Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([N+:24]([O-])=O)[CH:16]=1.[NH2:27][CH2:28][CH2:29][C:30]#N.C([O-])(=O)/C=C/C([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:16][C:17]=1[NH:24][CH2:30][CH2:29][C:28]#[N:27])([O-:23])=[O:22]
Reactant: N#CCCN
Reactant: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(NCCC#N)c2)c(Cl)c1
Yield: 70.9 %

Procedure:
A solution of 4.0 g of 2-chloro-4-isopropylsulphonyl-(3,4-dinitrophenoxy)benzene and 3.85 g of 3-aminopropionitrile. 0.5 fumarate in 100 ml of acetonitrile, to which 4.1 g of potassium carbonate was added, was refluxed for 6 hours. After evaporation the residue was dissolved in methylenechloride an extracted with water. After washing with water the organic layer was filtered and reduced. Recrystallisation from methanol yielded 3.0 g of the desired product; m.p. 140° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].N([O-])=O.[Na+].[C:30](O)(=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:30]=[N:24][N:23]=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-n3cnnn3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-aminobenzyl)piperidine (1 g, 3.46 mmol) in acetic acid (14 mL) were added orthoethyl formate (2.4 mL, 20.7 mmol) and sodium azide (0.27 g, 4.13 mmol), and the mixture was stirred at room temperature for 30 minutes and at 80° C. for 2 hours. The mixture was cooled to room temperature. To the mixture were added water (20 mL) and a solution of sodium nitrite (4.3 g) in water (20 mL), and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate. The extract was washed with aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=2/3) to give 1-tert-butoxycarbonyl-4-[4-(1H-tetrazol-1-yl)benzyl]piperidine (950 mg) as colorless powdery crystals. This compound (950 mg, 2.78 mmol) was dissolved in ethyl acetate (10 mL). To the solution was added 4N-hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 2 hours. The resulting crystals were collected by filtration, washed with ethyl acetate (5 mL) and dried to give the titled compound (697 mg) as colorless powdery crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:14].CS(C)=O>C(O)(=O)C.O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]=1
Reactant: Oc1ccccc1C1CCCCC1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Oc1ccc(Br)cc1C1CCCCC1
Yield: 93 %

Procedure:
To a stirring solution of 2-cyclohexylphenol (26.0 g, 146.8 mmol) in glacial acetic acid (100 mL) was added HBr in acetic acid (150 mL of 33% w/w,) and H2O (52 mL), followed by the dropwise addition of DMSO (100 mL) over 10 min. The reaction was then carefully quenched with saturated NaHCO3 and concentrated in vacuo. The residue was brought up in ether (400 mL), washed with water (2×100 mL) and brine (1×100 mL), and dried over anhydrous Na2SO4, filtered and concentration to yield a crude oil that was purified by silica gel column chromatography, using 15-30% EtOAc/hexane gradient to yield 4-bromo-2-cyclohexyl-phenol (35.0 g, 93%)
Reaction SMILES: [C:1]1([N:7]2[C:19](=O)[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].ICCCC.[O:31]1CCCC1>>[CH2:21]([C:19]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:11][C:10]2=[O:31])[CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: O=c1c2c([nH]n1-c1ccccc1)CNc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCCCI
Product: CCCCc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinoline-one (3.0 g, 11.5 mmol), N,N,N′N′-tetramethylethylenediamine (7.7 mL), and tetrahydrofuran (128 mL) was chilled to 0° C. A solution of n-butyllithium in hexanes (12 mL of 2.86 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes at 0° C. and then cooled to −78° C. To the cooled solution was added iodobutane (3.9 mL, 34.5 mmol). The reaction mixture was warmed to ambient temperature and stirred for 30 minutes before quenching with saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to 100 mL of solvent. This was placed directly on a silica gel column and purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-50% CMA in chloroform) to provide 3.7 g of 1-butyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a 2:1 mixture of product to starting material.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a mixture of 12.5 g (0.1 mol) of glycine, methyl ester hydrochloride in 120 ml of CH2Cl2, cooled in an ice bath was added 41.7 ml (0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4-methoxy-benzenesulfonyl chloride in 40 ml of CH2Cl2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated and washed with 2 N citric acid, H2O, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59°-61° C. Anal. for C10H13NSO5: Calc'd: C, 46.3; H, 5.1; N, 5.4; Found: C, 46.2; H, 5.0; N, 5.2.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][NH:26][CH3:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][N:26]([CH3:27])[S:33]([CH3:32])(=[O:35])=[O:34])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNC)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one (72 mg, 0.16 mmol; Example 134 Step A) in DMF (0.40 mL) was added methanesulfonyl chloride (61 μL, 0.79 mmol) and pyridine (76 μL, 0.95 mmol) successively at 0° C. After being stirred at 25° C. for overnight, the reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Separation by RP-HPLC (50 to 85% MeCN/H2O (0.1% TFA) a gradient elution) provided the title compound as a pale yellow film.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13](CC)[C@H]2CC[C@H](N(CCOC)C)CC2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N1CCOCC1)C#C.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 105 °C
Yield: 126.5 %

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was, purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.CS(C)=O>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:8](=[O:10])[C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[N:5][CH:6]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1cncc(C(=O)O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cncc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c1

Procedure:
From 5-methoxy-nicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+5.8° (c=0.10, DMSO), ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].C(OC(C)C)(C)C>>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 74 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]-ethanamine in a yield of 74% of theory. Colourless crystals, m.p. 123°-125° C. (diisopropylether).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(C(F)(F)F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
In an analogous manner, starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-trifluoromethylbenzoyl chloride, there is obtained ethyl N-(p-trifluoromethylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 112°-113° C.;
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=C[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.ClO[C:22](C)(C)C.BrBr.[C:28]([Cl:32])(Cl)(Cl)Cl>C(O)(=O)C>[Cl:32][C:28]1[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH3:22])=[N:6][N:5]([CH:4]([CH3:17])[C:3]([N:2]([CH3:1])[CH3:19])=[O:18])[CH:9]=1
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OCl
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccccc1-c1nn(C(C)C(=O)N(C)C)cc1Cl

Procedure:
Following the procedure of Example 108, but substituting N,N,α-trimethyl-3-(o-tolyl)pyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, tert-butyl hypochlorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent, there was obtained 4-chloro-N,N,α-trimethyl-3-(o-tolyl)pyrazole-1-acetamide having a melting point of 69°-71.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)=[N:8]1.Br[C:46]1[CH:51]=[N:50][CH:49]=[C:48]([CH:52]2[CH2:54][CH2:53]2)[N:47]=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>[CH:52]1([C:48]2[N:47]=[C:46]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[C:9]4[C:25]3[N:30]=[C:29]([O:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]4)[CH:28]=[N:27][CH:26]=3)[CH:51]=[N:50][CH:49]=2)[CH2:54][CH2:53]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)n2)C1
Reactant: Brc1cncc(C2CC2)n1
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: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cncc(C6CC6)n5)cc34)n2)C1
Temperature: 100 °C
Yield: 70 %

Procedure:
A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (1.315 g, 2.17 mmol) and Pd(PPh3)4 (0.125 g, 0.11 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 (g). A solution of 2-bromo-6-cyclopropylpyrazine (0.562 g, 2.82 mmol) in dioxane (1.8 mL) and 2 M Na2CO3 (5.43 mL, 10.86 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 2 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.910 g, 1.52 mmol, 70% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 598.2 (M+1).
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15](O)=[O:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:22])=O>>[CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([Cl:22])=[O:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc(C=CC(=O)O)cc1
Product: CCCCCCCCc1ccc(C=CC(=O)Cl)cc1

Procedure:
1.8 G. of p-n-octylcinnamic acid, prepared in a manner analogous to that described in Example 1, are boiled in 25 ml. of thionyl chloride for 30 minutes. The excess thionyl chloride is removed by distillation. The residue is taken up twice in absolute toluene, concentrated on a rotary evaporator and dried. There is thus obtained crude p-n-octylcinnamic acid chloride.
Reaction SMILES: [Br-].[CH3:2]C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)/C=C/C.[CH2:26]([Li])[CH2:27][CH2:28][CH3:29].[CH3:31]/[C:32](=[CH:35]\[C:36](\[CH3:39])=[CH:37]\[CH3:38])/[CH:33]=O.C/C(=C\C)/C=O>CCCCCC.O.O1CCCC1>[CH3:26]/[C:27](/[CH:31]=[C:32](\[CH3:33])/[CH:35]=[C:36](\[CH3:39])/[CH:37]=[CH:38]/[CH3:2])=[CH:28]\[CH3:29]
Reactant: C/C=C(C)/C=C(\C)C=O
Reactant: [Li]CCCC
Reactant: C/C=C/C(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C/C=C(\C)C=O
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(C)=C/C(C)=C/C(C)=C/C
Temperature: 25 °C

Procedure:
(1-Methyl-(E)-2-butenyl)triphenylphosphonium bromide from Example 9 (0.62 g, 0.0015 mole) was added to a dry flask with 5 ml tetrahydrofuran. The flask was equipped with magnetic stirrer and septum; the reaction was carried out under nitrogen. The salt did not dissolve completely but became a sticky suspension. The mixture was cooled over ice, and butyllithium (2.5M in hexane) was added dropwise, with stirring, until the color change became permanent; then an additional 0.0015 mole was added. The solid in the flask dissolved as it was converted to the ylide. One hundred milligrams of 2,4-dimethyl-(E,E)-2,4-hexadienal (0.0008 mole), compound 4, R1 =H, prepared previously by Pattel and Pattenden (1985), was added to the Wittig reagent, and the mixture was allowed to warm to room temperature. The mixture was stirred for 2 hr, and it was again cooled over ice. Water was added dropwise until the red color of the solution had disappeared, and ca. 2 ml more water was added. The mixture was diluted with hexane and the organic layer dried over sodium sulfate. The solvent was removed and the product passed through a silica column with hexane. By capillary GC the product was 61% the (E,E,E,E) isomer, ca. 31% the (E,E,Z,E) isomer, and ca. 8% by-products, after clean-up on silica. Further purification on the AgNO3HPLC column yielded the (E,E,E,E) isomer in >97% purity.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (1.45 g) and 1-(5-methylpyridin-2-yl)piperazine (1.06 g) described in Preparation Example 183, the title compound (2.01 g) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:21]=[CH:20][C:13](/[CH:14]=[CH:15]/[C:16](OC)=[O:17])=[CH:12][CH:11]=1>CO>[CH3:8][O:9][C:10]1[CH:21]=[CH:20][C:13]([CH:14]2[S:5][CH2:4][CH2:3][NH:2][C:16](=[O:17])[CH2:15]2)=[CH:12][CH:11]=1
Reactant: NCCS
Reactant: COC(=O)/C=C/c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CC(=O)NCCS2)cc1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
A mixture of 2-aminoethanethiol hydrochloride (31.0 g, 0.273 mol) and 140 mL of methanol is cooled to 0° C. and treated with pulverized sodium hydroxide (12.0 g, 0.475 mol) followed by trans-methyl 4-methoxycinnamate (52.4 g, 0.273 mol). The reaction mixture is allowed to warm to room temperature and stirred for 5 days. The mixture is then heated to 60° C. for 30 minutes and filtered while still warm. The methanolic solution is concentrated to ca 1/4 volume and the product is isolated by filtration (35 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
Piperidin-2-yl-methanol (60.77 mmol, 1 eq) was dissolved in methylene chloride (150 ml) and triethylamine (151.92 mmol, 2.5 eq) at 0° C. and a solution of 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (60.77 mmol, 1 eq) in methylene chloride (50 ml) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 14 h. The reaction solution was then diluted with methylene chloride (200 ml) and the organic phase was washed with saturated sodium chloride solution (2×50 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (5-20% ethyl acetate in hexane). Yield: 63%
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][C@H:8]([C:13](=[O:20])[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(OC([C@@H:29]1[CH2:33][C@H:32]([O:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=3)[N:38]=[C:37]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:36]=2)[CH2:31][C@H:30]1[C:53](=[O:65])[NH:54][C@:55]1([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:57][C@H:56]1[CH:58]=[CH2:59])=O)(C)(C)C.C(OC([C@@]1(NC([C@@H]2C[C@@H](OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)C[C@H]2C(=O)N[C@H](C(=O)N[C@@H](C2CCCCC2)C(=O)NC)C(C)(C)C)=O)C[C@H]1C=C)=O)C>>[CH2:63]([O:62][C:60]([C@@:55]1([NH:54][C:53]([C@@H:30]2[CH2:31][C@@H:32]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:36]=3)[CH2:33][C@H:29]2[C:6](=[O:21])[NH:7][C@H:8]([C:13](=[O:20])[NH:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:65])[CH2:57][C@H:56]1[CH:58]=[CH2:59])=[O:61])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)OCC
Yield: 63.2 %

Procedure:
Compound 51 (298 mg, 0.048 mmol) and 35 (16 mg, 0.054 mmol) was deprotected and coupled according to the method for the preparation of 39. Purification by HPLC (MeOH/H2O 90:10 with 0.2% triethylamine) gave 52 (22 mg, 63%) as a colorless solid.