Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16].C([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(OC(C)(C)C)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:76]([OH:83])(=[O:82])/[CH:77]=[CH:78]/[C:79]([OH:81])=[O:80]>C1(C)C=CC=CC=1.CO.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]>[C:76]([OH:83])(=[O:82])/[CH:77]=[CH:78]/[C:79]([OH:81])=[O:80].[CH3:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(Sc2ccccc2Br)c(C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(Sc2ccccc2N2CCNCC2)c(C)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A solution of 10 gram 1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene (34 mmol) in 50 ml dry toluene was added 7 gram boc-piperazine (38 mmol), degassed with nitrogen for 5 minutes, added 312 mg Pd2dba3 (2 mol-%) and 637 mg rac-BINAP (3 mol-%), degassed for another 5 minutes before adding 3.9 gram ButONa (41 mmol) and heated to 80° C. for 15 hours. The reaction mixture was cooled to RT and extracted twice with 20 ml 15% brine, dried over Na2SO4, added charcoal, refluxed for 15 minutes, filtered though celite and evaporated to 14.2 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine) having a purity of 95% determined by NMR. The crude oil was dissolved in 200 ml MeOH and 20 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC showed full deprotection. After cooling to RT the methanol was removed by vacuum on a rotary-evaporator, 20 ml conc. NaOH (pH was measured to 13-14) was added after which the mixture was stirred 15 minutes with 100 ml EtOAc. The organic phase was collected and extracted twice with 30 ml 15% brine, dried over Na2SO4 and added 5.2 g fumaric acid (44 mmol) in 30 ml MeOH. During heating to reflux a homogenous solution forms from which a rapid precipitation takes place either during further heating or upon cooling. The precipitate was collected, washed with 20 ml EtOAc and 20 ml acetone, dried in vacuum giving 9.3 gram of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (22 mmol) as a white powder in 66% overall yield having a purity of 99.5% by LC-MS.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH:48]3[C:46]([C:50](O)=[O:51])([CH2:47]3)[C:45]2=[O:53])=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[CH:19]1[CH2:20][CH2:21][N:16]([C:15]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:34]=[CH:35][C:2]([NH:1][C:50]([C:46]45[CH2:47][CH:48]4[CH2:49][N:44]([C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)[C:45]5=[O:53])=[O:51])=[CH:3][C:4]=3[F:36])[N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:14]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)ccnc32)cc1
Yield: 53.7 %

Procedure:
A solution of 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (39 mg, 0.079 mmol, obtained from Example 93, Step A), 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (37 mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol) and HOBT (64 mg, 0.48 mmol) was stirred in DMF (10 mL) for 12 hours. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer washed with NaHCO3, 10% aqueous LiCl, dry with Na2SO4, filtered and concentrated. The residue was purified with flash silica gel chromatography (5% MeOH in CH2Cl2) to afford the product (30 mg, 53%) as a white solid. LRMS (APCI pos) m/e 708.3 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)(=O)=O.[H-].[Na+].[F:19][C:20]([F:29])([F:28])[CH2:21][CH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25]>CN(C)C=O>[CH3:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[CH2:6][C:23]([CH2:22][CH2:21][C:20]([F:19])([F:28])[F:29])([C:24]#[N:25])[C:26]#[N:27]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Cc1cc(COS(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(C#N)(C#N)CCC(F)(F)F)ccc1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Using 0.49 g of 3-metyl-4-nitrobenzyl methanesulfonate, 5 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.3 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.51 g of 2-(3-methyl-4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (45)).
Reaction SMILES: [CH2:1]([P:5]1(=[O:13])[O:10][C@H:9]([CH3:11])[CH2:8][C@@H:7]([CH3:12])[O:6]1)[C:2]([CH3:4])=[O:3].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].N1CCCCC1.C(OCC)(=O)C.CO>C1C=CC=CC=1>[C:2]([C:1]([P:5]1(=[O:13])[O:6][C@H:7]([CH3:12])[CH2:8][C@@H:9]([CH3:11])[O:10]1)=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)(=[O:3])[CH3:4]
Reactant: CC(=O)CP1(=O)O[C@H](C)C[C@@H](C)O1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P1(=O)O[C@H](C)C[C@@H](C)O1
Yield: 33 %

Procedure:
3.38 g of 2-acetonyl-(4R,6R)-4,6-dimethyl-1,3,2-dioxaphosphorinane-2-oxide and 2.4 g of m-nitrobenzaldehyde were dissolved in 15 ml of benzene, and 0.5 ml of piperidine was added thereto. The mixture was refluxed for 5 hours. The reaction solution was subjected to silica gel chromatography (developer solution: ethyl acetate/methanol=9/1 (v/v), Rf value: 0.4) to obtain 1.78 g of desired 2-(1-acetyl-2-(3-nitrophenyl)ethenyl)-(4R,6R)-4,6-dimethyl-1,3,2-dioxaphosphorinane-2-oxide as a yellow viscous liquid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[C:19]([Cu])#[N:20]>CN(C=O)C.C(OCC)(=O)C>[OH:18][C:4]1[CH:3]=[C:2]([C:19]#[N:20])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 150 °C
Yield: 25.3 %

Procedure:
To 7-bromo-2-(4-hydroxy-phenyl)-benzooxazol-5-ol (96 mg) in DMF (3 mL) was added CuCN (84 mg). The mixture was placed in an oil bath and heated to 150° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with 1N HCl, saturated aqueous EDTA, brine (3×), dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 20% ethyl acetate-hexane afforded 20 mg (25%) of the title compound as a solid. MS: 253 (MH+), HPLC tR: 2.06 min.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.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.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:85])[C@@H:76]([NH2:84])[CH2:77][CH2:78][C:79]2[N:80]=[N:81][NH:82][N:83]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]>CN(C=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:85])[C@@H:76]([NH:84][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:29])[CH2:77][CH2:78][C:79]2[N:80]=[N:81][NH:82][N:83]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 126 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 2 ml DMF were added 160 μl DIPEA, 116 mg HATU and 130 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid ethyl ester hydrotrifluoroacetate. After 30 minutes the reaction mixture was concentrated and the crude product obtained purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 29 mg
Reaction SMILES: C(OCC)(=O)C.Br.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>O1CCCC1>[CH2:32]([S:34]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:36])=[O:35])[CH3:33]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CCS(=O)(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
In a mixed solution of 30 ml of ethyl acetate and 30 ml of tetrahydrofuran was suspended 3.22 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane hydrobromide. A sodium carbonate aqueous solution (5.30 g/30 ml of water) was added to the suspension. Under ice cooling, 3.32 g of ethanesulfonyl chloride dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred for 3 hours. 300 ml of ethyl acetate was added to the mixture. After the organic layer was collected by separation, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform-methanol (100:3)) to obtain 2.75 g of 2-(ethylsulfonylaminomethyl)-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[N:18]=[C:19]([NH:30]C(=O)C2C=CC(OC)=CC=2)[S:20][C:21]=1[C:22]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23]>>[O:27]1[CH2:28][CH2:29][CH:24]([C:22]([C:21]2[S:20][C:19]([NH2:30])=[N:18][C:17]=2[C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: COc1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Product: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1

Procedure:
In a manner similar to that in Example 456, by using 4-methoxybenzoyl chloride in place of cyclopropanecarbonyl chloride, the entitled Compound 463. (152 mg, 82%) was obtained as a grayish white solid from Compound 454 (125 mg, 0.450 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([CH2:14][C:15]#[N:16])[CH2:6]2.CO.N.[H][H]>CO.[Ni]>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([CH2:14][CH2:15][NH2:16])[CH2:8]2
Reactant: COc1cc2c(cc1OC)CC(CC#N)C2
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc2c(cc1OC)CC(CCN)C2

Procedure:
5 g (2.3 mmoles) of (5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)acetonitrile are dissolved in 50 ml of methanol. 50 mL of a (7N) MeOH—NH3 solution and 0.5 g of Raney nickel are then added. Hydrogen is carried out for 4 days under a pressure of 5 bar, at 25° C. Filtration over Celite and evaporation of the filtrate to dryness are carried out. The residue is taken up in 50 mL of HCl (1N) and washed with ethyl acetate; the aqueous phase is then brought to pH=10 by adding NaOH (20%). Extraction with Et2O, washing with water, drying over MgSO4, filtration and evaporation to dryness are carried out. The expected product is obtained in the form an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
The mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (300 mg), 3-[(methyloxy)carbonyl]benzoic acid (180 mg), HBTU (417 mg) and DIPEA (690 μL) in dichloromethane (DCM, 25 mL) was stirred at room temperature overnight. It was concentrated. Separation via CombiFlash (MeOH, DCM) then afforded the desired product (670 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>CO>[O:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]1=2
Reactant: O=[N+]([O-])c1ccc(CN2CCOc3ccccc32)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(CN2CCOc3ccccc32)cc1
Temperature: 50 °C

Procedure:
A mixture of 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1.4]oxazine (0.432 g, 1.6 mmol) and tin(II) chloride dihydrate (1.8 g, 8.0 mmol) in MeOH (10 mL) was heated to 50° C. After 3 hrs the mixture was concentrated in vacuo and the residue taken up in EtOAc. Saturated NaHCO3 was added and the mixture was filtered. The filtrate was washed with brine, dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography using 20-100% Hexanes:EtOAc to afford 4-((2,3-dihydrobenzo[b][1.4]oxazin-4-yl)methyl)benzenamine as an orange oil. MS found: M+H+=241.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.CO>[OH:16][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a mixture of 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (from Alfa Aesar, 3.3 g, 14 mmol) and triethylamine (3.8 mL, 27 mmol) in tetrahydrofuran (40 mL) at 0° C. was added dropwise ethyl chloroformate (1.9 mL, 20 mmol). The mixture was stirred at 0° C. for 10 min and then at room temperature for 20 min. The mixture was filtered to remove the white solid and then cooled to 0° C. A mixture of sodium tetrahydroborate (1.0 g, 27 mmol) and methanol (1 mL) was added slowly. The mixture was stirred at room temperature for 1 h. The mixture was quenched with 1N aq. HCl solution and extracted with EtOAc. The extracts were concentrated and purified on silica gel column (eluting with 75% EtOAc in hexanes) to give the desired product (2.88 g, 92%). LCMS calculated for C13H23NO3Na (M+Na)+: m/z=252.2. Found: 252.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
In tetrahydrofuran (100 mL) was dissolved methyl 6-chloropyridazin-3-carboxylate (1.726 g), the solution was cooled to 0° C., 1M diisobutyaluminum hydride-tetrahydrofuran solution (20 mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture were successively added water (10 mL) and 1N hydrochloric acid (20 mL) at 0° C. After adding a saturated aqueous sodium bicarbonate solution to the mixture at room temperature, the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the residue obtained by concentrating the extract under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 25:75) to obtain (6-chloropyridazin-3-yl)methanol (177 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:15]#[N:16])[CH2:13][CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].Cl>[Br-].[Zn+2].[Br-].C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:15]1[NH:19][N:18]=[N:17][N:16]=1)[CH2:13][CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C#N)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OCc1ccccc1)c1nnn[nH]1
Yield: 58.9 %

Procedure:
To N-benzyloxycarbonyl-(1R)-1-cyanopropylamine (85.6 mg) in suspension (3 ml), sodium azide (28 mg) and zinc bromide (88.3 mg) were added and the mixture was stirred under heating and reflux for 24 hours. 3N hydrochloric acid and ethyl acetate were added to the reaction solution and the mixture was stirred until there were no longer any insolubles. The obtained solution was extracted with ethyl acetate, then the organic layer was concentrated. 0.25N sodium hydroxide aqueous solution was added to the residue, the mixture was stirred for 30 minutes, and the insoluble compound was filtered. 6N hydrochloric acid was added to the filtrate to adjust to pH 1, then this was concentrated. The residue was diluted with 1N hydrochloric acid, then the solids were collected by filtration to obtain the title compound (60.4 mg).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CCC(C1C=CC=CC=1)C#N)(C)C.ClCCN(C(C)C)C(C)C>>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: ClCCN1CCCCC1
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Agent: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccn1)C(C)C

Procedure:
Substitution of equivalent quantities of α-[2-(diisopropylamino)ethyl]-α-(2-pyridyl)acetonitrile and 1-(2-chloroethyl)piperidine for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 2-chloro-N,N-diisopropylethylamine called for respectively in the procedure of Example 2, Method B affords α-[2-(diisopropylamino)ethyl]-α-(2-piperidinoethyl)-α-(2-pyridyl)acetonitrile, as an oil boiling at about 160°-170° C. at 0.5-0.7 mm. pressure.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate (0.81 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added a 1N aqueous sodium hydroxide solution (3.6 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3.7 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.75 g, 97%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-125° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:13]([O:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(C)cc1C(C)(C)C

Procedure:
To a 300-ml four-necked flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel were added 32.8 g (0.20 mole) of 2-tert-butyl-4-methylphenol, 22.3 g (0.22 mole) of triethylamine and 100 g of toluene, and after replacing air in the flask by nitrogen, 19.10 g (0.21 mole) of acryloyl chloride was added dropwise at a reaction temperature of 30° C. over 1 hour. After completion of the dropwise addition, excessive triethylamine was neutralized with hydrochloric acid, the reaction solution was washed with water, and toluene was then removed from the organic layer by evaporation under reduced pressure to obtain 43.0 g of a crude product (yield, 99%). This crude product was purified by distillation under reduced pressure to obtain a white and transparent 2-tert-butyl-4-methylphenol monoacrylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.Cl[O-].[Na+].C(O)(C)C.O>C(O)(=O)C.ClCCl>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: OCCC1CCC(O)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1CCC(CCO)CC1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of 10 g (69 mmol) of 4-(2-hydroxyethyl)cyclohexanol in 50 mL of acetic acid maintained at a temperature between 18 and 21° C. are added over 35 min 35.9 mL (79 mmol) of an aqueous sodium hypochlorite solution. The mixture is further stirred for 45 min, TLC analysis indicating disappearance of starting material. Isopropanol (0.8 mL) is added, followed 10 min later by water (75 mL) and dichloromethane (100 mL). The two phases are separated by decantation and the aqueous phase is extracted with dichloromethane (50 mL). Combined organic phases are washed with an aqueous 3N sodium hydroxide solution (70 mL). This alcaline aqueous phase is extraced back with dichloromethane (30 mL). Combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give 9.42 g (95%) of the title compound.