Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:25]=[CH:24][C:12]([CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)C1CCN(CCc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
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: C1COCCO1
Product: O=C(O)C1CCN(CCc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid 21 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated in a microwave oven at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid A6. MS (m/z) (M+1)+: 469.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]([CH3:27])[C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([O:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[Cl:67])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[O:60][CH:57]1[CH2:56][CH2:55][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([CH3:10])[CH3:27])[CH:13]=3)=[CH:23][CH:22]=2)=[O:26])[CH2:59][CH2:58]1
Reactant: CN(C)c1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cccc(-c2ccc(C(=O)NCC(=O)N3CCC(Oc4ccccc4Cl)CC3)cc2)c1
Reaction time: 0.03 h
Yield: 22.2 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of to a stirred solution of 3′-dimethylamino-biphenyl-4-carboxylic acid (80 mg, 0.33 mmol) (generated from methyl 3′-amino(1,1′-biphenyl)-4-carboxylate) in DMF (2 mL) followed by HOBt (49 mg, 0.36 mmol) and EDCI (126 mg, 0.66 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (110 mg, 0.36 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 36 mg (22% Yield) of 3′-dimethylamino-biphenyl-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 492, 86.69%. 1H NMR (300 MHz, DMSO-d6): δ 8.6 (t, 1H), 8.0-7.9 (d, 2H), 7.8-7.7 (d, 3H), 7.5-7.4 (d, 1H), 7.36-7.24 (m, 3H), 7.1-7.0 (m, 2H), 7.0-6.94 (m, 1H), 6.88-6.8 (d, 1H), 4.8 (q, 1H), 4.2 (d, 2H), 4.0-3.7 (m, 4H), 3.5 (m, 3H), 3.0 (s, 6H), 2.0-1.8 (m, 3H), 1.8-1.6 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[SH:19].CO>C1(C)C=CC=CC=1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[SH:19].[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[S:19][C:12]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(I)cc1
Agent: COc1ccc(N)c(S)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
2-Amino-5-methoxythiophenol was prepared as set forth in C. A. Mathis, Y. Wang, D. P. Holt, G-F. Huang, M. L. Debnath and W. E. Klunk, “Synthesis and Evaluation of 11C-Labeled 6-Substituted 2-Arylbenzothiazoles as Amyloid Imaging Agents.” J. Med. Chem., 46, pp 2740-2754 (2003). 4-Iodobenzyl chloride (5.0 g, 18.8 mmol) was added to a hot solution of 2-amino-5-methoxythiophenol (2.32 g, 15.0 mmol) in toluene (75 mL) and the reaction mixture was stirred at 100° C. for 1 h. Methanol (1 mL) was then added to destroy the excess 4-iodobenzoyl chloride. The hot toluene solution was then passed through a pad of silica gel (˜15 g) in a Buchner funnel. The silica gel was rinsed a few more times with hot toluene. The filtrate upon concentration gave pure 2-(4-iodophenyl)-6-methoxy-1,3-benzothiazole (4) (1.65 g, 40%) as off-white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:36])[C:28]=2[CH:37]=1>CC(C)=O>[CH:2]1([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[C:16]([NH:22][S:32]([C:30]4[S:31][C:27]5[CH:26]=[CH:25][C:24]([Cl:23])=[CH:37][C:28]=5[C:29]=4[CH3:36])(=[O:34])=[O:33])[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:12][CH2:13]2)[CH2:7][CH2:6]1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(N)cc1N1CCN(Cc2ccccc2)CC1
Solvent: CC(C)=O
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(CC2CC2)CC1
Reaction time: 14 h
Yield: 42 %

Procedure:
To a solution of 3-(4-benzyl-piperazin-1-yl)-4-methoxy-phenylamine (D22) (1 mmol) in acetone (5 ml) was added 5-chloro-3-methylbenzothiophene-2-sulphonyl chloride (1 mmol). Stirring was continued at room temperature for 14 hrs. The hydrochloride salt of the sulphonamide was collected by filtration, triturated with diethyl ether and dried in vacuo in 42% yield. Found MH+ 506/508.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17](I)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:17]2[CH:16]=[N:15][C:11]3[NH:12][CH2:13][CH2:14][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[C:10]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: Clc1ncccc1CN1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1

Procedure:
1-(2-Chloropyridin-3-ylmethyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (389 mg) was reacted with (4-ethoxycarbonylphenyl) boronic acid as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z=409.34 (M+H+).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Cl:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Cl:11][C:9]1[N:8]=[C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:25][CH3:26])=[CH:17][C:16]=3[Cl:15])[CH2:21][CH2:22]2)[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 143-145° C.; 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 1 H), 6.77-6.72 (m, 2 H), 4.96-4.89 (m, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.76 (s, 3 H), 3.07 (t, J=7.7 Hz, 2 H), 1.74-1.64 (m, 2 H), 1.33 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.6 Hz, 3 H); HRMS (ESI) calcd for C17H20N3O2Cl2 (M+H)+: 368.0933; found m/z 368.0927.
Reaction SMILES: C(O[C:4]([CH:6]1[CH:14]2[N:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[C:15]1([Li])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.CCOCC>[C:15]1([C:4]([CH:6]2[CH:14]3[N:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:8][CH2:7]2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN2CCCCC12
Reactant: Brc1ccccc1
Reactant: [Li]c1ccccc1
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccccc1)C1CCN2CCCCC12

Procedure:
A solution of 2.40 g. of 1-ethoxycarbonylindolizidine in 20 ml. of dry ether was dropwise added to a solution of phenyl lithium prepared from 0.51 g. of metal lithium, 6.32 g. of bromobenzene and 50 ml. of dryether under ice cooling. After refluxing for about 10 mins., water was dropwise added to the reaction mixture. The mixture was extracted with ether. The ethereal layer was extracted with a diluted hydrochloric acid solution and the aqueous layer was adjusted to alkaline with a causting soda solution and then extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, 3.58 g. of yellowish viscous substance was obtained. This substance was crystallized. By recrystallization from isopropyl ether, colorless needles with a melting point of 120°-121° C. was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]#[N:13].[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:27][C@H:18]([CH2:17][CH2:16][N:15]([CH3:14])[CH3:28])[CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)#[N:13]
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1C#N

Procedure:
The title compound was prepared from 4-fluoro-3-(cyano)benzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: O=Cc1cccc(B(O)O)c1
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: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1

Procedure:
Prepared by a method analogous to that described in example 1 from (R)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-formylphenyl boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions. The aqueous layer was extracted by chloroform and evaporated to gave the title compound; MS (ES+) 341 (MH+)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23]>>[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])#[N:23]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2C#N)c1
Yield: 57.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (231 mg, yield: 57.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](Br)[CH:11]=1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH:22]=1)[CH:20]=[O:21].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:22][C:19]=2[CH:20]=[O:21])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(F)cc2C=O)OC1(C)C
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: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cncc(-c2ccc(F)cc2C=O)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(5-Bromo-pyridin-3-yl)-acetic acid ethyl ester (1.91 g, 7.8 mmol), 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (50% pure; 2.94 g, 11.75 mmol), and potassium carbonate (3.25 g, 23.5 mmol) were combined in 2:1 DME:H2O, and the solution was purged with N2 for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.39 mmol) was added, and the reaction was purged with N2 for another 25 minutes and then stirred at 75° C. for 2 hours. The mixture was worked up with EtOAc and H2O, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give [5-(4-fluoro-2-formyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH:29]=[CH2:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:43].[Na+].OO>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][CH2:30][OH:43])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1[C@@H](CCCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (61.5 mg, 0.13 mmol) in dry THF (1 mL) at 0° C. and argon is added dropwise a 9-BBN solution (0.57 mL, 0.5 M in hexane). After the addition is complete, the reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The mixture is then cooled to 0° C. and treated with a 3M NaOH (0.3 mL). The oxidation is carried out by slow addition of 35% H2O2 (0.3 mL) at 0° C. The reaction mixture is stirred at 0° C. for 1 h and then at room temperature overnight. The resulting solution is poured into ethyl acetate (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one (64 mg, 100%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.60-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.28-7.22 (m, 2H), 6.93-6.83 (m, 4H), 5.24 (dd, J=10.5, 3.0 Hz, 1H), 3.70 (t, J=7.2 Hz, 2H), 2.87-2.75 (m, 1H), 2.45-2.33 (m, 1H), 2.26-2.16 (m, 1H), 2.11-1.98 (m, 1H), 1.87 (s, br, 1H), 1.75-1.58 (m, 3H). HPLC-MS calculated for C26H23ClF3NO3 (M+H+) 490.13, found 490.10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)[CH:7]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: COc1ccccc1COc1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: COc1ccccc1COc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 56 %

Procedure:
The product of Example 37A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 37A for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (47 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.85 (d, J=6.62 Hz, 1H), 8.59 (s, 1H), 7.64 (s, 1H), 7.41 (dd, J=7.35, 1.47 Hz, 1H), 7.30-7.38 (m, 1H), 7.24 (s, 1H), 7.16 (d, J=8.46 Hz, 1H), 7.08-7.14 (m, 2H), 7.05 (d, J=8.09 Hz, 1H), 6.89-7.01 (m, J=7.54, 7.54 Hz, 2H), 6.61-6.71 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI−) m/z 481.2 (M−H)−.
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:18])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>C(Cl)(Cl)Cl>[P:4]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)=[O:18])([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(OCC)c1cc(Br)ccc1NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1P(=O)(O)O
Temperature: 40 °C
Yield: 70.6 %

Procedure:
To a 40 mL vial containing a stirring bar, 1-(2-Diethylphosphono-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea (1.2 g, 2.42 mmol) was added along with 15 mL of CHCl3. This was cooled in an ice bath and then bromotrimethylsilane (5.0 g, 32.7 mmol) was added slowly under N2 while stirring. The bath was removed after the addition and then the vial was sealed and heated at 40° C. for 2 days. The resulting solution was cooled in an ice bath and water was added dropwise (5 mL) followed by 10 mL of isopropanol. After 10 minutes the bath was removed and the reaction was stirred at room temperature for one day. The mixture was then diluted with 50 mL water and concentrated until a precipitate formed. The precipitate was filtered and then recrystallized from ethyl acetate to give 750 mg of 1-(2-Phosphono-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid. 1H-NMR (400 MHz, DMSO-D6): δ=7.27 (d, 8.0 Hz, 1H, CHCHCCF3), 7.43 (m, 1H, CHCHCCF3), 7.60 (m, 2H, CHCBrCH), 7.70 (dd, 15 Hz, 2H2, 1H, BsCCHCP) 7.90 (s, 1H, CHCF3), 8.05 (m, 1H). 31P (400 Mz, CDCl3) δ=13.41 (s).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][C:7]1([CH3:15])[CH2:13][C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(OCC)C>[CH3:3][CH:2]([CH3:4])[CH2:1][N:5]1[C:9](=[O:10])[CH2:8][C:7]([CH3:15])([CH3:6])[CH2:13][C:12]1=[O:11]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CC(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)CN1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was added slowly to 3,3-dimethylglutaric anhydride (14.2 g, 0.1 mol) stirring at room temperature in a two neck round bottom flask fitted with a water condenser. After 30 minutes, acetic anhydride (20.4 g, 0.2 mol) was added, and the resulting mixture was boiled for two hours. After cooling, the mixture was poured slowly on to an aqueous NaOH solution (2N, 100 ml) stirring at room temperature. After one hour, the mixture was diluted with diethyl ether (50 ml), and the organic layer was separated. The aqueous layer was washed with more diethyl ether (2×50 ml), and the combined organic layer dried and concentrated to give the title compound as a pale yellow oil which solidified on standing, m.p. 48°-52° C., yield 18.5 g (94%). The product was suffuciently pure by NMR spectroscopy to be used directly in the following procedure.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].CO>[C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)N1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N1CCC(N)CC1
Yield: 64.7 %

Procedure:
A solution of N-benzyl-1-tert-butylpiperidin-4-amine (1.56 g) and 10% palladium on carbon (2 g) in MeOH (250 ml) was hydrogenated in a Parr shaker at 50 psi for 16 hours. The solution was filtered and the reaction mixture reduced in vacuo, to yield 1-tert-butylpiperidin-4-amine (0.64 g) (LC/MS: Rt 02.31, no [M+H]+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:14][NH2:15].[NH3:16]>O>[NH2:16][N:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[NH:14][NH2:15]
Reactant: NN
Reactant: N
Reactant: Oc1nc(Cl)nc2ccccc12
Solvent: O
Product: NNc1nc2ccccc2c(=O)n1N
Temperature: 25 °C

Procedure:
A mixture of 134 g of the product of Step B and 670 ml of hydrazine hydrate was refluxed with stirring for about 5 hours until evolution of ammonia ceased and the mixture was cooled slightly and was diluted with 670 ml of water. The mixture was cooled to room temperature and was filtered and the product was rinsed with water and methanol and dried to obtain 101.5 of 3-amino-2-hydrazino-quinazolin-4(3H)-one.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[S:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[S:34]>C(O)(=O)C>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:38]3[S:32][C:33](=[S:34])[NH:35][C:36]3=[O:37])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C=O)cc2)ccc(C(C)=O)c1OC(C)=O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(OCc2ccc(C=C3SC(=S)NC3=O)cc2)ccc(C(C)=O)c1OC(C)=O

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(4-acetyl-3-acetoxy-2-propylphenoxy)methyl]benzaldehyde (70 mg, 0.20 mmol) was dissolved in acetic acid (1 ml). To this solution was added sodium acetate (59 mg, 0.72 mmol) and then rhodanine (27.5 mg, 0.21 mmol). The reaction mixture was then heated to reflux and the progress of the reaction was monitored by thin layer chromatography.