrogen for 24 hours. The mixture is then poured into ethyl acetate (200 ml) and washed with water (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to give 3-fluoro-N-(4-hex-1-enyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide as a brown solid (2.7 g).
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:33])=[C:18]([CH2:20][NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[CH:19]=1)(OC(C)(C)C)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:46].Cl.Cl.Cl.O>>[ClH:33].[ClH:46].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:33])=[C:18]([CH2:20][NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Product: O=C(NCc1cc(OC[C@@H]2CCN2)cnc1Cl)c1cccc([N+](=O)[O-])c1
Yield: 37 %

Procedure:
The product of step 212a (0.18 g, 0.40 mmol) was deprotected and isolated as the free base in 37% yield according to the procedure of Example 20b, followed by conversion to the dihydrochloride with excess HCl/Et20. 1H NMR (D2O, 300 MHz) δ 2.62-2.71 (q, J=8.5, 17.0 Hz, 2H), 4.01-4.18 (m, 2H), 4.41 (d, J=4.0 Hz, 2H), 4.65 (s, 2H), 4.88 (m, 1H), 7.57 (d, J=3.0 Hz, 1H), 7.78 (t, J=3.0 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.61 (t, J=2.0 Hz, 1H); MS (CI/NH3) m/z 377 (M+H)+. Anal. Calcd for C17H17ClN4O4.2 HCl.H2O: C, 43.65; H, 4.53; N, 11.98. Found: C, 43.97; H, 4.54; N, 11.53.
Reaction SMILES: [CH:1]12[CH2:16][CH:12]([CH2:13][NH:14][CH2:15]1)[C:11]1[CH:10]=[C:9]3[C:4]([N:5]=[CH:6][CH:7]=[N:8]3)=[CH:3][C:2]2=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19]>CO>[C:22]([C@@H:20]([C@H:18]([C:17]([O-:26])=[O:25])[OH:19])[OH:21])([O-:24])=[O:23].[CH:12]12[CH2:16][CH:1]([CH2:15][NH:14][CH2:13]1)[C:2]1[CH:3]=[C:4]3[C:9]([N:8]=[CH:7][CH:6]=[N:5]3)=[CH:10][C:11]2=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: c1cnc2cc3c(cc2n1)C1CNCC3C1
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
One optimized procedure for making the anhydrous Form B comprises charging a speck-free vessel with between 1.1 and 2.2 equivalents of L-tartaric add and methanol (4 to 50 volumes), and stirring this mixture until dissolved and speck-free filtering the resulting solution into a crystallization vessel. 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene free base (1.0 equivalents) and methanol (4 to 50 volumes) are stirred in a vessel until dissolved at 0 to 50° C., more preferably at 20 to 25° C. The resulting solution of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene free base is then added over about a period of time ranging from 1 minute to 2 hours, more preferably over about 30 minutes, to the L-tartaric acid solution. The product was allowed to stir at 0 to 40° C., more preferably at 20 to 25° C., for between 1 and 48 hours, more preferably for about 1 hour, and then isolated by filtration. The product is dried generally under vacuum at 20 to 60° C., more preferably at 35 to 45° C., to give Form B of the L-tartrate salt of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene.