Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCCN(C)C)ccc1N
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 85.4 %

Procedure:
To a mixture of 1.1371 g (4.0 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.6131 g (6.0 mmole) of 3-dimethylamino-propylamine followed by 1.0119 g (10 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8587 g 4-amino-N-(3-dimethylamino-propyl)-3-methoxy-benzamide, which was used without further purification.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH3:11][O:12][C:13]([N:15]1[CH:20]=[CH:19][CH2:18][C:17]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])=[CH:16]1)=[O:14].CC([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:12][C:13]([N:15]1[CH:16]=[C:17]([C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH2:18][C:19]([CH:4]=[O:5])=[CH:20]1)=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)N1C=CCC(C2CCCN2C)=C1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)N1C=C(C=O)CC([C@@H]2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of DMF (0.04 mL, 0.54 mmol) in 4 mL of CH2Cl2 cooled at 0° C. was slowly added POCl3 (0.025 mL, 0.27 mmol). The ice bath was removed and the mixture was stirred at RT for 30 min. It was then transferred via a double tipped needle to a solution of 3-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II (0.0404 g, 0.18 mmol) in 4 mL of CH2Cl2 cooled at 0° C. The reaction mixture was stirred at RT for 1 day. A solution of NaOAc (0.024 g, 0.29 mmol) in 0.5 mL of water was added and the reaction mixture was stirred at RT for 20 min. A saturated aqueous solution of NaHCO3 was slowly added until pH was basic (about 10 mL). The aqueous layer was extracted with CH2Cl2 (4 times), and the combined organic layers were dried over MgSO4. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (15% EtOAc/hexanes) to afford 0.0241 g (54%) of (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1carboxylic acid methyl ester III as white crystals, mp 78–80° C. IR (thin film, neat, NaCl): 2955, 2767, 1731, 1667, 1620, 1437, 1394, 1203, 991 cm−1; 1H NMR (CDCl3, 300 MHz) δ 9.45 (s, 1 H), 7.65 (m, 1 H), 6.81 (s, 1 H), 3.91 (s, 3 H), 3.12–3.07 (m, 1 H), 2.93 (s, 2 H), 2.59 (m, 1 H), 2.20–2.12 (m, 3 H), 1.81–1.62 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 191.13, 141.44, 122.61, 120.52, 118.42, 69.75, 56.98, 54.47, 40.61, 29.45, 22.91, 19.86. HRMS Calcd for C13H18N2O3: 251.1396 [M+H]+. Found: 251.1390 [M+H]+. [α]25D −5.17 (c=0.8, CH2Cl2).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]([OH:27])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:25]([O:27][C:12]1[CH:13]=[CH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:11]=1)=[O:26])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: C=CCOC(=O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)c1
Yield: 99.7 %

Procedure:
Allyl 3-hydroxybenzoate (2.82 g, 15.8 mmol), 3,4,5-tribenzyloxybenzoic acid (10.7 g, 23.1 mmol), DMAP (5.51 g, 26.5 mmol), and CH2Cl2 (200 mL) were combined and stirred under a nitrogen atmosphere. EDC.HCl (5.51 g, 28.8 mmol) was added to the mixture and the reaction was allowed to reflux overnight under a nitrogen atmosphere. The reaction was then extracted with 5% citric acid (2×), saturated aqueous sodium bicarbonate (2×), and brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to obtain a solid (9.46 g, 99%) that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 91 %

Procedure:
From 4-nitro-bromobenzene and 4-methoxyphenyl boronic acid, yield 91%; mp 104-105° C. (lit.,3 106-107° C.); IR: 1597, 1509, 1342 and 125I; 1H NMR (600 MHz; CDCl3): 8.27 (2H, d, J 9), 7.69 (2H, d, J 8.4), 7.58 (2H, d, J 9), 7.02 (2H, d, J 8.4) and 3.87 (3 H, s); 13C NMR (CDCl3): 160.4, 147.1, 146.5, 131, 128.5, 127, 124.1, 114.6 and 55.4; m/z (EI) 229 (25%, M+), 169. (30), 131 (30) and 69 (100)(Found: M+, 229.073. C13H11NO3 requires M, 184.074).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-methylpyridazine. ESI-MS (m/z): 406 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([C:39]1[CH:43]=[C:42]([C:44]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]3[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]2=[O:25])=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
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: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cc(C(C)(C)C)nn3C)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (40 mg, 0.08 mmol) in DMF (2 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (18 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol). The reaction was stirred at RT for 14 h, partially concentrated, and purified by RP-HPLC to affor 20 mg of the title compound. MS found: (M+H)+=538.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC[C@H]1CO1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].NCCCN1CCN(C)CC1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Agent: CN1CCN(CCCN)CC1
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(Oc3ccc4[nH]cc(C)c4c3)c2c1
Temperature: 70 °C
Yield: 51.5 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described in Example 278), and 1-(3-aminopropyl)-4-methylpiperazine (132 mg, 0.84 mmol) in DMF (5 ml) was heated to 70° C. for 3 hours. The solvents were removed in vacuo and the residue taken up in dichloromethane. This was washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(344-methylpiperazin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (44 mg, 31%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:34]([O:36][C:37]([C@@:39]1([NH2:44])[CH2:41][C@H:40]1[CH:42]=[CH2:43])=[O:38])[CH3:35].[C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](O)=[O:55])([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>ClCCl>[C:48]([O:47][C:45]([N:52]1[CH2:60][C@H:58]([OH:59])[CH2:57][C@H:53]1[C:54](=[O:55])[NH:44][C@@:39]1([C:37]([O:36][CH2:34][CH3:35])=[O:38])[CH2:41][C@@H:40]1[CH:42]=[CH2:43])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
A solution of HATU (6 g), diisopropylethylamine (6.8 mL), (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.5 g) and BOC-L-hydroxyproline (1.6 g) in dichloromethane was stirred for 1 hrs. The mixture was extracted with DCM-NaHCO3 (aq) dried and concentrated. HPLC purity ca 90% M+H+ 369.1.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.Cl[C:16]1([C:28]([F:31])([F:30])[F:29])[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:18](=[O:27])[O:17]1>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[NH:19][C:18](=[O:27])[O:17][C:16]([C:2]#[C:3][C:4]3[O:5][CH:6]=[CH:7][CH:8]=3)([C:28]([F:29])([F:30])[F:31])[C:21]=2[CH:22]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(Cl)(C(F)(F)F)O1
Reactant: BrC(Br)=Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccco2)(C(F)(F)F)O1
Temperature: 25 °C
Yield: 110.5 %

Procedure:
To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at −20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to −50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to −35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][C:12]\1=[O:13].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:38]([O:37][C:35]([CH2:34][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:11][C:12]\1=[O:13])=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cccc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of (E)-3-[(pyrrol-2-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (7.16 g) and ethyl bromoacetate (8.60 g) in N,N-dimethylformamide (80 ml) were added potassium carbonate (7.10 g) and potassium iodide (8.50 g) with stirring at room temperature, and the resulting mixture was stirred at 80° C. for 4 hours. After filtration, the reaction mixture was diluted with dichloromethane, subsequently washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (1:2:1) as the eluent to afford the title compound (7.13 g, yield: 83%) as a yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C1(=O)[N:19](CC=O)[C:18](=O)[C:17]2=CC=CC=C12.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:19][CH2:18][CH2:17][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1OC)CNCC2
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1OC)CN(CCN)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 7,8dimethoxy-1,2,3,4-tetrahydroisoquinoline (421 mg, 2.2 mmol), 2-phthalimidoacetaldehyde (410 mg, 2.2 mmol) and NaOAc (180 mg, 2.2 mmol) in 27 mL of CH2Cl2 was added 690 mg (3.25 mmol) of NaBH(OAc)3 in small portions. After stirring 1 hour at room temperature, the reaction mixture was diluted with CH2Cl2 and washed with a saturated Na2CO3 solution and brine. The residue obtained after evaporation of CH2Cl2 was dissolved in 25 mL of EtOH and treated with 1.2 mL of hydrazine hydrate overnight. The reaction mixture was then filtered and evaporated to give 510 mg (100%) of the title compound; MS m/e 327 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:25]=1[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1>N1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:25]=1[C:26]([NH:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: Nc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(Nc1nnn[nH]1)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (1.03 g) was added to a solution of 2-benzyloxy-5-trifluoromethylbenzoic acid (1.48 g) and anhydrous 5-aminotetrazole (0.425 g) in dry pyridine (25 ml), and the resulting mixture was stirred at room temperature for 20 hours. The pyridine was removed in vacuo and the residue was treated with ammonia solution (4N; 75 ml) and stirred for one hour. The insoluble N,N'-dicyclohexylurea was filtered off, and the filtrate was acidified by treatment with concentrated hydrochloric acid. The precipitated solid was recrystallized from ethanol to give 2-benzyloxy-5-trifluoromethyl-N-(tetrazol-5-yl)benzamide (1.25 g), m.p. 248°-249° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:17][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:19]=1
Reactant: COc1ccc(OC)c(CCc2ccc(N)cc2)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(CCc2cc(OC)ccc2OC)cc1)C(=O)OCC

Procedure:
The mixture of 820 mg of 4-[(2,5-dimethoxyphenyl)ethyl]aniline and 690 mg of diethyl ethoxymethylene-malonate is heated to 95° for 2 hours. On cooling the product crystallises and is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][O:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[CH3:13][O:14][CH2:15][NH:16][C:17]([NH:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:18]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: COCN=C=O
Solvent: Cc1ccccc1
Product: COCNC(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 parts of 1,2,2,6,6-pentamethyl-4-aminopiperidine were dissolved in 100 parts of toluene, followed by the dropwise addition of 25° C. of 18.8 parts of 93% methoxymethyl isocyanate. After stirring for 1 hour at 25° C., the toluene was evaporated in vacuo and the residue was crystallised from cleaning spirit, giving 42.5 g of colourless crystals melting at 105° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[N-:15]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1.O>[NH2:15][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[CH3:49][C:39]1[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Charge 2-bromo-1-[3(trifluoromethyl)phenyl]-1-ethanone (1664.7 g; 1.00 equiv; 6.23 moles) and tetrahydrofuran (7500 mL) to a 12 L 3-necked round bottom flask (fitted with water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath. Charge sodium azide (425.6 g; 1.05 equiv; 6.55 moles) in one portion. Rinse into the flask with water (135 mL). Stir the pale yellow slurry at RT under nitrogen. After 6 hours, add water (260 mL) and continue to stir overnight. Filter the resulting orange slurry over a thin pad of Celite® and rinse with THF (1 L). Divide the resulting solution into two equal portions (5146.5 g each). Charge two identical 22 L 3-necked round bottom flask (fitted with addition funnel, water-cooled condenser, nitrogen blanket, mechanical stirrer and cooling bath) with triphenylphosphine (889 g, 3.43 mol, 1.1 eq), p-toluenesulfonic acid monohydrate (1304 g, 6.86 mol, 2.2 eq) and THF (5.6 L). Add the two portions of intermediate mixture via addition funnels to the individual flasks over four hours, controlling the foaming from nitrogen evolution by addition rate and the temperature by use of an ice bath. On completion of addition stir the slurry at ambient temperature for two hours, then filter solids from both reactors onto the same filter. Wash both flasks and the combined cake with a total THF (4 L). Dry in a vacuum oven at 40° C. overnight to afford (2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1:1) as a white, crystalline solid (2340 g, 6.23 mol, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=O)c2cc(C)ccc21
Temperature: 0 °C
Yield: 47.6 %

Procedure:
With stirring at 0° C., 8.06 g (50.0 mmols) of 5-methylisatin was added by small portions to a solution of 2.00 g (50.0 mmols) of sodium hydride in toluene. While stirring under ice cooling, 4.7 ml (50.0 mmols) of acetic anhydride was dropwise added to the mixture followed by heating at 80° C. for further an hour with stirring. After completion of the reaction, an aqueous saturated sodium bicarbonate solution was added to the reaction mixture. The crystals were filtered, washed with water and dried to give 4.84 g (yield, 47%) of 1-acetyl-5-methylisatin.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][CH:36]3[C:34]([N:38]([CH3:40])[CH3:39])([CH2:35]3)[CH2:33]2)[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][CH:36]3[C:34]([N:38]([CH3:40])[CH3:39])([CH2:35]3)[CH2:33]2)[N:3]=1
Reactant: CN(C)C12CC1CN(c1nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c1F)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C12CC1CN(c1nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c1F)C2
Reaction time: 6.5 h
Yield: 49.1 %

Procedure:
To a solution of [(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (assumed 0.6123 g, 1.067 mmol) in MeOH (10 mL) was added 20% Pd(OH)2/C (50% water, 61 mg). The mixture was hydrogenated for 6.5 h and then filtered. The filtrate was concentrated in vacuo and purified by Gilson RPLC to give [(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.2537 g, 49% yield for 2 steps, mixture of diastereomers) as a light pink solid. LCMS: (M+H)+: 484.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccc(I)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/c2ccccc2)cc1

Procedure:
4-Iodoanisole (58 mg, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above, but using triethylamine (0.375 mmol, 52 μL) in place of ethyldiisopropylamine, to give 100% conversion to (E)-4-methoxystilbene by GC analysis.