Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][N:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 4.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 6-aminonicotinonitrile (Oakwood) (0.09 g, 0.8°mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-pyridin-2-yl)-amide as a yellow solid (Yield 12 mg, 4%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18])(=[O:11])=[O:10].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]([CH3:29])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([NH:36][C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)=[O:18])(=[O:10])=[O:11]
Reactant: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.69 mmol) in dichloromethane (5 ml) was added dropwise over 1 minute to a stirred solution of 5-[(dimethylamino)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 63; 230 mg, 0.69 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (64.5 mg, 0.69 mmol) and diisopropylethylamine (0.12 ml, 0.69 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 mL) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 170 mg.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[NH2:28][C:25]1[C:24]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:23][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[C:9]2[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=2)=[CH:27][N:26]=1
Reactant: Nc1ccc(-c2ccc3nccc(-c4ccncc4)c3c2)cn1
Reactant: O=S(=O)(O)Cl
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 47 %

Procedure:
To cold (0° C.) chlorosulfonic acid (15 mL) under vigorous stirring was added 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine (4.348 g, 14.57 mmol) portionwise. The reaction mixture was then heated at reflux for 16 hrs. Upon cooling to room temperature, LCMS indicated 47% of the title compound MS(ES)+ m/e 396.9 [M+]+ and 37% of sulfonic acid by-product MS(ES)+ m/e 379.1 [M+]+. A 2 mL aliquot of this 0.456M solution of the title compound was used in the next reaction without further workup.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=2)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=2)=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: O=S([O-])OO
Reactant: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (I), a solution of Oxone® (3.68 g, 6.00 mmol) is dissolved in a minimum amount of water (30.0 mL) and is added to a cold solution (0° C.) of 512 (0.63 g, 2.0 mmol) dissolved in a minimum amount of methanol (200 mL). Workup and purification by flash chromatography affords 3 as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: NCCCO
Solvent: O
Product: CCOC(=O)CNCCCO
Temperature: 7.5 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
3-Aminopropan-1-ol (154 g; 2.05 mol) is cooled to −5° C. Ethyl bromoacetate (143.6 g: 817 mmol) is added dropwise over a period of 1.5 hours maintaining the temperature around 5-10° C. The stirring is continued for 10 minutes. LC-MS showed that all ethyl bromoactetate has reacted. Then water (570 ml) is added to the reaction mixture. The aqueous mixture is washed three times with ethylacetate (3 times 140 ml). The combined organic phases are back extracted with water (2 times 140 ml). The aqueous phases are combined and saturated with sodium chloride (255 g). The aqueous solution is extracted with methylene chloride (6 times 750 ml). The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. A yellow oil is obtained (83 g; yield 63%)
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:22]([C:29]1[O:33][C:32]([NH2:34])=[N:31][N:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C:29]1[O:33][C:32]([NH:34][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:10]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:2]=2[Cl:1])=[N:31][N:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Reactant: Nc1nnc(Cc2ccccc2)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nnc(Cc3ccccc3)o2)c(Cl)c1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90 mg (0.26 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoic acid and 45 mg (0.26 mmol) of 5-benzyl-1,3,4-oxadiazol-2-amine are dissolved at room temperature (RT) in 8 ml of CH2Cl2. Then 248 mg (0.398 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.181 ml (1.3 mmol) of triethylamine, 6 mg (0.052 mmol) of 4-dimethylaminopyridine are added. Then the mixture is stirred at RT for 20 h and washed twice with 4 ml each time of water, dried over Na2SO4 and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 70 mg (45%).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.C[O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH3:29]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@@H:27]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH3:29])[C:26]([OH:25])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(=O)O

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.22 min. MS (ESI−): mass calcd. for C23H17Cl3N4O5S2, 597.97; m/z found, 597/599 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.26 (s, 1H), 8.36 (d, J=7.0, 1H), 8.21 (d, J=8.8, 1H), 7.73-7.70 (m, 2H), 7.37 (d, J=8.3, 1H), 7.27 (m, 1H), 7.23 (d, J=6.4, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.96 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=8.6, 1H), 4.97-4.94 (m, 1H), 3.38-3.36 (m, 1H), 1.46 (d, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([NH2:16])=[O:15].C[Si]([N:21]=[C:22]=[O:23])(C)C>>[NH2:21][C:22]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([NH2:16])=[O:15])=[O:23]
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Product: NC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(3-chlorophenyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.C([O-])(O)=O.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19]>O.O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]2=[N:25][CH:1]=[CH:2][N:22]2[C:21]=1[CH3:26])=[O:19]
Reactant: COC(=O)c1sc(N)nc1C
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2nccn2c1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (29.3 mmol, 1.26 eq) in water (200 mL) is treated dropwise with conc. hydrochloric acid (3.0 mL), stirred for 14 h at RT and heated for additional 30 min at 80° C. After cooling to RT NaHCO3 (37.9 mmol) is added carefully and the mixture is stirred for 2 h and treated with 2-Amino-4-methyl-thiazole-5-carboxylic acid methyl ester (23.2 mmol, 1.00 eq). After 1 h dioxane (130 mL) is added and the mixture is stirred at RT for 30 min and at 100° C. for 48 h. The organic solvents are removed in vacuo and the mixture is extracted several times with DCM and chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give the desired ester which is used without further purification. LC-MS: tR=0.55 min; [M+H]+=197.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[O:29]C(=O)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].C(=O)(O)[O-].[Na+]>C(O)C.O>[ClH:34].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[OH:29])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]

Procedure:
A suspension of N-(1-benzylpiperid-4-yl)-2-acetoxy-4-acetamido-5-nitrobenzamide (4.5 g; 0.01 mol) [prepared by the procedure described in Example 1] in ethanol (25 ml), concentrated hydrochloric acid (4.5 ml) and water (50 ml) was boiled under reflux for 2 hours. The mixture was diluted with water, made alkaline with sodium bicarbonate and extracted with chloroform. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residue triturated with diethyl ether to give a solid which was treated with a saturated solution of hydrogen chloride in ethanol. After crystallization from ethanol, 3 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide hydrochloride were obtained, m.p. 248°-250° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:30][CH:31]=[O:32])#[N:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C=CC=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
To a solution of 3-cyanobenzaldehyde (4.5 g) in toluene (200 ml) was added (triphenylphosphoranylidene)acetaldehyde (13.6 g) and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant and then the product was recrystallized from a mixture of toluene and hexane to give the desired compound (3.09 g, yield 57%) as pale yellow needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:8]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Nc1cccnc1
Reactant: CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:3]1=2.[C:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([OH:27])=[O:26].[OH-].[K+]>>[O:16]=[C:14]([C:6]1[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)/[CH:15]=[CH:32]/[C:31]1[CH:34]=[CH:35][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 72 %

Procedure:
In a similar manner to that of Example 2b, by reacting 770 mg (2.4 mmol) of 1-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)ethanone with 320 mg (2.2 mmol) of 4-carboxybenzaldehyde and 1.2 mL (10 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m=780 mg; yield=72%; m.p.=242° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[CH3:32][Li].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26]([OH:31])([C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:32]
Reactant: [Li]C
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(C)(O)C(C)(C)C)c2)cc1
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-2,2-dimethylpropan-1-one (275 mg) in THF (5 mL) was added a solution (1.1 M, 1.7 mL) of methyllithium in diethyl ether at −78° C., and the mixture was stirred for 16 hr while allowing the temperature to gradually rise to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (182 mg) as a colorless oil.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(=O)N(C)C)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of dimethylcarbamic chloride (27.5 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[NH2:28])C.[OH-].[K+].Cl>C(O)C.O>[NH2:28][C:6]1[CH:7]=[C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
In a solution of 0.6 g of crude 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid ethyl ester in 7 ml of ethanol, a solution of 0.5 g of potassium hydroxide in 2.0 ml of water was added, and stirred at room temperature for 18 hours. After the completion of the reaction, 20 ml of ice water was added in the reaction mixture, adjusted to pH 2 to 3 with concentrated hydrochloric acid, and then extracted with ethyl acetate (20 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.6 g of crude aimed product as yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]#[N:18])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].CCN(CC)CC>CCO>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:18])[NH:21][OH:22])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2cccnc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1nc(C(=N)NO)c2cccnc21
Temperature: 65 °C

Procedure:
A mixture of (3-cyano-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester, hydroxylamine hydrochloride (8.28 g) and Et3N (22.6 mL) in EtOH (120 mL) was heated over night under N2 at 65° C. The resultant mixture was cooled to room temperature, filtered and the collected solid was washed with H2O (100 mL) and Et2O (50 mL×2) to afforded [3-(N-hydroxycarbamimidoyl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[C:12]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1)#[N:13]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(Br)ccc1O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)c1cc(C#N)ccc1O
Yield: 60 %

Procedure:
4-Bromo-2-isopropyl-phenol (500 mg, 2.3 mmol), Zn(CN)2 (270 mg, 2.3 mmol) and tetrakis(triphenylphosophine)palladium (237 mg) were mixed in DMF (1 mL) in a microwave reaction tube. It was reacted under microwave condition at 180° C. for 20 minutes. The mixture was filted and purified by by silica gel chromatography (40% -60% EtOAc/Hexane) to provide the title compound (220 mg, 60%). MS (DCI) m/z 162 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:41](N)(N)(=[O:43])=[O:42]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[NH:38][S:41](=[O:43])(=[O:42])[N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (8.0 mg, 0.014 mmol) and sulfamide (2.0 mg, 0.021 mmol) in pyridine (300 μL) was heated to 120° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature and diluted with 25 mL of EtOAc. The organic solution was washed with 1 N HCl (2×5 mL) and brine (1×5 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC with 25% EtOAc/hexanes afforded 4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine 1,1-dioxide. Rf=0.29 (25% EtOAc/hexanes). LCMS=641.1 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 7.58-7.85 (m, 5H), 7.35-6.86 (m, 4H), 4.82-4.94 (m, 2H), 3.54-4.42 (m, 6H), 2.71-2.91 (m, 2H), 1.11-1.26 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16]([OH:18])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]1[C:5]([C:16]([Cl:21])=[O:18])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Cl

Procedure:
D3 (43 mg, 0.17 mmol, 1.0 eq.) was heated in thionyl chloride (1 mL) for 4 h at 67° C. Solvent was removed in vacuo and the crude material was resolved in dry toluene and evaporated under reduced pressure again to yield D4. The crude material was used in the next step without further purification.