Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O.ClCCl>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCCCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
7-Fluoro-5-methyl-6-phenyl-2-(piperidin-1-yl)-1,3-benzoxazole-4-carbonitrile (I-136) (0.21 g, 0.63 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.91 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 10 g, dichloromethane:methanol=30:1) and preparative thin-layer chromatography (dichloromethane:methanol=20:1), then isopropyl ether was added, and the insoluble matter was collected by filtration to obtain a beige solid (0.12 g, 44%).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].NC(N)=O>O.Cl>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Nc1cccc(F)c1F
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: NNc1cccc(F)c1F
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
In each of two flasks, 775 mmol (100 g) of 2,3-difluoroaniline were added to 2 L of concentrated hydrochloric acid at -15° C. and treated dropwise with a solution of 852 mmol (58.9 g) of sodium nitrite in 500 mL of water. Ten minutes after the addition, the reaction was treated with 930 mmol (55.8 g) of urea. This was followed by rapid addition of a solution of stannous chloride dihydrate (968 mmol, 220 g) in 700 mL of concentrated hydrochloric acid precooled to -50° C. After 20 minutes, the solid from both reactions was filtered and combined. It was put into 3 L of 1M NaOH (aq) and extracted with 4×500 mL of ether. The extracts were combined, dried over MgSO4 and concentrated to afford 110 g of 2,3-difluorophenylhydrazine (763 mmol, 49%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[CH3:18][O:19][C:20](=O)C.COCCl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Reactant: COC(C)=O
Agent: COCCl
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 12 h

Procedure:
A mixture of 23 g. of methyl 6-hydroxy-2naphthyl-α-methylacetate, methylacetate, 25 g. of chlorodimethyl ether, and 500 ml. of dimethylformamide is allowed to stand at room temperature for 12 hours. The reaction mixture is evaporated under reduced pressure to give methyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2nc(-c3ccccc3)sc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2nc(-c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5,7-Dichloro-2-phenylthiazolo[5,4-d]pyrimidine 65 was suspended in methanol and treated with morpholine. The reaction mixture was stirred at room temperature for 4 h. Solid was filtered to yield pure 4-(5-chloro-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)morpholine 66 as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C[O-].[Na+].Cl[CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33]>C(Cl)(Cl)Cl.ClC1C=CC=CC=1.CO>[CH2:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH:10]=[C:9]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCN(CC)CCCl
Reactant: O=c1cc(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOc1ccc(-n2c(-c3ccccc3)cc(=O)c3ccccc32)cc1

Procedure:
By following a procedure similar to that described in Example 1 and using 49.5 g. 1-(4-hydroxyphenyl)-2-phenyl-4(1H)-quinolone, 10.5 g. sodium methoxide, 500 ml. chlorobenzene, 45 ml. dry methyl alcohol, and 26 g. N-(2-chloroethyl)diethylamine in 80 ml. chlorobenzene there was obtained on evaporation to dryness of the chloroform extract and recrystallization from isopropyl alcohol 32 g. 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-phenyl-4(1H)-quinolone; m.p. 115°-117°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[N:3]=1.[C:22]([Zn])#[N:23]>CN(C=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>[CH3:21][N:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=[C:10]1[CH:9]=[CH:8][C:4]1[N:3]=[C:2]([C:22]#[N:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(Br)n1
Reactant: N#C[Zn]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(C#N)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 2-bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (120 mg, 0.354 mmol) in dry DMF (3 mL) was added cyanozinc (97 mg, 1.062 mmol) and tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.035 mmol). The mixture was stirred at 130° C. for 3 h in a microwave. The residue was then filtered. The filtrate was concentrated and purified by reverse phase column chromatography to yield 6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-picolinonitrile (100 mg) as a yellow solid. MS (ESI): m/z 287 [M+H]+.
Reaction SMILES: C(O)=O.C([O:6][C:7](=[O:36])[CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([C:34]#[N:35])[CH:25]=3)[O:21][N:20]=2)[CH2:10]1)C.[Li+].[OH-].[ClH:39]>C1COCC1.CO.O>[ClH:39].[C:34]([C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:16]=3[CH2:17][CH2:18][N:9]([CH2:8][C:7]([OH:36])=[O:6])[CH2:10]4)[N:23]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:33])[CH3:32])#[N:35]
Reactant: CCOC(=O)CN1CCc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CC(=O)O)C4)no2)cc1C#N
Yield: 85 %

Procedure:
A solution of ethyl[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinyl]acetate formic acid salt (Preparation 5, 11.6 mg, 0.026 mmol) and LiOH (0.3 mg) in THF-MeOH-water (300 μl, 300 μl, 200 μL) was irradiated to 100° C. for 3 min in the microwave. 2M aqueous HCl (1 mL) was added, then the solution extracted with DCM (2×2 mL). The combined organics were concentrated in vacuo to give the title compound as a white solid (10.1 mg, 85%). 1H NMR (400 MHz, d4-MeOH) δ 8.48 (1H, d), 8.44 (1H, dd), 8.21 (1H, d), 7.44 (1H, t), 7.47 (2H, apparent d), 4.97 (1H, sept), 4.70 (2H, s), 4.32 (2H, s), 3.67 (2H, t), 3.57 (2H, t), 1.47 (6H, d); m/z (ES) 419 [M+H]+.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[N:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C)C=O>[CH:13]1[C:4]2[CH:5]=[CH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21]3)[C:3]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 gram (44 millimoles) of 5-chloro-5H-dibenzo-[a,d]cycloheptene prepared in a manner similar to that previously described was added to a solution of 1.4 grams of ethyl N-piperazinecarboxylate in 10 milliliters of dimethylformamide and the resulting mixture allowed to stir overnight at room temperature. At the end of this period, the mixture was subjected to reduced pressure to remove most of the dimethylformamide. Aqueous saturated sodium bicarbonate solution was added, mixed and then extracted with diethyl ether. The ether extract was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, the dried solution subjected to reduced pressure to remove the ether and to obtain the ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-piperazinecarboxylate product as residue. The crude product was treated with and crystallized from acetonitrile. The product after several recrystallizations had a melting point of 159°-160° C. and elemental analyses as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[N:5]=[C:4]([NH:26][CH:27]=[O:28])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:27]=[O:28])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOP(=O)(COCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A solution of 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-2,5-diformamidopyrimidine (4.48 g, 10 mmol) in diethoxymethyl acetate (40 ml) was heated at 120° C. for 2.5 h. After removal of the solvent in vacuo. the residue was dissolved in methanol (50 ml) and 0.88 ammonia (2 ml) then stirred at 25° C. for 2 h. The reaction was then reduced in vacuo and co-evaporated twice with methanol before chromatography of the residue in chloroform/methanol (100:1) to give 6-chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]-2-formamidopurine (2.92 g, 69.2%) as a yellow oil. νmax (film) 3117,1709, 1612, 1577, 1508, 1244, 1027 cm-1 ; δH [(CD3)2SO] 1.23(6H, t, J7 Hz,(CH3CH2O)2), 1.97(2H, m, CH2CH2CH2), 3.74(2H, t, J6.1Hz, CH2OCH 2 P), 3 84(2H, d, J8.0 Hz, CH2P), 4.04(4H, m, (CH3CH2O)2), 4.48(2H, t, J6.3 Hz, CH2ON), 8.83(1H, s, H-8), 9.37(1H, br.s, CHO), 11.30(1H, br.s, D2O exchangeable, NH); Found: C, 40.05; H, 5.22; N, 16.85%; M+, 421.0921. C14H23ClN5O7P requires: C, 39.87; H, 5.02; N, 16.60%; M+, 421.0918.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.I[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH:28]=[C:29]([C:31]1[CH:40]=[CH:39][C:38]2[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:44])([CH3:43])[C:33]=2[CH:32]=1)[CH3:30]>C(#N)C>[CH2:30]([C:29]1([C:31]2[CH:40]=[CH:39][C:38]3[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:43])([CH3:44])[C:33]=3[CH:32]=2)[C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH2:28]1)[CH:1]=[CH2:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1ccc(I)c(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Solvent: CC#N
Product: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2cc(C(=O)OC)ccc21
Temperature: 80 °C

Procedure:
A mixture of palladium bis(triphenylphosphine)diacetate (0.15 g, 0.2 mmol), tributylvinyltin (0.56 ml, 1.92 mmol) and methyl 4-iodo-3-[2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]-1-propenyloxy]benzoate (1 g, 1.99 mmol) in acetonitrile (20 ml) is heated at 80° C. for 3 days, adding tributylvinyltin (0.28 ml, 0.96 mmol) every 24 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 40 ml of water and 40 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(OCC1C=CC=CC=1)=O)=O)(C)(C)C.[CH2:49]([O:56][C:57](=[O:81])[NH:58][C@H:59]1[CH2:63][CH2:62][N:61]([C@H:64]2[CH2:69][CH2:68][C@@H:67]([NH:70]C(OC(C)(C)C)=O)[CH2:66][C@H:65]2[CH2:78][CH3:79])[C:60]1=[O:80])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:70][C@@H:67]1[CH2:68][CH2:69][C@H:64]([N:61]2[CH2:62][CH2:63][C@H:59]([NH:58][C:57](=[O:81])[O:56][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:60]2=[O:80])[C@H:65]([CH2:78][CH3:79])[CH2:66]1
Reactant: CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedures described in Example 2a, Steps 1-4, and substituting methyl triphenylphosphonium iodide in Step 1, (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester was converted to {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-ethyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester. A portion of this material (995 mg, 2.2 mmol) was dissolved in 20 mL of 4:1 CH2Cl2/TFA. The resultant solution was stirred at RT for 3 h and concentrated in vacuo. The residue was dissolved in methylene chloride and concentrated in vacuo; this procedure was repeated twice more to afford benzyl (S)-1-((1S,2R,4R)-4-amino-2-ethylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=360.2.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31].C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:28][CH2:29][CH:30]([OH:32])[CH3:31])=[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: CC(O)CN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(O)CNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 90 %

Procedure:
To a solution of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (3.0 g, 5.8 mmol) in 1,4-dioxane was added 1-amino-2-propanol (0.52 g, 7.0 mmol) and triethylamine (0.76g, 7.5 mmol). The mixture was heated at 100° C. for 2 hours. After extractive workup and recrystallisation from heptane-ethyl acetate (1:1) there was obtained 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(2-hydroxypropylamino)-4-trifluoromethylsulfonylpyrazole (Compound number 1-5, 2.67 g), 19F: −64.2; −80.9.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccc(Cl)nc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 6-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 490.2 (MH+).
Reaction SMILES: C(Cl)Cl.C(N(CC)CC)C.C(O)=O.[C:14]([NH:33][CH:34]([C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[C:14]([NH:33][C@H:34]([C@H:40]([OH:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Solvent: O
Solvent: ClCCl
Solvent: O=CO
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A methylene chloride solution (0.5 ml) of triethylamine (131.6 mg, 1.30 mmol) and a methylene chloride solution (0.5 ml) of formic acid (64.5 mg, 1.37 mmol) were added to a methylene chloride solution (4.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (18.9 mg, 0.03 mmol) and ethyl 2-octadecanoylamino-3-oxooctadecanoate (121.6 mg, 0.20 mmol) synthesized in the same method as Example 9. After the mixture was stirred for 16 hours at room temperature, water was added thereto and extraction with methylene chloride was carried out three times. After the organic layers were combined and dried with magnesium sulfate, the solvent was removed in reduced pressure. The obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=4:1) to obtain the title compound (109.6 mg, yield: 90%). The product was analyzed by HPLC to find that anti-form:syn-form was 91:9 and the optical purity of the anti-form was 95% ee.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C.Br.C(O)(=O)C.CCOCC>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: BrBr
Reactant: CSc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CSc1ccc(C(=O)C(Br)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone from step1 (8.4 g, 0.024 mol) in acetic acid (130 mL), bromine (3.8 g, 0.024 mol) in 25% hydrogen bromide-acetic acid solution (50 mL) was added dropwise at room temperature. After stirring for 4 h at room temperature, concentrated gave the yellow solid. The solid was suspended in ether and collected by filtration, washed with ether to give the title compound (7.5 g, 73%).
Reaction SMILES: CC1C(C)=C(C2C=C(C=CC=2C)C(O)=O)NN=1.[CH3:18][C:19]1[C:23]([CH3:24])=[C:22]([C:25]2[C:26]([CH3:36])=[CH:27][C:28]([CH3:35])=[C:29]([CH:34]=2)[C:30]([O:32]C)=[O:31])[NH:21][N:20]=1.CC1C(C)=C(C2C=C(C=CC=2C)C(OC)=O)NN=1>>[CH3:18][C:19]1[C:23]([CH3:24])=[C:22]([C:25]2[C:26]([CH3:36])=[CH:27][C:28]([CH3:35])=[C:29]([CH:34]=2)[C:30]([OH:32])=[O:31])[NH:21][N:20]=1
Reactant: COC(=O)c1cc(-c2[nH]nc(C)c2C)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1
Agent: Cc1ccc(C(=O)O)cc1-c1[nH]nc(C)c1C
Product: Cc1cc(C)c(-c2[nH]nc(C)c2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 59.3, except methyl 5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 242.1) was used in place of methyl 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoate (compound 59.2). m/z (ES+) 245 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@@H:6]([C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[CH3:17])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH2:16][CH2:15][CH2:14][CH2:17][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1=C([C@H]2CN(C)CCc3cc(Cl)c(O)cc32)CCC1
Agent: Cl
Product: CN1CCc2cc(Cl)c(O)cc2[C@H](C2=CCCCC2)C1

Procedure:
(R)-7-chloro-8-hydroxy-3-methyl-(2-methyl-1-cyclopentenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. of hydrochloride 249°-251°C. (dec.);
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:15]1([C:14]2[O:21][CH:13]=[N:12][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)cc1

Procedure:
A mixture of tosylmethyl isocyanide (5.86 g, 30 mmol), benzaldehyde (3.18 g, 30 mmol) and K2CO3 (6.22 g, 45 mmol) in 60 ml MeOH was refluxed for 2 hr and concentrated. 250 ml EtOAc was added and the mixture was washed with H2O, brine, dried and concentrated. The residue was chromatographed on silica gel using 15:1 hexane/EtOAc to afford the title compound of this step (2.5 g, 57%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](C(=O)O)([C@H]2CCOC2)C1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)O)([C@H]2CCOC2)C1
Yield: 0.1 %

Procedure:
(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylic acid (0.79 g, 2.6 mol) was dissolved in ethanol (20.0 mL), degassed-purged with N2, followed by the addition of platinum dioxide (0.150 g, 0.528 mol). The reaction mixture was placed on a Parr apparatus and hydrogenated under hydrogen at 55 psi for 18 h. The mixture was filtered through celite pad, washed with MeOH, concentrated to provide the desired product (730 mg, 91.8%). MS calculated for C15H26NO5 (M+H) 300.2; found 200.2 (M+H-Boc).