Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[C:18]=2[CH:19]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Temperature: 0 °C

Procedure:
95 G. of 1-carbethoxy-4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine are stirred together with 1,000 ml. of ethyleneglycol, 77 g. of potassium hydroxide and 10 ml. of water on a bath of 160° for 6 hours. The reaction mixture is poured over ice water and extracted with ether. The ether extract is washed with water, dried and evaporated, whereby 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine is obtained as a red-brown viscous oil. After recrystallization from acetone/petroleum ether the product is obtained as crystals having a melting point of 125°-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH4+:15].[OH-]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [OH-]
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A 0° C. solution of 4-chloro-3-nitrobenzenesulfonyl chloride (12.8 g, 50.0 mmol) in diethyl ether (1 L) was slowly treated with 0° C. concentrated NH4OH (50 mL) and stirred for 30 minutes. The organic layer was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 90.1 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (3.00 g, 10.46 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (2.76 g, 11.51 mmol) were refluxed in N-ethyldiisopropylamine (8 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (4.62 g) as an oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 90.1%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[C:28](O)[CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[N:23][N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[C:28]([O:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[N:23][N:24]=2)[CH:21]=1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[S:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[C:26]=3[O:33]C)(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[S:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[C:26]=3[OH:33])(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COc1c(C(=O)O)csc1S(=O)(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4scc(C(=O)O)c4O)c(C4CCCC4)c3)c2c1C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
At -78° C., to a stirred suspension of 5-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid (0.286 g, 0.426 mmol) in CH2Cl2 (2.86 mL) was added 1M BBr3 /CH2Cl2 (1.32 mL, 1.32 mmol). After the addition was complete the dry ice/acetone bath was replaced with an ice water bath and the reaction was stirred for 1 h. The reaction was quenched with crushed ice, diluted with H2O (40 mL) and extracted with EtOAc. The combined organic extracts were combined with product from an identical experiment and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 35% EtOAc/hexane gave 0.273 g (95%) of the title compound as a pale yellow solid, mp >230° C.; 1H NMR (DMSO-d6) δ 1.31-1.40 (m, 2 H), 1.47 (s, 3 H), 1.50-1.67 (m, 5 H), 1.80-1.83 (m, 1 H), 2.42 (s, 3 H), 3.32 (quintet, 1 H), 7.22 (dd, 1 H), 7.31-7.37 (m, 3 H), 7.48 (t, 1 H), 7.64 (t, 1 H), 8.19 (d, 1 H), 8.64 (s, 1 H). IR (KBr) 3400, 2950, 1650, 1375 and 1150 cm-1. mass spectrum (-ACPI), n/z 665 (M-H). Anal. Calcd. for C30H25BrO6S3.0.5H2O: C, 54.05; H, 3.93 N, 0.00. Found: C, 54.09; H, 3.98 N, 0.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Product: N#CC(=C(Nc1cccc(C#N)c1)NC1CCCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 16 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in cyclopentylamine (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 51 mg (16%) of the title compound as light brown crystals. 1H NMR (200 MHz, CDCl3): δ=1.43-1.54 (m, 4H), 1.68-1.78 (m, 4H), 3.64 (sextet, 1H), 7.07 (d, 1H), 7.21 (s, 1H), 7.40-7.55 (m, 6H), 7.77 (dd, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: Cc1ccc(C)c(C(=O)Cl)c1

Procedure:
2,5-Dimethylbenzoyl chloride was prepared from reaction of 2,5-dimethylbenzoic acid and thionyl chloride as described in Example 8.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
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: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of methyl 6-chloropyridazine-3-carboxylate (36 mg, 0.2 mmol) in DME (6 mL) was added Pd(PPh3)4 (20 mg, 0.02 mmol) under N2. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one (96 mg, 0.2 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for another 2 h under N2. The reaction mixture was quenched by addition of H2O, and extracted by EtOAc. The combined organic phase was dried and concentrated to give the crude product, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-pyridazine-3-carboxylic acid (63 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][CH3:15].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 3-bromo-5-Iodo-benzoic acid (4.0 g, 12.2 mmol) in 100 mL of thionyl chloride was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then dissolved in 80 mL of CH2Cl2. Dimethylamine hydrochloride (1.5 g, 18.3 mmol) and DIPEA (4.3 mL, 24.5 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure and the crude material was purified by column chromatography (Isco™ 330 g) using 50% hexanes/EtOAc as eluting solvent to afford 3.8 g (88%) of 3-bromo-5-iodo-N,N-dimethyl-benzamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][CH2:17][CH2:18][CH2:19]N>>[CH3:15][O:16][CH2:17][CH2:18][CH2:19][NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: COCCCN
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COCCCNc1cccc([N+](=O)[O-])c1C#N
Yield: 83 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and 3-methoxypropylamine in 83% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.81 (m, 2H), 3.23 (s, 3H), 3.28-3.33 (m, 2H), 3.40 (t, J=5.6 Hz, 2H), 6.66 (t, J=4.8 Hz, NH), 7.30 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([S:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>ClCCl>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([S:7]([C:3]2[CH:2]=[C:1]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[CH:5][CH:4]=2)=[O:34])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Sc2cccc(-c3ccccc3)c2)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(S(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Yield: 87 %

Procedure:
At 0° C., to a solution of 500 mg (1.42 mmol) of compound (4a) and 5 mL of dichloromethane was added very slowly 1 equiv. of m-CPBA over 3 h. Sulfoxide formation was monitored by thin-layer chromatography. Purification was performed with a flash chromatographic column, and an amorphous powder of (4c) was obtained (87% yield). 1H NMR (500 MHz, CDCl3) δ 7.92 (br, 1H), 7.71 (d, 2H), 7.62-7.60 (m, 3H), 7.58-7.40 (m, 4H), 6.94 (s, 2H), 3.79 (s, 3H), 3.74 (s, 6H). MS (ESI) m/z 369.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][CH2:18][N:19]([CH3:20])[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: CNCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
500 mg (2.64 mmol) of 3-fluoro-5-(trifluoromethyl)benzonitrile, 338 mg (2.91 mmol) of N,N,N′-trimethylpropane-1,3-diamine and 767 mg (5.52 mmol) of potassium carbonate in 5.0 ml of DMSO were stirred at 110° C. for 8 h. The reaction mixture was then separated directly into its components by preparative HPLC (Method 12). The product fractions were freed from the solvent, the residue was suspended in ethyl acetate and the suspension was washed successively with saturated aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated. This gave 290 mg (38% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][C:3]2([NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])[CH2:4][CH2:5]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 1-(hydroxymethyl)cyclopropylcarbamate (290 g, 1.55 mol) in DCM (2900 mL) was added DMAP (227 g, 1.86 mol) followed by 4-methylbenzene-1-sulfonyl chloride (323 g, 1.69 mol) in several batches at 10° C. After 2 hours, the reaction mixture was washed with water (2×1000 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford {1-[(tert-butoxycarbonyl)amino]cyclopropyl}methyl 4-methylbenzenesulfonate. The material was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:35])[C@@H:6]([NH:16][C:17](=[O:34])[C:18]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:20]([C:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)=[N+]=[N-].[C:36]([O:39]CC)(=[O:38])[CH3:37]>C(O)(=O)C.[Pd]>[C:36]([OH:39])(=[O:38])[CH3:37].[NH2:1][CH2:4][C@@H:5]([OH:35])[C@@H:6]([NH:16][C:17](=[O:34])[C:18]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:20]([C:21]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])=[O:22])[CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN=[N+]=[N-])c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN)c1
Reaction time: 2 h

Procedure:
N1-[(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropyl]5-methyl-N3,N3-dipropylisophthalamide (XV, EXAMPLE 167, 0.3 g, 0.62 mmole) in ethyl acetate (20 ml) and acetic acid (5 ml) is placed in a Parr pressure bottle. Palladium on carbon (10%, 5 g) is added and the mixture shaken under hydrogen at 50 psi for 2 hours. The mixture is filtered through a diatomaceous earth and the filtrate is concentrated to give the title compound; MS (MH+)=462.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([O-])=O.O.NN>COCCO>[NH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:33]=[CH:34][CH:35]=[C:4]([NH2:1])[CH:5]=3)=[CH:9][CH:10]=2)([CH3:15])[CH3:16])=[CH:22][CH:21]=1
Reactant: CC(C)(c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: NN
Solvent: COCCO
Solvent: O
Product: CC(C)(c1ccc(Oc2cccc(N)c2)cc1)c1ccc(Oc2cccc(N)c2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In the second step, a 500 ml glass reaction vessel was charged with 100 grams (0.21 mol) of 2,2-bis[4-(3-nitrophenoxy)phenyl]propane, 10 grams of active carbon, 1 gram of ferric chloride hexa-hydrate and 300 ml of ethyleneglycol monomethylether. The mixture was refluxed with stirring for 30 minutes, followed by dropping 42 grams (0.84 mol) of hydrazine hydrate at 70°-80° C. during 2 hours, and stirred for further 5 hours at 70°-80° C. The resultant reaction mixture was cooled, filtered to remove the catalyst and 150 ml of ethyleneglycol monomethylether was distilled off. To the residual matter, 270 grams of 20% aqueous hydrogen chloride solution and 30 grams of sodium chloride were added, and cooled to 20°-25° C. with stirring. The separated crystals were filtered, dissolved into 30% aqueous IPA solution and neutralized with aqueous ammonia to separate crystals. The crystals were filtered, washed with water, dried and recrystallized from a mixture of benezene and n-hexane. Colorless crystals of 2,2-bis[4-(3-aminophenoxy)phenyl]propane thus obtained were 69.2 grams (75% yield) and had a melting point of 106°-108° C. and their analytical results were as follows.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-valine (217.1 mg, 1.00 mmol) was added 2.5 mL CH2Cl2, and pyridine (81 μL, 1.00 mmol). The solution was cooled to −15 C, and to the reaction was added cyanuric fluoride (450 μL, 5.0 mmol). The reaction remained clear, but turned yellow green. The reaction was stirred at −15° C. for 60 minutes, with the gradual formation of a precipitate and transition to pale yellow. Without warming, the crude reaction was poured over ice and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with ice-cold water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 222.2 mg of 25f as a white solid. FTIR (neat) 1844 cm−1.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:36]3[CH2:38][CH2:37]3)=[N:19][C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:21][C:22]=2[CH2:23][O:24][CH3:25])=[CH:11][C:10]=1C)([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH:36]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:10][CH:11]=3)=[C:22]([CH2:23][O:24][CH3:25])[N:21]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[N:19]=2)[CH2:37][CH2:38]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1COc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 85.5 %

Procedure:
A solution of 198 mg (0.385 mmol) 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml 1N LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude residue was suspended in Ethylacetate/heptane 1:19. The resulting crystals were filtered off to provide 170 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][C@H:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:27][C@H:26]([N:38]([C:43](=[O:47])[C:44](O)=[O:45])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]=1[NH:9][C:44](=[O:45])[C:43]([N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:26]1[CH2:27][C@@H:28]([C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH2:29][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:23])[CH2:25]1)=[O:47]
Reactant: COCCCCNc1cccc(OC)c1N
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCCCNc1cccc(OC)c1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
6-Methoxy-2-(4-methoxybutylamino)aniline (210 mg), {{(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}(2-methylpropyl)amino}(oxo)acetic acid (308 mg), HOBt (97 mg) and triethylamine (370 μl) were dissolved in 1,2-dichloroethane (15 ml), WSC.HCl (430 mg) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:8)-ethyl acetate was concentrated under reduced pressure to give the object product (240 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][NH:5][C:6]([NH2:8])=[O:7])[CH3:2].[C:13](O)(=[O:18])[CH2:14][C:15](O)=[O:16]>C(O)(=O)C>[CH2:1]([CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][N:5]1[C:13](=[O:18])[CH2:14][C:15](=[O:16])[NH:8][C:6]1=[O:7])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCC(CC)CNC(N)=O
Solvent: CC(=O)O
Product: CCCCC(CC)CN1C(=O)CC(=O)NC1=O
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 500 g of N-(2-ethylhexyl)urea and 36 g of malonic acid in 100 ml of acetic acid was heated at 80° C. and stirred for 4 hours. After allowing to cool, the acetic acid was removed under reduced pressure and extracted by adding 100 ml of water and 500 ml of chloroform. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and then washed with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure, the residue was washed with n-hexane and collected by filtration to obtain 64 g of N-(2-ethylhexyl)barbituric acid.