Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[Si](COCC[N:15]1[C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=[N:16]1)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[C:31]1[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[CH:35][N:36]=1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O.C(#N)C>[NH2:38][C:32]1[N:33]=[C:34]([NH:37][C:20]([C:19]2[NH:15][N:16]=[CH:17][CH:18]=2)=[O:22])[CH:35]=[N:36][C:31]=1[C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[Cl:23]
Reactant: C[Si](C)(C)COCCn1nccc1C(=O)O
Reactant: Nc1cnc(-c2cc(Cl)ccc2Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nc(NC(=O)c2ccn[nH]2)cnc1-c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.17 ml, 1.9 mmol) was added to a slurry of 2-(2-trimethylsilanylmethoxy-ethyl)-2H-pyrazole-3-carboxylic acid) (Heterocycles (1992) 34 303-314), (428 mg, 1.76 mmol) in dichloromethane (15 ml), 1 drop of dimethylformamide was added and the reaction stirred at room temperature under N2 for 1 hour before concentrating in vacuo and azeotroping with dichloromethane. The resulting acid chloride was dissolved in 5 ml acetonitrile and added to a solution of 3-(2,5-dichloro-phenyl)pyrazine-2,6-diamine (Preparation 11, 300 mg, 1.18 mmol) in acetonitrile (15 ml) and 2,6-lutidine (0.21 ml, 1.8 mmol). The reaction was stirred at room temperature under N2 for 72 hours before concentrating in vacuo then partitioning between 50 ml ethyl acetate and 50 ml water. The organic layer was dried over MgSO4 and concentrated in vacuo to give a brown oil which was purified by column chromatography (ethyl acetate, heptane, 1:2) to give 52 mg of the title product.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CS(C)=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][CH:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[OH:2])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(C(O)Cc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 10° C. solution of 4-formyl benzonitrile (65.6 gm, 0.500 mol), 4-methyl-3-nitro benzonitrile (81.1 gm, 0.500 mol) and 750 mL of dry dimethylsulfoxide (DMSO), was added sodium methylate (4.01 gm, 75 mmol) in one portion. After 4 hrs, the reaction was added dropwise to 6 L of ice water and then allowed to stir for 1 hr. The product was collected via vacuum filtration and washed with water (3×1 L) and then dried over night in a vacuum oven at 40° C. to give 2-(4-cyano-2-nitro-phenyl)-1-(4-cyano-phenyl)-ethanol.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:20]2[CH2:19][CH2:18][C@@:15]2([CH:16]=O)[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25][C:26](=[O:28])[CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[Cl-].[Cl:30][CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.C([Li])CCC>O1CCCC1.CCCCCC>[C:1]([O:4][C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7](=[CH:8][CH2:9][C@H:10]3[C@H:11]4[C@@:15]([CH:16]=[CH:31][Cl:30])([C@@H:14]([O:25][C:26](=[O:28])[CH3:27])[CH2:13][CH2:12]4)[CH2:18][CH2:19][C@@H:20]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C=O)CC[C@@H]32)C1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C=CCl)CC[C@@H]32)C1

Procedure:
A solution of 2.92 g of 3β,17β-diacetoxy-androst-5-en-18-al in 30 ml of tetrahydrofurane is added dropwise to a solution of a Wittig reagent prepared from 7.83 g of chloromethyl-triphenyl-phosphonium chloride, 144 ml of tetrahydrofurane, 2.23 ml of piperidine and 11.25 ml of a 1.56 molar solution of butyl-lithium in hexane and the mixture is allowed to react for 40 minutes at room temperature and is worked up as indicated in Example 1. On purification by chromatography, as also indicated in Example 1A, this gives the cis and trans isomers of 3β,17β-diacetoxy-13-(2-chlorovinyl)-10-methyl-gon-5-ene in a ratio of 1:3. The cis isomer crystallises from methylene chloride/hexane and then melts at 161°-162° C; [α]D25 = -70° (in chloroform); the trans isomer crystallises from methylene chloride/hexane, melting point 155°-156° C, [α]D25 = -42° (in chloroform).
Reaction SMILES: [C:1]1([C:7](=[O:40])[CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[O:44]CC1.[OH-].[K+]>CO>[C:1]1([C:7](=[O:40])[C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(-c2cnc3c(n2)c(CC(=O)c2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(=O)c4ccccc4)c3n2)cc(OC)c1OC
Temperature: 40 °C

Procedure:
1-Phenyl-2-[5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone (100 mg, 0.18 mmol) was suspended in 4 ml of a 1:1 mixture of THF and methanol and 5N potassium hydroxide (0.180 ml, 0.9 mmol) was added dropwise. The reaction was heated at 40° C. for 2 hours. The solvents were evaporated using a rotary evaporator. Ethyl acetate and 1M hydrochloric acid were added to the residue and the layers were separated. The organic layer was washed with water, dried and concentrated. The crude reaction mixture was purified by preparative thin layer chromatography (50% ethyl acetate in hexanes) and flash chromatography to yield 4 mg of 1-phenyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethane-1,2-dione. MS: (M+H)+=418.
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH:21]=[CH:22][C:23]3[CH:24]=[C:25]([C@@H:29](OS(C)(=O)=O)[CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([OH:41])([CH3:40])[CH3:39])[CH:26]=[CH:27][CH:28]=3)=[N:18]2)=[CH:13][CH:12]=1>>[CH3:40][C:38]([OH:41])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH2:30][C@@H:29]([S:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1)[C:25]1[CH:26]=[CH:27][CH:28]=[C:23](/[CH:22]=[CH:21]/[C:17]2[CH:16]=[CH:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:20][C:19]=3[N:18]=2)[CH:24]=1)[CH3:39]
Reactant: CC(C)(O)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: O=C(O)CC1(CS)CC1
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
In U.S. Pat. No. 5,614,632, montelukast is prepared by condensing 1-(mercaptomethyl)cyclopropaneacetic acid then condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol compound to afford Montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:19]4[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)cn1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)cn1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([C:30](NN)=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2.[NH4+].[OH-]>C(Cl)Cl.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([CH:30]=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4cc(C(=O)NN)ccc4nc3C2)c2cccnc21
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4cc(C=O)ccc4nc3C2)c2cccnc21

Procedure:
To a rapidly stirred solution of (2S)-2′-oxo-1′-{[2-(trimethylsilyl)eth-oxy]methyl}-1,1′,2′,3-tetrahydrospiro[cyclopenta[b]quinoline-2,3′-pyrrolo[2,3-b]pyridine]-7-carbohydrazide from Step H (317 mg, 0.667 mmol) in DCM (6.8 mL) was added water (2.7 mL) plus concentrated aqueous NH4OH (0.6 mL) and lastly potassium ferricyanide (549 mg, 1.67 mmol). After 4.5 hours the reaction was diluted with water (20 mL) and DCM (40 mL). The aqueous layer was extracted once with DCM (20 mL). The combined organics were washed successively with water then half-saturated brine and then dried over sodium sulfate. The organics were then filtered, concentrated in vacuo, and applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99:1 to 90:10. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=446 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7][N:8]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Yield: 38.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-3 using 5-nitro-N-(4-(trifluoromethyl)phenyl)isoquinolin-1-amine (750 mg, 2.25 mmol), iron powder (1.26 g, 22.5 mmol), and NH4Cl (963 mg, 18.0 mmol) in EtOH—H2O (5:2, 7 mL) to afford 260 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.09 (d, J=9.0 Hz, 2H), 7.94 (d, J=6.0 Hz, 1H), 7.64 (m, 3H), 7.44 (d, J=5.7 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 5.87 (br s, 2H); MS (m/z): 304.28 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[C:4]([F:7])([F:6])[F:5].CCN(C(C)C)C(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:10][CH3:11])([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]([F:7])([F:6])[F:5]
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N)CC1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.71 g (1.87 mmol) of trans 4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexylamine in 5 mL of CH2Cl2 was treated with 0.64 mL (3.74 mmol) of DIPEA and 0.24 mL (1.87 mmol) of benzenesulfonylchloride and stirred at RT for 3 hrs. Distribution of the crude mixture between a diluted aqueous solution of HCl and Et2O, drying of the combined organic phases over Na2SO4 and chromatography on silica gel with EtOAc/heptane 1:1 gave 0.9 g (93%) of trans-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a light yellow semisolid, MS: 518 (M−H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
To a solution of N-Boc-piperazine (2.02 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluoro-6-chlorobenzonitrile (1.55 g, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL) and then dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (4:1 hexanes/ethyl acetate) gave the title compound (2.5 g, 86%) as a colorless oil.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@H:30]([CH2:33][O:34][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:31][CH3:32])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@H:30]([CH2:33][OH:34])[CH2:31][CH3:32])[N:27]=2)[CH2:20]1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.52 g, 3.50 mmol) (obtained as described in Reference Example 34(2)) in anhydrous tetrahydrofuran (126 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (8.40 ml, 8.40 mmol) in an ice bath. The mixture was stirred overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (9:1) as the eluant to afford 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (947 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:23]C=O)[CH:6]=[C:7]([CH2:12][P:13]([O:19]C(C)C)([O:15]C(C)C)=[O:14])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2].C[SiH](C)C.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH2:23])[CH:6]=[C:7]([CH2:12][P:13]([OH:15])([OH:19])=[O:14])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCOCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Agent: C[SiH](C)C
Solvent: CCO
Solvent: ClCCl
Product: CCOCC(=CC(N)C(=O)OCC)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
1.10 g (2.8 mmol) of 5-ethoxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 1.6 ml (12.3 mmol) of trimethylsilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 7 hours, 20 ml of ethanol are added, the mixture is left to stand for a further 15 hours and is concentrated by evaporation, the residue is dissolved in 10 ml of ethanol, and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 217°-218° C. (decomp.).
Reaction SMILES: [N:1]#[C:2]Br.C([O-])([O-])=O.[K+].[K+].Cl.C[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)[CH2:14][CH2:13]1.O>CS(C)=O>[C:27]1([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:2]#[N:1])[CH2:13][CH2:14]3)=[N:19]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of cyanogen bromide (5.76 g, 0.054 moles) and K2CO3 (8.82 g, 0.064 moles) in dimethylsulfoxide (110 ml) was added 3-(1-methyl-4-piperidinyl)-1-phenyl-1H-indazole (14.8 g, 0.051 moles) of Example 66 in dimethylsulfoxide (DMSO) (15 ml). The reaction was stirred at ambient temperature for 16 hours and then poured into water and extracted with ether. A precipitate formed in the ether which was collected and then the ether was concentrated to yield additional product. The crude product (11.5 g) was recrystallized three times from isopropyl alcohol which yielded 6.75 g (37%) of 4-(1-phenyl-1H-indazol-3-yl)-piperidine-1-carbonitrile, m.p. 124°-125° C.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COC(Cc1ccc(C#CCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](Cc1ccc(CCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared as follows: (2S) 3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid (0, Step C) (0.0325 g, 0.08 mmol) was dissolved in methanol (10 mL). Palladium 10% an activated carbon (0.004 g, 0.004 mmol) was added and the solution saturated with hydrogen (1 Atm) and stirred for 5 hours. The mixture was filtered through a pad of celite and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hexanes/Ethyl acetate-Acetic acid 50:50:1, Rf0.23) (85%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.56–7.24 (m, 11H), 6.94 (d, 2H, J=8.8), 4.02–3.95 (m, 3H), 3.38 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.98 (dd, 1H, J=14.3, 7.3), 2.79 (t, 2H, J=8.1), 2.16–2.03 (m, 3H). MS (ES) for C25H26O4 [M+NH4]+: 408.2, [M+Na]+: 413.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31]([N:77]3[CH2:82][CH2:81][O:80][CH2:79][CH2:78]3)=[CH:30][N:29]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
(4-Benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (433 mg) is dissolved in toluene (5 ml) and thereto are added tris(dibenzylideneacetone)dipalladium (107 mg), sodium tert-butoxide (168 mg), 2-(di-tert-butylphosphino)biphenyl (69.4 mg) and morpholine (152 mg) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to give (4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (384 mg). MS (m/z): 751 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:33])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][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].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][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])([CH2:6][O:7][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][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])[CH2:4][O:5][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][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:33])[CH2:11][CH2:12][CH2:13][CH2:14][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: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: N#N
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCCCCCC)(COC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 165 °C

Procedure:
A 1000 ml round bottomed flask was charged with 648.0 g. (0.15 mol) PEG 105 pentaerythritol and 186 g. (0.60 mol) behenic acid. The mass was heated at 100° C. with a N2 sparge, 0.75 g. methane sulfonic acid and 0.1 g. hypophosphorus acid were charged. The batch was heated to 165° C. while collecting the water of reaction, and maintained until an acid value of 11.5 was reached. The finished material was a white waxy solid having an acid value of 11.5, and a hydroxyl value of 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([OH:32])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:35]1C=CC(C2CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(O)C=4C3)CC2)=C[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:35][CH3:36])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: CCOc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 46, but replacing the product of example 44 with the product of example 151.