Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH2:14].CCN(CC)CC.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COc1ccc(F)c([C@@H]2C[C@H]2CN)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c([C@@H]2C[C@H]2CNC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a magnetically stirred solution of (trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropanemethanamine (600 mg, 3.1 mmol), Et3N (909 mg, 9.0 mmol), in dry dichloromethane (15 mL) at 0° C. was added isobutyryl chloride (352 mg, 3.3 mmol) dropwise. The resulting suspension was then allowed to warm to room temperature and stirred for 18 h. The solvents were removed and the residue was taken into EtOAc (100 mL) and washed sequentially with H2O, 5% citric acid, 5% K2CO3, brine, and dried over K2CO3. Concentration by rotary evaporation yielded a crude oil which was then purified by Kugelrohr distillation. Recrystallization of the resultant solid from Et2O/hexane (1:1) gave 380 mg (47% yield) of the title compound: mp 93°-94° C.; 1H NMR (300 MHz, CDCl3) δ0.82-0.88 (m, 1H), 0.97-1.03 (m, 1H), 1.13 (d, J=8.1 Hz, 6H), 1.14-1.24 (m, 1H), 1.85-1.91 (m, 1H), 2.25-2.30 (m, 1H), 2.93-3.02 (m, 1H), 3.52 (dt, I=7.8, 13.8 Hz, 1H), 3.72 (s, 3H), 5.74 (br s, 1H), 6.41-6.44 (m, 1H), 6.59-6.64 (m, 1H), 6.91 (t, J=6.5 Hz, 1H); IR (NaCl Film) 3298, 2962, 1642, 1546, 1502, 1428 cm-1 ; MS (isobutane--DCI) m/e 253; Analysis calc'd for C15H20NO2F: C, 67.90; H, 7.60; N, 5.28; found: C, 68.18; H, 7.77; N, 5.24.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([O:22]C)=[CH:17][CH:18]=2)[O:13][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=2)[O:13][CH:12]=1
Reactant: COc1ccc(-c2coc3cc(OC)ccc3c2=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccc(O)cc2O)coc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
At 0° C., a solution of 14 (1.0 g, 3.2 mmol) in CH2Cl2 was treated with BBr3 (16 mL, 16 mmol, 1 M in CH2Cl2) and the reaction mixture was allowed to stir at rt for 18 h. The reaction was quenched slowly with MeOH, concentrated and taken up in EtOAc. The EtOAc layer was washed with 2N HCl aq. And the EtOAc was dried over MgSO4, filtered, concentrated and chromatographed on silica gel (EtOAC/hexanes; 1:1) to yield 15 as a white solid (0.5 g).
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:11]=32)[CH2:7]1)=O)C.[OH-].[K+]>CCO.C(Cl)Cl>[Cl:17][C:16]1[C:10]2[CH2:9][CH:8]3[CH:12]([C:11]=2[S:14][C:15]=1[CH3:18])[CH2:13][NH:6][CH2:7]3
Reactant: CCOC(=O)N1CC2Cc3c(sc(C)c3Cl)C2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1sc2c(c1Cl)CC1CNCC21

Procedure:
The product of step d) was treated with 40% aqueous KOH in EtOH at 105° C. for 16 hours. The reaction was cooled, diluted with CH2Cl2 and passed through an extrelut column to remove the water. The organic layer was concentrated and the residue purified by preparative LC/MS to give the title compound. MS calculated for C10H12ClNS+H 214, observed 214.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:26]([N:34]2[CH2:45][CH2:44][N:43]3[C:36](=[CH:37][C:38]4[CH2:39][C:40]([CH3:47])([CH3:46])[CH2:41][C:42]=43)[C:35]2=[O:48])=[N:27][CH:28]=[CH:29][C:30]=1B(O)O)(=[O:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:34]2[CH2:45][CH2:44][N:43]3[C:36](=[CH:37][C:38]4[CH2:39][C:40]([CH3:47])([CH3:46])[CH2:41][C:42]=43)[C:35]2=[O:48])=[N:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccn3ccnc3n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccn4ccnc4n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 27 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 199b (500 mg, 1.5 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1200 mg, 3.0 mmol), Pd(dppf)Cl2 (65 mg, 0.075 mmol), K3PO4 (650 mg, 3.0 mmol), sodium acetate trihydrate (420 mg, 3.0 mmol), water (6 drops), and acetonitrile (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 199f (240 mg, 40%) as a yellow-brown solid. MS-ESI: [M+H]+ 593.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]2[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1>O1CCOCC1>[N:1]1([C:8]2[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(N3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of piperazine (7.0 g) in 1,4-dioxane (100 ml) was added a solution of crude 4,6-dichloro-pyrido[3,2-d]pyrimidine in 1,4-dioxane (50 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a methanol/dichloromethane mixture (in a ratio gradually ranging from 1:10 to 1:5), resulting in the pure title compound as a yellowish solid (3.1 g, yield 76%) which was characterized by its mass spectrum as follows: MS (m/z): 250.1 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]3[C:16]([CH3:24])([C:21]([NH2:23])=[O:22])[CH2:17][C:18]([CH3:20])([CH3:19])[C:12]3=[C:11]2[CH3:25])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:26]O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([CH3:15])=[C:13]3[C:16]([CH3:24])([C:21]([NH2:23])=[O:22])[CH2:17][C:18]([CH3:19])([CH3:20])[C:12]3=[C:11]2[CH3:25])=[CH:8][CH:9]=1)([O:3][CH3:26])=[O:2]
Reactant: Cc1c2c(c(C)n1-c1ccc(C(=O)O)cc1)C(C)(C(N)=O)CC2(C)C
Reactant: CO
Product: COC(=O)c1ccc(-n2c(C)c3c(c2C)C(C)(C(N)=O)CC3(C)C)cc1

Procedure:
Reaction of the 2-(4-carboxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide described above in Example 20BZ with methanol in the presence of a small amount of a mineral acid affords 2-(4-carbomethoxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH2:12][OH:13])[C:10]#[N:11].[OH:14][CH2:15][CH2:16]C#N>>[C:15]([O:13][CH2:12][CH:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]#[N:11])(=[O:14])[CH3:16]
Reactant: N#CCCO
Reactant: N#CC(CO)c1cc(Cl)ccc1Cl
Product: CC(=O)OCC(C#N)c1cc(Cl)ccc1Cl

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2,5-dichlorophenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-2,5-dichlorophenyl)-3-hydroxypropanenitrile is described in Example 4. The recovered ester product was a white solid (92% yield), m.p. 79-80.5° C.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:15]=[O:16])[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:17][O:18][C:19](=[O:24])[CH2:20][N+:21]([O-:23])=[O:22].C(OCC)(=O)C.Cl>CCO.N1CCCCC1>[CH3:17][O:18][C:19](=[O:24])[CH:20]([N+:21]([O-:23])=[O:22])[CH:15]1[C:13]2[C:14]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[C:3](=[O:4])[O:16]1)[CH:10]=[CH:11][CH:12]=2
Reactant: COC(=O)c1cccc2cccc(C=O)c12
Reactant: COC(=O)C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(C1OC(=O)c2cccc3cccc1c23)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 8-formylnaphthalene-1-carboxylic acid methyl ester (2.5 g, 11.68 mmol) in EtOH (20 mL) is added 8 drops of piperidine followed by nitroacetic acid methyl ester (2.78 g, 23.4 mmol) and the mixture is stirred at RT for 20 h. Ethyl acetate is added followed by 1N HCl. The resulting precipitate is filtered to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:20]=O)[CH3:2].[NH2:22][C:23]1[C:24]([CH2:32][CH2:33][CH3:34])=[N:25][N:26]([CH3:31])[C:27]=1[C:28]([NH2:30])=[O:29]>[Pd].C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:30][C:28](=[O:29])[C:27]2[N:26]([CH3:31])[N:25]=[C:24]([CH2:32][CH2:33][CH3:34])[C:23]=2[N:22]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C=O
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 200 °C
Reaction time: 46 h

Procedure:
A solution of xylene (60 mL) containing 1-(4-ethoxy-3-formylphenylsulfonyl)-4-methylpiperazine (4.0 g, 0.013 mol, prepared analogously to the methods described in DE 24 44 720) and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (Example 37 of EP 0463756) (2.6 g, 0.014 mol) was submitted to 46 hours at 200° C. and 34.5 kPa (5 psi). The reaction was allowed to cool and the catalyst (10% Pd/C, 3.1 g, 50% w/w) was added. The reaction was heated at 200° C. under 34.5 kPa (5 psi) of pressure for a further 12 hours. The catalyst was recovered by filtration and the organic solvent removed in vacuo to give 4.2 g of crude product, which was purified by trituration in methyl ethyl ketone (MEK). This yielded 3.3 g (53%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]Br.[CH3:12][C@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16][C:15](=[O:24])[NH:14]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:14]1[C@@H:13]([CH3:12])[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:16][C:15]1=[O:24]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: COc1ccc(Br)c(CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: 2-bromo-5-methoxybenzyl bromide and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27]O)=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:27][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCCC2
Product: CCOC(=O)CCc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 4D] and 4E], 3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 5B]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)CCC.O1CCOCC1>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.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Temperature: 110 °C
Yield: 45.3 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.15 g, 0.66 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.066 mmol) and then purged with N2 (g) inlet prior to addition of 4-(tributylstannyl)thiazole (0.42 g, 1.13 mmol), dioxane (1.2 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (71 mgs, 45%) Retention time (min)=1.656, method [4], MS(ESI) 238.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[ClH:9].ClCl.S(=O)(O)[O-].[Na+].[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([Cl:9])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cl
Agent: ClCl
Agent: O=S([O-])O
Agent: [Na+]
Product: Nc1ncc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To produce 2-amino-3-chloro-5-bromopyridine, chlorine is slowly introduced in the course of 8 hours at about 50° C. into a solution of 25 parts of 2-amino-5-bromopyridine in 70 parts of concentrated hydrochloric acid. After complete reaction, the solution is poured into ice-water, and the unreacted chlorine is decomposed with sodium bisulphite. Whilst ice is added, the solution is adjusted at 15° with 30% sodium hydroxide solution to pH 8 and subsequently stirred for one hour; the precipitate is then filtered off and washed with water. Recrystallisation from cyclohexane yields 28.5 parts (95.4% of theory) of 2-amino-3-chloro-5-bromopyridine in the form of white needles, m.p. 94°-96° C.
Reaction SMILES: C([N:20]1[N:24]=[N:23][C:22]([C:25]2([C:33]#[N:34])[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:26]2)=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.C1COCC1.O=[Pt]=O>[NH:23]1[C:22]([C:25]2([CH2:33][NH2:34])[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:26]2)=[N:21][N:20]=[N:24]1
Reactant: N#CC1(c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC12CCCCC2
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCC1(c2nnn[nH]2)CC12CCCCC2
Reaction time: 20 h
Yield: 80.7 %

Procedure:
To a solution of the 1-(2-trityl-2H-tetrazol-5-yl)-spiro[2.5]octane-1-carbonitrile (2.40 g, 2.39 mmol) in 100 mL MeOH:THF (1:1) was added PtO2 (0.15 g), concentrated HCl (1.67 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 20 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2) furnished 0.40 g (36%) of C-[1-(1H-tetrazol-5-yl)-spiro[2.5]oct-1-yl]-methylamine as a colorless solid. 1H NMR (CD3OD) δ 3.77 (d, J=13.2 Hz, 1H, —CH2H2), 3.07 (d, J=13.2 Hz, 1H, —CH2H2), 1.66 (m, 1H), 1.53 (d, J=5.1 Hz, 1H, cyclopropyl —CHH), 1.47-1.59 (m, 4H), 1.22-1.42 (m, 3H), 1.06 (m, 1H), 0.97 (m, 1H), 0.88 (d, J=5.1 Hz, 1H, cyclopropyl —CHH). 13C NMR (CD3OD) δ 161.18, 31.61, 31.51, 26.00, 25.76, 25.30, 24.78, 21.67. LRMS: m/z 206.1 (M−1). Anal. Calc'd for C10H17N5: C, 57.95; H, 8.27; N, 33.79. Found: C, 56.83; H, 8.24; N, 33.40.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[N:19]=[C:18]([CH3:34])[N:17]=2)C(=O)OC(C)(C)C)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[CH3:34][C:18]1[N:17]=[C:16]([NH:8][CH2:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:21]=[C:20]([O:22][CH2:23][C@H:24]2[CH2:26][C@@H:25]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[N:19]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C)s3)C(=O)OC(C)(C)C)nc(C)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)nc(C)n2)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of 2-2 (51.0 mg, 0.11 mmol) in MeOH (0.53 mL) was added K2CO3 (17.5 mg, 0.13 mmol). The resulted suspension was stirred at 70° C. for 2 hour. The mixture was diluted with EtOAc, and then extracted with 1N HCl. The aqueous layer was basified with 5N NaOH and extracted with DCM three times. The combined DCM layers were dried over Na2SO4 and concentrated to give 2-3″ as an off white solid (29 mg, 72%). MS (M+H)+: observed=383.1654, calculated=383.1649. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.82 (br t, J=5.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 5.64 (s, 1H), 4.76 (d, J=5.0 Hz, 2H), 4.23 (m, 1H), 4.14 (m, 1H), 2.65 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.09 (m, 1H), 1.71 (m, 1H), 1.12 (m, 1H), 0.98 (m, 1H)
Reaction SMILES: CC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:39]=[CH:38][C:20]([O:21][C:22]4[CH:31]=[C:30]5[C:25]([CH:26]([C:32]([O:34]C)=[O:33])[CH2:27][CH2:28][O:29]5)=[CH:24][C:23]=4[C:36]#[N:37])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)=CC=1.O[Li].O.O1[CH2:48][CH2:47]OCC1.Cl>C1COCC1>[C:36]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:22]=1[O:21][C:20]1[CH:38]=[CH:39][C:17]([C:15](=[O:16])[NH:14][C:11]3[CH:10]=[C:9]([C:8]4[CH:13]=[CH:12][C:47]([CH3:48])=[CH:10][CH:9]=4)[CH:8]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[O:29][CH2:28][CH2:27][CH:26]2[C:32]([OH:34])=[O:33])#[N:37]
Reactant: C1COCCO1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C)cc5)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 187.5 %

Procedure:
A mixture of methyl 7-(4-(4′-methylbiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (33 mg, 0.063 mmol), 1M solution of LiOH—H2O (127.3 μl, 0.127 mmol), and THF (1.5 ml) was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (47.73 μL, 0.190 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 29.8 mg of the title compound as a white solid (93%). MS (apci) m/z=505.1 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#N)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl.[OH2:28]>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Diisobutyl-aluminum hydride (86 mL of a 1 M solution in methylene chloride, 86 mmol) was added under nitrogen dropwise over 1 h to a solution of 4′-methoxy-1,1′-biphenyl-4-carbonitrile (15.0 g, 71.7 mmol), prepared in the previous step, in 500 mL of methylene chloride at ice bath temperature. After the addition the ice bath was removed and the reaction was stirred at room temperature for 1 h. By TLC starting material remained. The reaction was cooled to ice bath temperature and an additional 60 mL (60 mmol) of the diisobutylaluminum hydride was added dropwise over 1 h. After the addition the reaction was stirred at room temperature for 16 h. At room temperature 2 N HCl was added slowly until the reaction was acidic. Additional water and methylene chloride were added and the mixture filtered. The organic layer was then separated and the aqueous layer extracted multiple times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 4′-methoxy-1,1′-biphenyl-4-carbaldehyde (12.5 g, 82%) as a pale yellow solid, MS (EI) m/z 212. Elemental Analysis for C14H12O2. Calc'd: C, 79.23; H, 5.70; N, 0.00. Found: C, 77.92; H, 5.87; N, 0.00
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][OH:17].N1C=CC=CC=1>O>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][O:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COCCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
4-Methyl-benzenesulfonyl chloride (21 g, 110.0 mmol, 1.1 equiv.) was added at 0° C. to a solution of 3-methoxy-propan-1-ol (9 g, 100.0 mmol, 1.0 equiv.) in pyridine (16.1 ml, 200.0 mmol, 2.0 equiv.). After 1 hr at 0° C. a white solid was formed. It was diluted with water and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and crystallized from ether (hygroscopic) to give toluene-4-sulfonic acid 3-methoxy-propyl ester, 21.4 g, m/e 245.0 (MH+).
Reaction SMILES: [Li]CCCC.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH:21]1([CH2:26]I)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)[CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 1 L round bottom flask containing 250 mL of 9:1 THF/DMPU at −78° C. are added under nitrogen 11 mL (78.6 mmol) anhydrous DIEA followed by rapid addition of 32 mL of 2.5 M n-BuLi in hexanes. After 10 min at −78° C. a solution of 15.4 g (74 mmol) of p-nitrophenylacetic acid, ethyl ester in 100 mL of 9:1 THF/DMPU is added dropwise over 30 min. A deep purple solution results, and the reaction mixture is stirred at −78° C. for 30 min and then cyclopentyl methyl iodide (17.6 g, 78 mmol) in 50 mL of 9:1 THF/DMPU is added. The reaction is stirred while warming slowly to RT overnight. The mixture is poured into 1 L of 1 N HCl and extracted twice with MTBE. The combined MTBE extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and reduced to an orange oil. Flash chromatography over silica eluting with 4:1 hexane/MTBE affords 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester as an orange oil: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.2 (t, 3H, J=7.2), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8), 4.1 (m, 2H), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8); LC/MS 290 (M−1).