Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[Br:10][CH2:11][CH2:12][CH2:13][Cl:14].CO>C(OC)(C)(C)C>[Br-:10].[Cl:14][CH2:13][CH2:12][CH2:11][N+:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: CN(C)C1CCCCC1
Reactant: ClCCCBr
Solvent: CO
Solvent: COC(C)(C)C
Product: C[N+](C)(CCCCl)C1CCCCC1
Product: [Br-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A one-liter, 3-necked, Morton flask equipped with an air condenser and a magnetic stirring plate was charged with N,N-dimethylcyclohexylamine (210.06 grams, 1.65 moles), 1-bromo-3-chloropropane (259.99 grams, 1.65 moles) and methanol (250 mL). Reaction was maintained at 65° C. for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to yield a brown sludge. To the sludge was added tert-butylmethylether (600 ml) causing an oil to form. The liquid phase was decanted from the oil and a second portion of methyl-tert-butylether (600 ml) was added. The mixture was stirred and liquid phase was decanted off from a thick sludge. To the sludge was added diethylether (600 mL) causing a white, semi-solid layer to form. The mixture was stirred and a liquid phase was removed. A white solid was placed in a vacuum oven at 35° C. for 24 hours. Yield 404.9 grams (1.42 molest 85%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:28]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
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: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (20 mg, 0.043 mmol) and cyclohexen-1-ylboronic acid (13 mg, 0.103 mmol) in 2M Na2CO3 (1.3 mL) and DME (2.6 mL) for 6 min. Pd(PPh3)4 (4.4 mg) was added and the mixture was refluxed for 1 h and 30 min. It was cooled, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane:EtOAc—9:1 and 4:1 as eluents) yielding pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 50%).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:32]=[CH:31][C:13]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]([C:25]([O:27]C)=[O:26])[CH2:20][CH2:21][O:22]4)=[CH:17][C:16]=3[C:29]#[N:30])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.O[Li].O.O1CCOCC1.Cl>C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:32]=[CH:31][C:13]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][O:22]4)=[CH:17][C:16]=3[C:29]#[N:30])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5)c4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3cccc(-c4ccccc4)c3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of methyl 7-(4-(biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (55.6 mg, 0.1102 mmol) in THF (2 ml) was added 1M solution of LiOH—H2O (220.4 μl, 0.2204 mmol). The mixture was stirred for 1 hour at ambient temperature. The mixture was quenched with 4M HCl dioxane (82.65 μl, 0.331 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 40.4 mg of the title compound as a thin film (75%). MS (apci) m/z=491.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>CO.C(OCC)(=O)C>[S:28]([O:30][S:28]([OH:31])(=[O:30])=[O:29])([OH:29])(=[O:32])=[O:31].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)O
Agent: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(O)OS(=O)(=O)O
Temperature: 0 °C

Procedure:
3-(3-(4-(Pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-yl amine (150 mg) was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and concentrated sulfuric acid (0.026 mL) was added thereto. The solvent was concentrated under a reduced pressure, to the residue was added ethanol (10 mL), and dissolved by heating. Then, the solution was cooled to 0° C, concentrated sulfuric acid (0.026 mL) was added to be solidified. The solids were filtered to obtain the title compound (47 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:39][OH:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C=O.[Br:46][CH2:47][CH2:48]Br>C(Cl)Cl.O>[C:8]([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:39][O:40][CH2:48][CH2:47][Br:46])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
4.14 g of potassium carbonate were added over 3 minutes under argon at room temperature to a mixture of 4.94 g of syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetate hydrochloride and 10 ml of dimethylformamide, and after stirring the mixture at 20° C. for 20 minutes, 8.65 ml of 1,2-dibromoethane were added thereto. The mixture was stirred for 30 hours and was poured into 100 ml of distilled water and 20 ml of methylene chloride. The mixture was decanted and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried and vacuum filtered. The filter was rinsed and the filtrate was evaporated to dryness to obtain a raw product which was chromatographed over silica gel. Elution with benzene containing 5% of ether yielded a first fraction which was crystallized from methanol after dissolution at 50°-60° C. Vacuum filtration at 0° to 5° C. yielded 1.16 g of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate in the form of a white cream product melting at 117° C. Next obtained was a homogenous fraction of 1.258 g of product.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: C#C[C@@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-But-3-yn-2-ol (189 mg, 2.71 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (30 mg, 0.03 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 40 mg, 47%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:26][C:24]1[CH:23]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:29][CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3,5-dichlorophenyl)-piperazine.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[C:24]2=[C:25]3[C:13]([N:14]([Si](C(C)(C)C)(C)C)[CH:15]=[C:16]3[CH2:17][C@@H:18]3[C:23]2=[CH:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]3[CH3:34])=[CH:12][CH:11]=1>>[Cl:1][C:11]1[CH:12]=[C:13]2[C:25]3[CH:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:10]=1)[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]4[CH3:34])[CH2:15][NH:14]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(12-bromo-1-tert-butyldimethylsilyl-9,10-didehydro-6-methyl-8α-ergolinyl)1,1-diethylurea:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][NH:40][CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][N:40]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (5.8 mg, 0.054 mmol) was added to a solution of 2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (14.3 mg, 0.027 mmol) and triethylamine (11 μL, 0.080 mmol) in DCM (270 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (14.3 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H), 1.40-1.49 (m, 1H), 1.55-1.77 (m, 2H), 2.01 (d, J=13.1 Hz, 2H), 2.70-2.84 (m, 4H), 2.87-2.94 (m, 6H), 3.40-3.52 (m, 2H), 3.53-3.57 (m, 2H), 4.11 (quin, J=6.4 Hz, 1H) 4.29 (s, 2H) 5.53 (dd, J=46.2, 7.3 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([C:13](=[O:15])[CH3:14])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1cc(C)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1c(C)sc(C)c1C(C)=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of methyl 2,5-dimethyl-3-thiophene acetate (33.2 g, 0.18 mol) in CH2Cl2 (150 ml) was added to a solution of acetylchloride (15.5 ml, 0.216 mol) and tin (IV) chloride (23.2 ml, 0.198 mol) in CH2Cl2 (200 ml) at 0°-5° C. over a 15 minute period. The solution became a deep red color and was stirred at 0°-5° C. for two hours. H2O (200 ml) was added to the mixture, and the organic layer was separated, washed with saturated aqueous NaHCO3 (1×100 ml), dried over MgSO4, and treated with activated charcoal. The solvent was removed in vacuo to give the product (40.2 g, 97% yield) as an oil with crystallized slowly on standing; mp 68°-71° C.; IR (KBr) 1745 and 1650 cm-1 ; mass spectrum m/z 226 (M+); 1H NMR (CDCl3) δ 2.30 (s, 3H, thiophene-CH3), 2.47 (s, 3H, COCH3), 2.60 (s, 3H, thiophene-CH3), 3.67 (s, 5H, CH2CO2CH3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:16][N:17]([CH2:30][CH2:31][CH2:32]O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=2[Cl:29])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.OC1C=C(C=CC=1)CC1N(COCC)N=NN=1.BrCCCO.Cl.C(OCC)C>C(OCC)C>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:32][CH2:31][CH2:30][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=2[Cl:29])[CH2:16][CH:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(Cl)n1
Agent: CCOCn1nnnc1Cc1cccc(O)c1
Agent: Cl
Agent: OCCCBr
Solvent: CCOCC
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Cl)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Yield: 32 %

Procedure:
Following the procedure of Example 6(d), except 6-chloro-2-pyridinol (Aldrich) and N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine were used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole and 3-bromo-propanol in step 6(d), the title compound was synthesized as the free base. The tertiaryamine was then dissolved in diethyl ether and acidified with 1.0 M HCl/diethyl ether to give 90 mg (32% yield) of the title compound as a white solid. MS (ESI) 559.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)[N:10]=3)=[CH:17][C:18]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (8.77 g, 11.45 mmol) in DCM (25.00 mL, 389 mmol) was treated with TFA (15.00 mL, 195 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residual sticky material was taken up in DCM (100 mL) and carefully quenched with saturated NaHCO3 (aq) until slightly basic. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a yellow solid. A portion of this solid (0.349 g, 0.524 mmol) was dissolved in DCM (5.00 mL, 78 mmol) and Et3N (0.365 mL, 2.62 mmol) at −15° C. The mixture was treated slowly with dimethylcarbamic chloride (0.169 g, 1.573 mmol) and stirred for 1 h before warming up to room temperature overnight. The reaction mixture was concentrated, the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (10 to 100% EtOAc in hexanes) to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide (0.3555 g, 92%) as a yellow solid (ESI, +ve ion) 736.7 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:16]=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[C:13]([Cl:12])[CH:18]=2)[CH:10]=1
Reactant: CCOc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1Cl

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-chlorophenetole.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@@H:4]([NH:6][C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[C:3]1([CH3:20])[CH3:19].[NH2:21][CH2:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][C:33]([F:36])([F:35])[F:34])[CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([CH2:23][CH2:22][NH:21][C:9]2[N:8]=[C:7]([NH:6][C@@H:4]3[CH2:5][C@H:2]([OH:1])[C:3]3([CH3:20])[CH3:19])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:25][C:26]=1[O:32][C:33]([F:34])([F:35])[F:36])#[N:29]
Reactant: N#Cc1ccc(CCN)cc1OC(F)(F)F
Reactant: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@@H](O)C[C@H]1Nc1nc(NCCc2ccc(C#N)c(OC(F)(F)F)c2)ncc1C#N
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
A mixture of 4-(((1R,3S)-3-hydroxy-2,2-dimethylcyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, 0.27 mmol), 4-(2-aminoethyl)-2-(trifluoromethoxy)benzonitrile (60 mg, crude)) and DIEA (105 mg, 0.81 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (34.4 mg, 0.077 mmol, 40% yield, over two steps). 1H NMR (400 MHz, CD3OD) δ8.14-8.07 (m, 1H), 7.82-7.80 (m, 1H), 7.45-7.43 (m, 2H), 3.97-3.93 (m, 1H), 3.83-3.70 (m, 2H), 3.68-3.59 (m, 1H), 3.10-2.01 (m, 2H), 2.58-2.54 (m, 1H), 2.15-2.06 (m, 1H), 1.21 (s, 3H), 0.95 (s, 3H). MS (ESI) m/z 447.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH3:34][C:27]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10](=[O:11])[NH:12][CH:22]([C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
7.84 g (38.4 mmol) N-[3-(trifluoromethyl)phenyl]urea, 5.81 g (38.4 mmol) 4-nitro-benzaldehyde, 5.0 g (38.4 mmol) ethyl 3-oxobutanoate and 15 g polyphosphoric acid ethyl ester are suspended in 100 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with toluene/etiyl acetate as eluent.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:24][CH:23]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nc3)c2CC1
Product: Cl
Product: Clc1ccc2c(c1SCc1ccc(N3CCCCC3)nc1)CCNCC2

Procedure:
Use a method similar to the Example 369, using 3-tert-butoxycarbonyl-7-chloro-6-(6-chloropyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine and piperidine, to give the title compound as a white solid. MS (ES+) m/z: 388 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[CH2:41][C:31]3([C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30][C:27]2=[N:28][CH:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([NH:23][C:24]2[CH:25]=[C:26]3[CH2:41][C:31]4([C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:40])[CH2:30][C:27]3=[N:28][CH:29]=2)=[O:17])[C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)O)c1=O
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [5-chloro-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl]acetic acid (74 mg, 0.23 mmol) [Parlow et al. (2003) J. Med. Chem. 46, 4050], (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol) [Wood et al. US 2007/265225], N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.