Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH3:73])[CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][N:65]([CH2:63][CH3:64])[CH3:73])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C)CC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-ethyl-N-methyl-N-(piperidin-2-ylmethyl)-amine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>O1CCCC1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:28]([NH:27][CH2:26][CH2:25][Cl:24])=[O:29])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Yield: 52.2 %

Procedure:
N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (400 mg), 2-chloroethyl isocyanate (150 mg) and tetrahydrofuran (5 ml) were stirred at 80° C. for 1.5 hours. The mixture was returned to room temperature, silica gel was added, and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 280 mg of a colorless powder.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][CH:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC(O)CN
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A solution of 1.88 g of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 0.99 g (44%) of (RS)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C@:12]1([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:20])[F:19])[O:15][C:14]([NH2:22])=[N:13]1.N#N.C(O)(=O)C>CCO.[Pd]>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[C:3]([C@:12]2([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:19])[F:20])[O:15][C:14]([NH2:22])=[N:13]2)[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Agent: [Pd]
Agent: N#N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Yield: 96.1 %

Procedure:
A solution of (4S,6S)-4-(2-fluoro-3-methyl-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.26 g, 3.57 mmol) in EtOH (15 mL) was purged with N2 followed by the addition of acetic acid, glacial (0.412 ml, 7.13 mmol) and palladium, 10% wt. on activated carbon (0.047 ml, 5.35 mmol). The resulting mixture was purged with N2 again and H2 was bubbled through a balloon for 1 h. The mixture was filtered through celite, concentrated, diluted washed with 10% Na2CO3, 1 N NaOH, extracted with DCM and chromatographed on silica gel using 0-5% MeOH/DCM to afford a white solid as (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.11 g, 3.43 mmol, 96% yield). MS m/z=323.9 [M+H]+. Calculated for C13H14F5N3O: 323.11.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:68])[C@H:53]([OH:67])[C@H:54]([NH2:66])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:64])[F:63])[CH3:50]>C(Cl)Cl>[CH2:49]([O:51][C:52]([C@H:53]([OH:67])[C@H:54]([NH:66][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:63])[F:64])=[O:68])[CH3:50]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1C(F)(F)F
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1C(F)(F)F)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 34.6 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol, 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-2-hydroxy-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl and the product was extracted with DCM, dried, evaporated, and purified by preparative HPLC to yield the title compound (40 mg, 100% purity). MS m/z [M+H]+ calc'd for C24H26F3NO6, 482.17. found 482.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(O)=[O:45].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:9]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][NH:7][C:6](=[O:45])[C:5]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccccc1C(CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2)CC1
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(C2CCCCC2)CC1
Temperature: 3 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
317 mg (1 mmol) of 2-Methoxyphenyl-2-(4-cyclohexylpiperazine-1-yl)-ethylamine (prepared as described in Example 1) are combined with 272 mg (1 mmol) of 3,5-bistrifluoromethylbenzoic acid in 30 ml of DMF. The mixture is cooled to about 3° C. and combined with 501 ml (3.3 mmol) of diethylphosphorylcyanide and 1.4 ml triethylamine. After about 1 hour the ice bath is removed and the mixture is stirred overnight at ambient temperature. It is evaporated down in vacuo and the residue is stirred with a little water and 20% sodium hydrogen carbonate solution. It is suction filtered and washed thoroughly with water. The crude product is chromatographed over silica gel with ethyl acetate/methanol 1:1. The fractions which are uniform according to TLC are combined and freed from solvent in vacuo. The residue is dissolved in a little isopropanol and the N-[2-(2-methoxyphenyl)-2-(4-cyclohexylpiperazine-1-yl)-ethyl]-3,5-bistrifluoromethyl-benzamide is precipitated therefrom in the form of the hydrochloride using ethereal hydrochloric acid and diisopropylether. The product is suction filtered, washed with diisopropylether and dried in vacuo at about 50° C. 200 mg of the substance are obtained as a slightly beige solid (yield 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23](=[O:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]([OH:28])([CH3:29])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(3-oxocycloheptyl)-1-piperazinecarboxamide (8 mg, 0.02 mmol) in THF (3 mL) was added a solution of MeMgBr (3M, 0.1 mL) at 0° C. After 5 h at 0° C., the reaction mixture was quenched with MeOH and Na2CO3 (sat. 50 mL). The reaction mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by preparative TLC gave the title product. LC-MS: 401 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (m, 1H), 6.85 (d, 1H), 5.75 (d, 1H), 4.45 (d, 1H), 4.05 (m, 1H), 3.65 (m, 4H), 3.20 (m, 4H), 1.55–1.95 (m, 10H), 1.35 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:5]([O:18][CH:19]1[CH2:23][CH:22]2[CH:21]([CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reaction time: 12 h
Yield: 538 %

Procedure:
To a stirred solution of tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane (0.100 kg, 310 mmol) and rhodium acetate dimer (1.37 g, 3.10 mmol) in anhydrous dichloromethane (1.2 L) at room temperature was added a solution of ethyl 2-diazoacetate (63.68 mmol) in dichloromethane (300 mL) over 8 h. After an additional 12 h. The reaction mixture was filtered through Celite. Concentration of the filtrate afforded crude ethyl 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylate (140 g) which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][NH2:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCCCCCC>[C:1]([NH:18][CH2:17][CH:16]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
62 ml of pivaloyl chloride were dissolved in 180 ml of heptane and then added to 150 g of 2-octyldodecylamine at a temperature of 60° C. After addition of 70 ml of triethylamine, the reaction medium was stirred for 2 hours and then purified on silica. 118 g of the desired amide were thus obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([Cl:19])[N:7]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.C(O)C>[Cl:19][C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1nc(Cl)ccc1Nc1cncnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1nc(Cl)ccc1Nc1cncnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 6-chloro-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (98 mg, 0.35 mmol) in THF (1 ml) and ethanol (0.5 ml) was cooled to 0° C. and treated with 1M LiOH (0.7 ml, 0.7 mmol). The ice bath was removed and the reaction mixture was stirred at rt. for 2 h. 1M HCl (0.7 ml, 0.7 mmol) was added and stirring was continued until a precipitate was forming. The reaction mixture was sucked off and the product was obtained upon drying of the precipitate as yellow solid (60 mg, 67%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=C([N+]([O-])=O)C=CC=3N=2)[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([S:51](C#N)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:51]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:52])=[O:53])[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 81 %

Procedure:
A 362 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 112 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 81%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 13.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:11]=1[NH2:12]>C(#N)C.C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[C:11]([NH2:12])=[C:10]([Cl:9])[CH:16]=1
Reactant: Nc1c(Cl)cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1c(Cl)cc(Br)cc1C(F)(F)F

Procedure:
N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux to 18 h. The reaction mixture was then filtered through Celite and concentrated to give the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]N(CCN(C)C)C.C([Li])(CC)C.COS(OC)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH:13]1[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2)CC1
Agent: [Li]C(C)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CC1CC(N2CCCCC2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-tert-Butoxycarbonyl-[1,4′]-Bipiperidine 1 (5.1 g, 19.0 mmol), TMEDA (19 ml) in dry Et2O (40 ml) at −78° C. is slowly added a solution of sec-butyllithium (19.0 ml, 24.7 mmol, 1.3 M in cyclohexanes) over a period of 30 min. The mixture is stirred at −78° C. for 3 hr, and then is treated with a solution of Dimethylsulfate (3.6 g, 28.5 mmol) in Et2O (5 ml). The cooling bath is removed and the reaction mixture is stirred at ambient temperature for 16 hr. After cooling to 0° C., the reaction mixture is quenched with water, extracted with Et2O (5×100 ml), and the combined ether layers is dried over K2CO3. The solvent is removed in vacuo and the residue is purified on silica gel chromatography (eluting 40% ethyl acetate in hexane) to give 2.51 g of 1′-tert-Butoxycarbonyl-2′-methyl-[1,4′]-Bipiperidine, 2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N:12]1([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)n1
Yield: 57.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol), piperazine (2.8 g, 33 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (10 mL) was stirred at 100° C. in a sealed tube overnight. After removal of most of the solvent, the residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/NEt3 9/1/0.5) to give 1.48 g (56%) of desired product. MS calculated for C9H11F3N4: (M+H) 233; found 233.1.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:66][O:67][C:68](=[O:72])[CH2:69][CH2:70][SH:71].C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:7][C:2]=1[S:71][CH2:70][CH2:69][C:68]([O:67][CH3:66])=[O:72]
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Yield: 34.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) (0.05749 g, 0.06278 mmol), 5-bromo-4-(2,6-difluorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 128; 1.0 g, 2.511 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.07265 g, 0.1256 mmol), methyl-3-mercaptopropanoate (0.2920 ml, 2.637 mmol), N-ethyl-N-isopropylpropan-2-amine (0.8748 ml, 5.022 mmol) and dioxane (50 mL) were heated under argon at 80° C. overnight and then concentrated. The residue was purified by column chromatography to provide the desired product (0.375 g, 33.79% yield) as a yellow solid. 1H NMR (CDCl3) δ 10.97 (s, 1H), 8.37 (s, 1H), 7.26 (m, 1H), 7.03 (t, 2H), 6.26 (s, 1H), 6.03 (s, 1H), 3.67 (s, 3H), 3.12 (t, 2H), 2.62 (t, 2H), 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3Cl)[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3[S:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]3)[CH2:12]1)[CH2:14]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)nc1Cl
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 150 °C
Yield: 121.1 %

Procedure:
1-Propanethiol (0.499 mL, 5.50 mmol) was added dropwise to N-adamantan-1-yl-2,6-dichloronicotinamide (1.63 g, 5 mmol) and potassium carbonate (2.07 g, 15.00 mmol) in butyronitrile (15 mL) at 20° C. over a period of 2 minutes under nitrogen. The resulting suspension was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (2.21 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].COC(OC)N(C)C.CN(C)C=O.C(OCC)(=O)C>>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[O:8][CH:9]=[CH:12]2
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])c(Br)ccc12
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A pressure tube (150 mL) was charged with methyl 4-bromo-2-methyl-3-nitrobenzoate (2.1 g, 0.0077 mol), 1,1-dimethoxy-N,N-dimethylmethanamine (3.6 mL, 0.027 mol) and N,N-dimethylformamide (5 mL, 0.06 mol) and heated at 120° C. for 20 hours. The reaction gave multiple products. The solvent was removed and the residue was dissolved in Ethyl acetate (100 mL, 1 mol). Silica Gel (20 g, 0.3 mol) was then added and the reaction stirred at room temperature for 12 h. The reaction was filtered and the solvent removed and the residue purified by flash chromatography. MS m/z=271.2 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[N-:8]=[N+:9]=[N-:10].[Na+]>C(O)(=O)C.O>[N:8]([C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=CC(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CC(=O)O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,3-dimethylacrylic acid (20 g, 0.2 mol) in glacial acetic acid (50 mL) was added a solution of sodium azide (52 g, 0.8 mol) in water (100 mL) in one portion. The clear yellow solution was stirred for 1 hour at room temperature and then heated in an oil bath at 95° C. for 2 days. Water (50 mL) was added to the cooled orange solution. This solution was poured into a separatory funnel and extracted with ether (5×200 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated to an orange oil. This oil was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 6H), 2.55 (s, 2H), 11.80 (bs, 1H).