Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:21]C(OC(C)(C)C)=O)[S:9][C:10]=1[CH:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:21])[S:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1C(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(N)sc1Cc1ccccc1OC
Yield: 65.5 %

Procedure:
A mixture of 2-tert-butoxycarbonylamino-5-[hydroxy-(2-methoxy-phenyl)-methyl]-thiazole-4-carboxylic acid ethyl ester (12 g, 29 mmol), triethylsilane (52 g, 45 mmol), and trifluoroacetic acid (100. g, 89.6 mmol) was stirred for 15 hours in dichloromethane (150 mL). The mixture was evaporated to dryness and then diluted with water. The precipitated solid was filtered and washed with water, diethyl ether, and petroleum ether to give the pure target molecule as a trifluoroacetic acid salt (7.6 g, 19 mmol, 64%). ESI-MS m/z calc. 292.09. found; 292.25 (M+1)+ 1H NMR (CDCl3) δ 7.7 (br, 2H), 7.24 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 6.88 (t, 1H), 4.22-4.25 (m, 4H), 3.78 (s, 3H), 1.26 (t, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=3)[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[C:19](=[O:26])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)COCCOC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)COCCOC)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl [4-({{4-[(4-butylphenyl)ethynyl]benzyl}[(2-methoxyethoxy)acetyl]amino}methyl)phenoxy]acetate and NaOH 1N in the presence of MeOH/THF as a yellow oil (94%). 1H NMR (DMSO-d6, 300 MHz) δ 7.54-7.43 (m, 4H), 7.24 (m, 4H), 7.14 (d, J=8.3 Hz, 2H), 6.86 (m, 2H), 4.62 (s, 2H), 4.41 (m, 4H), 4.28 (s, 1H), 4.20 (s, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 3.21 (s, 1.5H), 3.19 (s, 1.5H), 2.60 (t, J=7.5 Hz, 2H), 1.55 (m, 2H), 1.30 (m, 2H), 0.89 (t, J=7.2 Hz, 3H). M− (ESI): 542.4; M+ (ESI): 544.4. HPLC, Rt: 4.82 min (Purity: 90.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[CH3:15]O.S(=O)(=O)(O)O>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C=Cc1cccc(N)c1

Procedure:
While mixing and stirring 193 g of 3-nitrocinnamic acid, 2 of methanol and 50 g of concentrated sulfuric acid, the mixture was heated under reflux for 2 hours. The reaction solution was poured into water and the crystals obtained were filtered. To a reaction solution under heat-refluxing while mixing and stirring 2 of 2-propanol, 200 ml of water, 20 g of ammonium chloride and 200 g of reduced iron, the crystals obtained above were gradually added, and the solution was further heated under reflux for one hour. The reaction solution still being hot was filtered, the filtrate was poured into 10 of water, and the crystals (methyl 3-aminocinnamate) obtained were collected by filtration. Yield: 108 g.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[OH-].[K+:12].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].OO.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.Cl.Cl.N(C(C)(C)C(N)=N)=NC(C)(C)C(N)=N>C(C=CC(N)=O)C=CC(N)=O.O>[C:6]([O-:10])(=[O:9])[CH:7]=[CH2:8].[K+:12].[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Agent: C=CC(N)=O
Agent: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
In a polymerization vessel, 0.9 g methylene bisacrylamide and 192 g acrylamide were dissolved in 500 g water first and mixed with 84 g acrylic acid. Then, the monomer solution was neutralized with 102 g potassium hydroxide solution (45%), cooled to 10° C. and blown out with nitrogen. After addition of the catalyst solutions (1.6 g sodium peroxidisulfate, 0.2 g hydrogen peroxide (35%) and 0.01 g ascorbic acid) and 10 g 2,2'-azobis(2-methyl-propionamidine)dihydrochloride used as blowing agent, the polymerization was initiated. Thorough mixing of the catalyst solutions with the monomer solution is a precondition for a homogeneous polymerization in the whole polymer block. The maximum temperature of 100° C. (in a well-insulated polymerization vessel) was reached within 10 minutes. After completed polymerization, the polymer gel was crumbled, dried at 120° C. and ground to the desired size fraction. A cross-linked potassium acrylate/acrylamide copolymer was obtained which had a porous structure resulting from the entrapped nitrogen bubbles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:32]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])[CH:33]=[CH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:32][CH:33]=[CH2:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: C=CCOCCn1c(C(=O)C2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1-(2-allyloxy-ethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2)=[O:5])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.O>[CH:11]1[C:10]([OH:17])=[CH:9][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14](=[O:16])[C:13]=2[CH:12]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(=O)c2ccc(O)cc2o1
Temperature: 80 °C

Procedure:
2-Ethoxycarbonyl-7-hydroxychromone (14.5 g, 62 mmol) is initially introduced dissolved in ethanol (400 ml) at 50° C., and sodium carbonate (20 g, 190 mmol) dissolved in deionised H2O (200 ml) is added dropwise. The mixture is refluxed at 80° C. for 3 hours with stirring. After cooling, the mixture is acidified using 2N HCl. The precipitated white solid is filtered off with suction, washed until neutral and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C([O-])(O)=O.[Na+]>ClCCl>[F:23][CH2:24][CH:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)[CH2:26][F:27]
Reactant: O=C(CF)CF
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCC1CCN(C(CF)CF)CC1
Reaction time: 8 h

Procedure:
A suspension of piperidin-4-ylmethanol (0.250 g), sodium triacetoxyborohydride (0.690 g) and 1,3-difluoropropan-2-one (0.245 g) were stirred together in dichloromethane. After stirring overnight the reaction was poured into saturated aqueous NaHCO3 solution (10 mL) and stirred for 15 minutes. The reaction was extracted with dichloromethane (3×25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.75% to 3% methanol/dichloromethane gave the title compound.
Reaction SMILES: BrC1C(F)=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:37])[C:32]=2[Br:36])[CH:27]1[CH2:38][C:39]([O:41]C)=O)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>O.CO>[Br:36][C:32]1[C:31]([F:37])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH2:34][CH2:35][N:26]1[C:23](=[O:25])[CH2:24][NH:6][C:39](=[O:41])[CH:38]=[C:27]12
Reactant: COC(=O)CC1NCCc2c1ccc(F)c2Br
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL, 1383 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (47.6 g, 138 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (244 g) in water (500 mL). The slightly basic aqueous solution was extracted with AcOEt (3×). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (41.58 g) which was used without further purification. UPLC-MS: MS 302.1/304.1 (M+H+); UPLC rt 0.51 min.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@@H](CCl)NC(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To the compound (500 mg) obtained in Step 3 were added 3-fluorophenol (84 μl), potassium carbonate (250 mg) and DMF (2 ml), and the mixture was stirred overnight at 95° C. The reaction mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:6]1[CH:5]=[C:4]2[C:9](=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1)[N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][CH2:3]2
Reactant: COC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
1-(1,1-dimethylethyl) 7-methyl 2,3-dihydro-1H-indole-1,7-dicarboxylate (3.1 g, 11.2 mmol) and N-bromosuccinimide (2.0 g, 11.2 mmol) were dissolved in dry dichloromethane (100 mL) and stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction was partitioned with sodium hydroxide solution (2 M), separated and washed with more sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a gummy red solid (3.55 g).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([CH:23]=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([CH:23]=[CH2:1])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
A slurry of methyltriphenylphosphonium bromide (450 g, 1.3 mmol, 3.0 eq.) in THF (200 mL) was cooled to −78° C. 2M Sodium bis(trimethylsilyl)amide (580 mL, 2.8 eq.) was added and the mixture was stirred for 3 hours. A solution of (R)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (84 g, 421.6 mmol, 1.0 eq.) in THF (100 mL) was added dropwise at −65°. Upon completion of the reaction, the product was purified by column chromatography (200-300 mesh, hexanes:EtOAc=1:3, 3 L) to yield (S)-3-vinyl-pyrrolidine-1-carboxylic acid t-butyl ester (40 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O.O1CCOCC1>[OH-].[K+].CCO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Yield: 10.1 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g, 1.56 mmol) was reacted with 4-formyl benzoic acid (0.351 g, 2.34 mmol) in 5.0 mL of 4% KOH in EtOH and 1 mL of dioxane at room temperature for 6 days. The reaction was diluted with minimal water to achieve complete solution and then extracted with DCM. The resulting aqueous solution was acidified to pH 2 with 1N HCl. After standing at room temperature for 3 weeks, 0.061 g (10%) of the title compound was isolated by filtration as a fine cream powder, nmp 267-267.5° C.: CI-MS m/e 388 (M+), 389 (M+ +1);
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][NH:6][C:7]([N:9]1[CH2:13][C@@H:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])([C:19]#[N:20])[C@H:10]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:8])C.O.[OH-].[Li+]>>[Cl:35][C:31]1[C:30]([F:36])=[C:29]([C@@H:10]2[C@:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:12]([CH2:14][C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:13][N:9]2[C:7]([NH:6][CH2:5][C:4]([OH:37])=[O:3])=[O:8])[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)CNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 94 %

Procedure:
In a manner similar to the method described in Example 52, rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid ethyl ester (83 mg, 0.144 mmol, example C16) was reacted with lithium hydroxide hydrate (36 mg, 0.945 mmol, Aldrich) to give rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (71 mg, 92%) HRMS (ES+) m/z Calcd for C25H25Cl2F2N3O3+H [(M+H)+]: 524.1314; Found: 524.1315.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:35](=[O:37])[CH3:36])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: CC(=O)Cl
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CC(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 6 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 13 mg (6%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d5) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.10 (d, 2 H), 1.90 (s, 3 H); ES-MS m/z 488.4 [M+H]+, HPLC RT (min) 2.69.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH:21]1([C:24](=N)OCC)[CH2:23][CH2:22]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:17][N:16]=2)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Reactant: CCOC(=N)C1CC1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2nnc(C3CC3)o2)cc1
Yield: 40 %

Procedure:
4-(((Tert-butyldimethylsilyl)oxy)methyl)benzohydrazide was reacted with ethyl cyclopropanecarbimidate hydrochloride according to the procedure used for the synthesis of Example 18. Purification by chromatography (EtOAc-hexanes) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cyclopropyl-1,3,4-oxadiazole as a brown oil (3.7 g, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[C:19]([F:31])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([F:24])=[CH:22][CH:23]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:31][C:19]1[C:18]([CH2:17][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1ccc(CCl)c(F)c1-c1ccccc1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Fc1ccc(CO/N=C(/c2ccc(Cl)cc2)C2CC2)c(F)c1-c1ccccc1

Procedure:
In a manner similar to Example 2, the reaction of 0.59 g (0.003 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime with 0.072 g (0.003 mole) of sodium hydride and 0.72 g (0.003 mole) of 3-chloromethyl-2,6-difluoro[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2,6-difluoro[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[CH3:11].C([BH3-])#N.[Na+].C(O)(=O)C>ClCCl>[CH2:10]([O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([N:19]2[CH2:24][CH2:23][CH:22]([NH:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[OH:9])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1)[CH3:11]
Reactant: CCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Reactant: Cc1ccc(O)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCO[C@H]1CC[C@H](N2CCC(Nc3cc(C)ccc3O)CC2)CC1
Temperature: 25 °C

Procedure:
2-Amino-4-methylphenol (56.1 mg, 0.456 mmol) was dissolved in dichloromethane (3 mL) and 1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinone (D66, 103 mg, 0.456 mmol), polymer supported sodium cyanoborohydride (212 mg, 0.912 mmol, 4.3 mmol/g) and acetic acid (0.13 mL, 2.28 mmol) were all added at rt. The mixture was reacted at 100° C. in the microwave for 10 min. The mixture was then cooled to rt, filtered and concentrated by rotary evaporation to give 2-({1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}amino)-4-methylphenol (D29, 215 mg, 92% yield) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:31])[CH:14]=[C:15]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C.[Fe]>[CH3:1][CH:2]([NH:12][C:13](=[O:31])[CH:14]=[C:15]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1cccc(N)c1

Procedure:
Reduction of 11.6 g. of N-(1-methyldecyl)-3-phenyl-3-(3-nitrophenyl)propenamide with 7.7 g. of iron powder in glacial acetic acid, according to the procedure of Preparation 25, afforded the title compound as an oil. This product was chromatographed on 350 g. of silica gel, eluting with chloroform containing 1% ethanol. This gave 2.3 g. of trans-N-(1-methyldecyl)-3-phenyl-3-(3-aminophenyl)propenamide, 0.25 g. of cis-N-(1-methyldecyl)-3-phenyl-3-(3-aminophenyl)propenamide and 6.2 g. of a mixture of these two isomers. Rechromatography of the mixture afforded a further 0.6 g. of the cis-isomer. The NMR spectrum of the trans-isomer (in CDCl3) showed absorptions at 0.85 (m), 1.25 (s), 3.60 (b), 5.15 (b), 6.35 (s), 6.65 (m) and 7.30 (s) ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CNC(=O)C(N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
A solution of give (RS)-[(4-cyano-benzylcarbamoyl)-phenyl-methyl]-carbamic acid tert-butyl ester (0.77 g, example 86.1) in dichloromethane (20 ml) was cooled to 0° C. and treated with trifluoro acetic acid (5 ml). The reaction mixture was stirred at rt for 5 hrs, then diluted with dichloromethane, cooled to 0° C. and brought to pH 9 by dropwise addition of saturated aqueous Na2CO3. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give (RS)-2-amino-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.56 g). Off-white amorphous solid. MS 266.2 ([M+H]+)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]CC.[Na+].Cl>C(O)C>[C:12]1([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:9][N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)noc1/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid ethyl ester (2.28 g, 10 mmol) and benzaldehyde (1.01 mL, 10 mmol) in ethanol (15 mL) was added sodium ethoxide (0.74 g, 11 mmol) and the reaction mixture was heated under reflux for 10 min. Aqueous hydrochloric acid (1 M, 12 mL) was then added and after stirring for 15 min the precipitate was filtered and dried to afford the title compound as a light brown solid (2.0 g, 71%). MS: m/e=292.1 [M+H]+.