Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 32 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-methoxyphenethyl bromide. Yield: 32%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.78 (t, J=7.4 Hz, 2H), 3.50 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 4.02 (s, 2H), 5.16 (s, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 410.18; found 410.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: I.[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][N:17]=[C:18]([NH2:21])SC)=[CH:14][CH:15]=2)[N:10]=1)[NH2:4].[N:22]#[C:23][NH2:24].C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][NH:17][C:18]([NH2:21])=[N:24][C:23]#[N:22])=[CH:14][CH:15]=2)[N:10]=1)[NH2:4]
Reactant: N#CN
Reactant: CSC(N)=NCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CN=C(N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 24.5 %

Procedure:
A solution of 2-(diaminomethyleneamino)-4-[5-(2-methyl-3-isothioureido)methylfuran-2-yl]thiazole hydriodide (1.0 g), cyanamide (120 mg) and triethylamine (1.2 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 3 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1, V/V). Recrystallization from 20% methanol afforded 2-(diaminomethyleneamino)-4-[5-(2-cyanoguanidino)methylfuran-2-yl]thiazole (170 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][Cl:23])[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(#N)C>[ClH:23].[ClH:23].[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:35]3[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNC1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCCN3CCC(N(C)C)C3)cc2c1C(=O)OCc1ccccc1
Product: Cl
Yield: 93.9 %

Procedure:
5-(2-Chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.400 g, 1.163 mmol, 1 eq, Example 1, Step A) was suspended in dry acetonitrile (50 mL) under Ar. K2CO3 (0.320 g, 2.32 mmol, 2 eq) and KI (0.020 g, 0.116 mmol, 0.1 eq) were added followed by the addition of 3-(dimethylamino)pyrrolidine (0.198 g, 1.740 mmol, 1.5 eq). The reaction mixture was stirred and heated to reflux for 3 days. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.270 g (55%) of the indole-pyrrolidine was obtained as a white solid. This was converted to the .2HCl salt. LC/MS (ESI+) 422 (M+1); Anal. Calcd for C25H31N3O3.2HCl.2H2O.0.25AcOEt: C, 56.52; H, 7.11; N, 7.61; Found: C, 56.50; H,. 6.73; N, 7.23.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:11]1([NH:10][CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (1.05 g, 8.6 mmol) and aniline (821 μL, 9.0 mmol) in dichloromethane (35 mL) was added acetic acid (516 μL, 9.0 mmol). The reaction mixture was stirred at room temperature for 24 hours. Sodium triacetoxyborohydride (4.55 g, 21.5 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added to quench the reaction and the mixture was diluted with dichloromethane. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo to afford the title compound as a brown oil (1.7 g, quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: N#Cc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.25 g (9 mmol) of 4-cyanobenzaldehyde, 1.91 g (9 mmol ) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene under nitrogen were heated for 18 hours to give 2.58 g (86%) of SULF-7 as a white powder: IR (Nujol) 3400-2400 (br), 2224, 1682, 1605, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.35 (s, 1), 8.3-7.8 (m, 8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:23](=[O:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Ca+2].[H-].[CH3:29][N:30]=[C:31]=[O:32]>C1C=CC=CC=1>[C:23]([N:10]1[CH:11]([CH3:22])[CH2:12][C:13]2[CH:18]=[C:17]3[O:19][CH2:20][O:21][C:16]3=[CH:15][C:14]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][CH3:29])=[O:32])=[CH:3][CH:4]=2)=[N:9]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reactant: CN=C=O
Agent: [Ca+2]
Agent: [H-]
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
0.70 g (2 mmol) of the product of Example 15 was dissolved in benzene dehydrated over calcium hydride, 0.3 ml (5 mmol) of methyl isocyanate was added and the reaction mixture was stirred at 50° C. for 4 hours. The crystals formed after coling were filtered, washed with 3×3 ml of benzene, then triturated with 20 ml of hot benzene. The hot mixture was filtered, the precipitate was washed with 3×3 ml of benzene and dried to give 0.65 g (79.6%) of the aimed product, m.p.: 68°-170° C.(decomp.).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[Br:35])=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[Br:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2Br)c1N
Reactant: CCOC(OCC)OCC
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4Br)csc3c2=O)cc1
Yield: 23 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-bromophenyl)thiophene-2-carboxylate (1.4 g, 4.48 mmol), triethyl orthoformate (12 ml), p-anisidine (930 mg, 8.52 mmol), and acetic acid (1.2 ml) were used to give 422 mg (1.02 mmol, 23% yield) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:55][CH2:56][N:57]([C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])[CH2:58][CH2:59]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g (45.8 mmol) of pyridine-4-carboxylic acid were suspended with stirring in 150 ml of DMF. With further stirring, 6.93 g (68.5 mmol) of N-methylmorpholine and then a solution of 35.6 g (68.5 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 10.18 g (45.8 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 60 ml of DMF were added to this mixture. The mixture was stirred at room temperature for 24 hours, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([O:26][CH2:25][CH2:24][O:23][C:22]3[CH:27]=[CH:28][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Product: CCc1cc(CC)n2nc(OCCOc3ccc(Cl)cc3)nc2n1
Yield: 80 %

Procedure:
The title compound was prepared according to the experimentals described for Example 14 above from 2-methanesulfonyl-5,7-diethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-(4-chlorophenoxy)ethan-1-ol in 80% yield. EM (calc.): 346.1; MS (ESI) m/e: 347.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:6]([S:8]([NH:11][C:12](=[O:20])[C:13]([O:16]C(=O)C)([CH3:15])[CH3:14])(=[O:10])=[O:9])[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:6]([S:8]([NH:11][C:12](=[O:20])[C:13]([OH:16])([CH3:14])[CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)NS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(=O)(=O)NC(=O)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of acetic acid 2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonylamino)-1,1-dimethyl-2-oxo-ethyl ester (0.14 g, 0.21 mmol) in tetrahydrofuran (2 mL), methanol (0.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (0.020 g, 0.48 mmol). The resulting reaction mixture was stirred at ambient temperature overnight. Chromatography on silica gel of the reaction mixture provided the title compound (0.104 g, LRMS: 556.3).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C-]#N.[K+].[CH2:11]1[O:13][CH:12]1CO>C1(NC2C=CC(C3C=CC(NC4C=CC=CC=4)=CC=3)=CC=2)C=CC=CC=1>[C:1]([O:6][CH2:7][CH:12]1[O:13][CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCC1CO1
Reactant: C=C(C)C(=O)OC
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Product: C=C(C)C(=O)OCC1CO1
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
400 grams (4 moles) of methyl methacrylate, 4.74 (73 millimoles) grams of KCN and 0.118 gram (250 ppm) of N,N'-diphenylbenzidine in a 1 liter round bottom flask were heated to 90° to 100° C. with passage of air therethrough. Within one further hour there were charged 74 grams (1 mole) of glycidol and thereby the methyl methacrylate-methanol azeotrope withdrawn from the column head via a 1 meter Vigreux column at about 65° C. After 2.5 hours, the reaction was ended, which was shown by the increase of the head temperature. The sump was filtered free of potassium cyanide and washed with a little methyl methacrylate. After distilling off the methyl methacrylate there remained behind 132 grams of glycidyl methacrylate (93% yield). The product can be worked up by distillation for further purification (B.P.10, 71°-75° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C@@H:21]2O>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:21]3[C:22]4[C:18](=[C:17]([Br:16])[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O[C@H]1CCc2c1ccc(C(F)(F)F)c2Br
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21

Procedure:
The title compound is prepared from [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester and (S)-4-bromo-5-trifluoromethyl-indan-1-ol following a procedure analogous to that described in Step 2 of Intermediate 2. LC (method 5): tR=1.62 min; Mass spectrum (ESI+): m/z=471/473 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[I:15]N1C(=O)CCC1=O.C(#N)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[I:15][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:5][C:6]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(C)nc(N2CCOCC2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)nc(C)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4,6-dimethylpyrimidin-2-yl)morpholine (20.6 g, 107 mmol), N-iodosuccinimide (28.8 g, 128 mmol) and ACN (400 ml) is stirred at RT for 24 h. DCM and an aqueous solution containing 3% sodium thiosulfate is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. This material is used without further purification. Yield: 33.7 g (89%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.C(Cl)Cl.CO.[CH3:43][C:44]([CH3:46])=O>CC(O)=O>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:44]([CH3:46])[CH3:43])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h
Yield: 3.1 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was added acetone (100 μL, 1.36 mmol), borane-pyridine complex (100 μL, 0.8 mmol), and left to stir for 3 h. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (3.3 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.06 Hz, 4H) 1.05 (d, J=6.57 Hz, 2H) 1.44-1.80 (m, 6H) 1.95 (br. s., 2H) 2.27 (dt, J=12.32, 6.09 Hz, 1H) 2.89 (t, J=7.33 Hz, 2H) 3.50 (t, J=7.33 Hz, 1H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz, 2H) 4.29-4.42 (m, 1H) 4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]CC2C=CC(OC)=CC=2)=[CH:6][C:5]([Cl:18])=[CH:4][C:3]=1[O:19][CH3:20].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([Cl:18])=[CH:6][C:7]=1[SH:8]
Reactant: COc1ccc(CSc2cc(Cl)cc(OC)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O
Product: COc1cc(Cl)cc(S)c1Cl
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
The mixture of 2,5-dichloro-1-methoxy-3-((4-methoxybenzyl)sulfanyl)benzene (5.56 g) and anisole (9.18 mL) was added TFA (22.13 mL) at room temperature. The mixture was stirred at 80° C. for 20 min. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.38 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24].S(=O)(=O)(O)O>O>[OH:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[C:5]([Cl:9])[C:4]=1[CH:23]=[O:24]
Reactant: Oc1cc(Cl)c(F)cc1Br
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c(O)c(Br)cc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A mixture of 90.4 gm (0.40 mole) 2-bromo-4-fluoro-5-chlorophenol (containing 10% 2-bromo-3-chloro-4-fluorophenol) and 64 gm (0.45 mole) hexamethylenetetramine was cooled in an ice bath. To this cooled mixture were added 306 mL trifluoroacetic acid. After stirring at about 0° C. for 15 minutes, the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then cooled in an ice bath and treated with 439 mL of water followed by 220 mL 50% sulfuric acid. The reaction mixture was stirred without cooling for two hours. The reaction mixture was then diluted with 500 mL water and the resulting solid collected by filtration. The solid was washed with water until the wash was neutral (pH about 7). The solid was dried under reduced pressure and was then subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-2% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro-6-chlorobenzaldehyde.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]=[O:13]>ClCCCl>[CH2:12]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[OH:13]
Reactant: C=O
Reactant: O=C1NC(=O)c2ccccc21
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CO

Procedure:
Heterodisperse gel-type or macroporous anion exchangers are obtained, for example, by the phthalimide process according to U.S. Pat. No. 4,952,608, the contents of which are incorporated into the present application by reference. In this process, for example, phthalimide and formalin in 1,2-dichloroethane are first introduced and reacted to form N-methylolphthalimide. From this is produced bis(phthalimidomethyl) ether. First oleum, then polystyrene polymer beads crosslinked at 5% by weight are introduced. The suspension is heated to 70° C. and stirred for a further 18 hours. Dichloroethane is removed from the system by distillation. The resultant polymer beads are taken up in water, sodium hydroxide solution is added and the mixture is treated for 8 hours at 180° C. After they are cooled, the resultant aminomethylated polymer beads are extracted with water by washing.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: N
Product: Fc1cc(F)c(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.55 (td, J=10.3, 6.4 Hz, 1 H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.23 (ddd, J=10.3, 8.6, 6.4 Hz, 1 H), 8.56 (dt, J=8.1, 1.9 Hz, 1 H), 8.75 (dd, J=5.1, 1.7 Hz, 1 H), 9.29 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21]CC)=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([OH:21])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (320 mg, 0.647 mmol) was dissolved in a MeOH/THF/H2O (10 mL/10 mL/5 mL) mixture, LiOH (163 mg, 3.88 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification was achived by re-crystallization in hexane/ether mixture to give 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (220 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.01 (s, 2H), 4.44 (q, 2H), 3.68 (t, 1H), 1.98 (m, 2H), 1.61 (m, 1H), 1.54 (m, 1H), 0.95 (d, 6H)
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:16])[CH:9]([OH:15])[C:10]([CH3:14])([CH3:13])[CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N([CH2:22][CH3:23])CC)C.[C:24]1(C)[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=C[CH:29]=1.[H-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[CH2:11][C:10]([CH3:14])([CH3:13])[CH:9]([O:15][S:30]([C:25]3[CH:26]=[CH:27][C:22]([CH3:23])=[CH:29][CH:24]=3)(=[O:32])=[O:31])[C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(CO)C(O)C(=O)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2C(=O)N(C3CCCCC3)CC2(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Place N-cyclohexyl-2,4-dihydroxy-3,3-dimethyl-butyramide (2.178 g, 9.51 mmol), triethylamine (2.7 ml, 19.31 mmol) and toluenesulfonyl chloride (3.70 g, 19.21 mmol) in CH2Cl2 (50 mL) at 0° C. Stir for 30 minutes at 0° C. Quench with hexane and warm to room temperature. Filter white precipitate. Strip the solvent and dissolve the residue in 40 ml of dry THF under the nitrogen atmosphere. Add sodium hydride (3.4 g, 85 mmol) and stir at room temperature for 12 hours. Quench the reaction with methanol/water mixture. Extract with ethyl acetate. Wash the extract with brine and dry over magnesium sulfate. Purification by flash chromatography affords 1.25 g (36%) of the title compound: Mass spectrum (apci) m/z=366 (M+H).