Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([O:24]CC)=[O:23])=[C:14]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C(F)(F)F)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([OH:24])=[O:23])=[C:14]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)O
Yield: 89.1 %

Procedure:
A mixture of the product of Step 3 (1.4 g, 3.1 mmol), in anhydrous CF3COOH (3 ml) was stirred for 24 h at room temperature under N2, than evaporated to dryness under reduced pressure. The residue was dried in vacuo for 1 h and suspended in H2O (10 ml) and the pH of the mixture was adjusted to ˜8 with NH4OH. This was filtered and filtrate was partially evaporated under reduced pressure. The precipitate formed was filtered off, washed with H2O, small volume of EtOH, Et2O and dried in vacuo to give pure product as a deep yellow solid (1.09 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=9.0 Hz, 1H), 7.3-7.5(m, 5H), 7.06-7.2(m, 5H), 6.42(m, 1H), 6.28(d, J=2.4 Hz, 1H), 3.93(m, 1H), 3.08(dd, J=7.0, 16 Hz, 2H), 2.72(dd, J=7.0, 16 Hz, 2H), 2.55(s, 3H). MS m/z M+ 395.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-])=[O:5].Cl.C(N=C=NCCCN(C)C)C.[N:22]1([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:5]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: OCCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCCCCN1CCOCC1

Procedure:
Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0° C. 4-Morpholin-4-yl-butan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][C:43]=1[C:51]([F:54])([F:53])[F:52]>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]2[CH2:27][N:26]([CH:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25]2)=[O:47])=[CH:44][C:43]=1[C:51]([F:52])([F:53])[F:54]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)NCC(=O)NC2CN(C3CCC(c4ccccc4)CC3)C2)cc1C(F)(F)F

Procedure:
The title compound was prepared as a white solid from EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 4-methoxy-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[CH2:58][N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1>CN(C=O)C.ClCCl>[N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:53]4[CH2:57][CH2:56][CH2:55][C@H:54]4[CH2:58][N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)N3CCCC3)s2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1)N1CCCC1
Yield: 57.1 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 5 mL 20% DMF/dichloromethane using 4-[5-(Pyrrolidine-1-carbonyl)-thiophen-2-yl]-benzoic acid (121 mg, 0.40 mmol), EDC-HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), DIEA (0.17 mL, 1.0 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (52 mg, 0.34 mmol) to give the title compound (85 mg, 57% yield). MS (ES+) 438.3 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[CH:4]=1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>O.CN1CCCC1=O>[NH:16]1[C:1]([C:3]2[CH:15]=[CH:14][C:6]3[O:7][C:8]([CH3:12])([CH3:13])[C:9]([CH3:11])=[CH:10][C:5]=3[CH:4]=2)=[N:2][N:18]=[N:17]1
Reactant: CC1=Cc2cc(C#N)ccc2OC1(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=Cc2cc(-c3nnn[nH]3)ccc2OC1(C)C
Temperature: 150 °C

Procedure:
A mixture of 6-cyano-2,2,3-trimethyl-2H-benzo[b]pyran (see J. Med. Chem., 1991, 34, 3074) (4 g), sodium azide (4.0 g), triethylamine hydrochloride (4.2 g) and 1-methyl-2-pyrrolidinone (40 ml), was heated at 150° C. for 1 hour. On cooling to room temperature water (200 ml) was added and the mixture was brought to pH 14 by the addition of solid sodium hydroxide. The solution was extracted with ethyl acetate (200 ml) then acidified to pH 3-4 with concentrated hydrochloric acid to give a solid which was filtered off, washed with water and dried to give the title compound, 4.5 g, m.p. 179°-181° C. Found: C, 64.58; H, 5.81; N, 23.46; C13H14N4O requires: C, 64.45; H, 5.82; N, 23.13%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([CH:13]=[CH2:14])[CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Nc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)ccc1NC(C)=O
Temperature: 95 °C
Yield: 63.9 %

Procedure:
To a stirred solution of N-(2-bromo-4-chloro-phenyl)-acetamide (2 g, 8 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (3.05 mL, 10.5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (1.41 g, 2 mmol). The reaction mixture was heated at 95° C. for 1 hour, and the solvent removed in vacuo. The residue obtained was purified by flash chromatography eluting with 20% ethyl acetate/CH2Cl2 to give N-(4-Chloro-2-vinyl-phenyl)-acetamide (1 g, 64%). HPLC: Rt=2.16 min. m/z=196 (M+H+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[S:18][C:19]3[CH2:25][CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[CH:13][CH:12]=1)(C)(C)C>C(O)C.Cl.O>[S:18]1[C:19]2[CH2:25][CH2:24][CH2:23][CH2:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][OH:6])=[N:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(-c2nc3c(s2)CCCC3)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: OCCCOc1ccc(-c2nc3c(s2)CCCC3)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
A mixture of 2-{6-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-pyridin-3-yl}-4,5,6,7-tetrahydro-benzothiazole (Example 77, 0.29 g, 0.71 mmol) in ethanol/HCl/water (95:1:4; 10 mL) was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (1:4 MeOH/CH2Cl2) to give the title compound (0.098 g, 46%). 1H NMR (400 MHz, CDCl3) δ 8.60 (dd, 1H), 8.10 (dd, 1H), 6.75 (dd, 1H), 4.51 (t, 2H), 3.73 (t, 2H), 2.95-3.10 (broad s, 1H), 2.80-2.86 (m, 4H), 2.00-2.12 (m, 2H), 1.80-1.96 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH:33]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Product: CCOC(=O)c1ccc(C2=CCCc3ccccc32)cc1
Yield: 93.5 %

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (2.58 g, 5.88 mmol) and 3,4-dihydro-naphthalen-1-yl trifluoromethanesulfonate (1.80 g, 6.47 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane followed by recrystallization from pentane (−20° C.) afforded the title compound (1.53 g) as slightly yellow crystals, m.p. 81° C.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[N:36][C:35]4[C:34](=[O:38])[NH:33][C:32]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])=[N:31][C:30]3=4)[C@@H:26]([F:45])[C@@H:25]2[OH:46])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:49](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Si:49]([O:46][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[N:36][C:35]3[C:34](=[O:38])[NH:33][C:32]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])=[N:31][C:30]2=3)[C@H:26]1[F:45])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2F)c(=O)[nH]1

Procedure:
This compound is prepared from 9-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N2 -isobutyrylguanine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: [N+:1]([CH:4]([C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])([O-])=O.Cl.[N:20]#[C:21][NH2:22]>[Pd]>[CH3:5][C:4]1[NH:1][C:21]([NH2:22])=[N:20][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Reactant: N#CN
Agent: [Pd]
Agent: Cl
Product: Cc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
2-Nitro-8-phenyloctan-3-one (0.025 g, 0.10 mmol) reacted with concentrated HCl (0.50 mmol) and palladium, 5 wt. % on activated carbon (0.043 g, 0.020 mmol) under H2, then reacted with cyanamide (0.021 g, 0.50 mmol) according to the general procedure. Purification by column chromatography gave 0.010 g (41%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.22 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.01 (s, 3H) 1.60 (m, 4H), 1.31 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 142.5, 128.3, 128.1, 125.5, 121.9, 117.5, 35.5, 31.1, 28.6, 28.1, 22.9, 7.5 ppm; IR νmax (cm−1) 3169, 2929, 2857, 1680, 1453, 1020, 749, 700; HRMS (FAB) calcd for C15H21N3 (MH+) 244.1808, found 244.1814.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]([F:30])([F:29])[F:31])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(SC(F)(F)F)cc1

Procedure:
Example 34 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-[(trifluoromethyl)thio]benzene (21.9 μl) to give the title compound (0.0122 g). LC-MS (System A): Rt 2.70 mins, Mass Spectrum m/z 494 [MH+].
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[CH3:23][S:20]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=NO)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-bromobenzyl cyanide was prepared in the following manner. Thus, 81.0 g (0.36 mole) of α-hydroxyimino-4-bromobenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 49.0 g (0.43 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 103.0 g of a solid residue which was purified by repeating recrystallization from acetonitrile to give 81.8 g of a white crystalline product having a melting point of 128° C., which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 75.0% of the theoretical value.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15]COCCOC[CH2:8][O:7][CH2:6][CH2:5][O:4]1.C(OCC(OCCOC)COCCOC)(C)(C)C.F[B-](F)(F)F.[H+].C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:8][O:7][CH2:6][CH2:5][O:4][CH:3]([CH2:20][O:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:2][OH:1]
Reactant: OCC1COCCOCCOCCOCCOCCO1
Agent: COCCOCC(COC(C)(C)C)OCCOC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCC(CO)OCCOC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 29 was prepared by a method similar to that described by Montanari and Tundo20 for the synthesis of 2-(hydroxy methyl)-1,4,7,10,13,16-hexaoxacyclooctadecane. KBF4 complex, (2-(hydroxy methyl)-18-crown-6). To a solution of compound 23 (10.0 g, 0.038 mol.) in dichloromethane (100 ml) was added tetrafluoroboric acid-diethyl ether complex (54% in diethyl ether), (13.7 ml). The mixture was left stirring at room temperature for 20 minutes. The acid was neutralized with solid potassium carbonate, inorganic salts were filtered, the solvent was removed by rotary evaporation to give a pale yellow oil. The crude product was distilled under vacuum (bpt. 94°-95° C., 0.02 torr) to give a colorless liquid (18.75 g, 78%): 1H-NMR (CDCl3), d (ppm) 3.5-3.9 (m, 13H), 3.35-3.4 (s, 6H), 2.75-2.8 (s, 1H); 13C-NMR (CDCl3), d (ppm) 79.56, 72.07, 71.73, 71.16, 70.59, 69.35, 62.40, 58.83, 58.75.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH2:5]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:27]=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].N>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:2][N:3]([CH2:27][C:26]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:24]([O:23][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:25]=1)[CH3:4]
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C=O)cc1OCCCCCCCC/C=C\CCCCCCCC
Reactant: CNC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(CN(C)C)cc1OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of triethylamineamine (2.0 mL, 14 mmol) in ethanol (20 mL) was added dimethylamine hydrochloride (1.63 g, 20 mmol), titanium tetraisopropoxide (5.96 mL, 20 mmol) and 3,4-dioleyloxybenzaldehyde (6.39 g, 10 mmol). The mixture was allowed to stir under argon for 10 h at room temperature. Sodium borohydride (0.57 g, 15 mmol) was added to the reaction mixture which was then allowed to stir at room temperature overnight. Concentrated aqueous ammonia (4 mL) was added slowly to the reaction mixture. The reaction mixture was filtered and the solids washed with dichloromethane. The filtrate was dried over K2CO3, filtered and concentrated. The resultant oil was purified via flash chromatography (2-10% acetone in dichloromethane, 0.5% TEA gradient) to afford 5.81 g (87-+%) of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][N:20](C)[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][NH:20][CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2CCCN(C)C
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CNCCCC1c2ccccc2CCc2c(C)cccc21

Procedure:
12.2 g. of 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene, dissolved in 180 ml. of dry benzene, are added dropwise to a mixture of 13.6 g. of ethyl chloroformate and 50 ml. of dry benzene. The mixture is boiled and stirred under reflux for 20 hours. After cooling, the benzene solution is washed with dilute hydrochloric acid and water and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)-5H-dibenzo[a,d]cycloheptene distils at 180° C/0.01 mmHg. 10.6 g. of 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)-5H-dibenzo[a,d]cycloheptene, 12.6 g. of potassium hydroxide and 110 ml. of n-butanol are boiled at reflux for 20 hours under an atmosphere of nitrogen with strong stirring. The butanol is removed by distillation under reduced pressure. The residue is taken up in ether and the etheral solution shaken with dilute hydrochloric acid. By treatment of the aqueous acidic phase with excess potassium carbonate, 1-methyl-10,11-dihydro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene separates out as an oil which distils at 150° C. under 0.01 mmHg. After recrystallization from ethanol-ether, the hydrochloride has a melting point of 173°-175° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:17][CH3:18])[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[K+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:17][CH3:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)C(OC)c1ccc(-n2cccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a stirred solution of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (0.204 g, 0.83 mmol) in dry MeOH (5 mL) under argon was added a solution of KOH in MeOH (1.6 mL of a 0.5 M solution, 8.3 mmol) and the reaction was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NH4Cl and extracted with EtOAc. Additional EtOAc was then used to extract the aqueous phase as the pH was adjusted from ˜8 to ˜2 using concentrated HCl. The combined organics were dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetic acid (0.18 g, 95%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH2:26].Cl>C(C#N)(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:26][C:18]1[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=1[F:16]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: CC(=O)C#N
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinazoline (548 mg, 2.4 mmol), 2-fluoro-4-nitro-phenylamine (392 mg, 2.5 mmol), AcCN (10 ml), and conc'd HCl (0.050 ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mgs, 80%). 1H-NMR (400 MHz, DMSO): 12.18 (br s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.36 (dd, 1H), 8.24 (dd, 1H), 7.91 (dd, 1H), 7.44 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). LC/MS Calcd for [M+H]+ 345.1, found 345.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl.[O:19]([NH2:21])[CH3:20]>O>[CH3:20][O:19][N:21]=[CH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: CON
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
An amount of 1H-Indole-6-carbaldehyde (50 mg, 0.34 mmol) is added to pyridine (2.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (31.6 mg, 0.38 mmol). The mixture is stirred at ambient temperature for 24 h, and 10 mL of water is added. After the solvents were evaporated, the residue is dissolved 10 mL of anhydrous ether, washed successively with 10 mL of aqueous sodium bicarbonate, 10 mL of sodium bisulfite, and 10 mL of brine. Dried over magnesium sulfate, evaporated to give a white solid (49 mg, 0.281 mmol). MS (ESI) m/z 176.3 (M+1)
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:23][CH3:24])=[O:5]
Reactant: CCO
Reactant: COc1c(F)ccc(C(=O)O)c1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)c(OC)c1F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
2,4-Difluoro-3-methoxybenzoic acid (18.8 g) was placed in a reaction vessel and was suspended in 100 ml of toluene added thereto at room temperature. After dropwise addition of 0.5 mL of N,N-dimethylformamide, 14.6 mL of thionyl chloride was added dropwise, and the resulting mixture was heated to 60° C. with stirring. After 7 hours, 50 mL of ethanol was added and an insoluble matter was filtered out. The filtrate was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled away to give the title compound (21.4 g) as a pale yellow oil.