Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH2:15][O:16][Si](C(C)(C)C)(C)C)=[CH:9][CH:8]=1.COB(OC)OC.Br[C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>COCCOC.Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:42]([C:34]1[CH:33]=[C:32]([C:7]2[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][CH:12]=2)[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccc(/C=C/CO)cc2)cc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 19.7 %

Procedure:
tert-Butyllithium (1.7M in pentane, 3.5 ml, 6.0 mmol) was added dropwise, at −78° C. to a stirred THF (10 ml) solution of (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (982 mg, 3.0 mmol) and the resulting solution stirred for 45 min. Trimethylborate (0.51 ml, 4.50 mmol) was added, the solution allowed to warm to room temperature over 2h, and the solvents evaporated to give the crude boronate ester as a yellow gum, which was dissolved in DME (10 ml). Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol), was added to a stirred DME (20 ml) solution of 1-bromo-3,5-di-tert-butylbenzene (538 mg, 2.0 mmol), the solution stirred for 10 min, aqueous sodium carbonate (2M, 9 ml, 18.0 mmol) added, and stirring continued for a further 10 min. The boronate ester solution was added and the mixture heated to 80° C., under reflux, for 24 h. The resulting mixture was diluted with 1N HCl (50 ml), the products extracted into ethyl acetate (3×50 ml), and the combined extracts washed with brine, dried (MgSO4), and evaporated. The resulting yellow gum was dissolved in dry THF (20 ml), tetra-n-butyl ammonium fluoride (1.26 g, 4.0 mmol) added and the solution stirred at room temperature for 18h. The resulting mixture was diluted with 1N HCl (50 ml), and the products extracted into ethyl acetate (2×50 ml). The combined organic phases were washed with brine, dried (MgSO4), and evaporated to give the colourless glass, (E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-prop-2-en-1-ol (127 mg, 20%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[C:41]1([Si:47]2([CH2:61][CH2:62][CH3:63])[CH2:52][CH2:51][CH:50]([CH:53]3[CH2:58][CH2:57][CH:56]([CH:59]=O)[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCCCCC.O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:59][CH:56]2[CH2:57][CH2:58][CH:53]([CH:50]3[CH2:49][CH2:48][Si:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([CH2:61][CH2:62][CH3:63])[CH2:52][CH2:51]3)[CH2:54][CH2:55]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC[Si]1(c2ccccc2)CCC(C2CCC(C=Cc3ccc(F)c(F)c3)CC2)CC1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
12.0 g of potassium t-butoxide was added to a mixture of 48.0 g of 3,4-difiuorobenzyltriphenylphosphonium bromide and 400 ml of tetrahydrofuran to obtain a ylide solution. 32.9 g of 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexane carbaldehyde was dropped in the solution. After agitation at room temperature for 2 hours, the reaction mixture was charged into water and extracted with ethyl acetate. The ethyl acetate phase or solution was subjected to washing with brine, drying and concentration to obtain a residue, to which n-hexane was added. The resultant crystals of triphenylphosphine oxide were removed by filtration and the flitrate was concentrated. The resultant residue was purified through column chromatography to obtain 39.9 g (yield: 91%) of 4-(4-(2-(3,4-difluorophenyl)ethenyl)cyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N+:19]([O-])=O)=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:19][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: O=C(c1ccccn1)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12

Procedure:
A mixture of 6-chloro-3-nitro-2-(pyridine-2-carbonyl)indole (step 3, 92 mg, 0.30 mmol), ammonium chloride (8 mg, 0.15 mmol) and iron powder (89 mg, 1.52 mmol) in 70% aqueous ethanol (6 ml) was heated at reflux for 2 h, and then cooled and filtered through a pad of Celite. The pad was washed copiously with a mixture of ethanol/ethyl acetate (1:1 v/v) and the combined washing evaporated. The residue was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodim bicarbonate (30 ml) and dried (Na2SO4). Removal of solvent gave product as crystals.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:18][OH:19].Cl>O.C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[CH:8]=[C:9]([NH2:10])[O:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C

Procedure:
(4-Fluorobenzoyl)acetonitrile (10 g., 0.063 mol) and 200 ml. of ethyl alcohol were placed in a 500 ml. 1-neck flask. To the reaction mixture was added in portionwise fashion a solution comprised of 24 g. of sodium acetate and 18.3 g. of hydroxylamine.HCl in 200 ml. of H2O. After refluxing for three days, the reaction mixture was cooled to room temperature. About half the solvent was removed and then an oily layer formed. The residue was extracted thoroughly in ether and then the combined ether extracts were washed in water, brine, and then dried over MgSO4. When the ether was removed orange crystals formed which were recrystallized from diethyl ether/hexane, m.p., 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH2:16].B(O[O-])=O.[Na+]>>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]=[N:1][C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=3[C:9]=2[CH:14]=1
Reactant: Nc1ccc(Br)cc1-c1cc(Br)ccc1N
Agent: O=BO[O-]
Agent: [Na+]
Product: Brc1ccc2nnc3ccc(Br)cc3c2c1

Procedure:
The 2,9-dibromo-benzo-[c]-cinnoline is prepared from the 2,2'-diamino-5,5'-dibromo-biphenyl described by Le Fevre (J. Chem. Soc. 1929, 736) according to the oxidation method with sodium perborate of J. F. Corbett, P. F. Holt (J. Chem. Soc. 1961, 3698).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:24]([NH:26][C:27](=[O:44])[NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>COC1CCCC1.CCO.O>[CH2:24]([NH:26][C:27](=[O:44])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC1CCCC1
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 130 °C
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 2) (300 mg, 0.88 mmol) and 4-(3-ethylureido)phenylboronic acid pinacol ester (281 mg, 0.97 mmol) in CPME/EtOH/H2O (7/2/3) (4.0 mL) was added Pd(PPh3)2(Cl)2 (31 mg, 0.04 mmol) and Na2CO3 (140 mg, 1.32 mmol). The reaction mixture was then heated by microwave at 130° C. for 0.5 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the solvent removed in vacuo. The residue was purified by flash chromatography (0-40% EtOAc/Petroleum Ether 40-60) to yield an off-white solid (275 mg, 67%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:31])[C:27](=[O:30])[CH2:28][CH3:29])=[N:24][CH:25]=1>>[CH3:31][N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: CCC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-propionamide. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:30])[CH2:28][CH3:29]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:30][CH2:27][CH2:28][CH3:29])[CH:7]=1
Reactant: CCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and propan-1-ol (60 μl; 0.789 mmol), example 43 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: O1C2C=CC(C3(C(NC4C=CC(CC5C=CC=CC=5)=CN=4)=O)CC3)=CC=2OC1.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1.[Cl-].[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55][Zn+]>>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([CH2:55][C:54]5[C:53]([Cl:52])=[CH:60][CH:59]=[CH:58][C:57]=5[Cl:61])=[CH:46][N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Reactant: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2c(Cl)cccc2Cl)cn1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2,6-dichlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with (2,6-dichlorobenzyl)zinc(II) chloride.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9])=[O:2].[CH3:27][Mg]Br.O>O1CCCC1>[OH:2][CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9])[CH3:27]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-formyl-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (790 mg) in tetrahydrofuran (20 mL) was added methylmagnesium bromide (3.0 M, 1.5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (272 mg, yield 33%) as white crystals. melting point 193° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of 7-[(R)-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.9 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.13 (d, J=6.6 Hz, 3H), 3.96 (s, 3H), 6.33 (q, J=6.6 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.63 (d, J=9.9 Hz, 1H), 7.85 (s, 1H), 7.93 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H). MS (ES+): m/z 377.11 (100) [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH2:12](O)/[CH:13]=[CH:14]/[CH3:15]>>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)/[CH:13]=[CH:14]/[CH3:15]
Reactant: C/C=C/CO
Reactant: COC(=O)c1ccc(O)cc1
Product: C/C=C/COc1ccc(C(=O)O)cc1
Yield: 91.4 %

Procedure:
A reaction similar to that described in Example 1 (1a) was conducted using methyl 4-hydroxybenzoate (5.00 g, 32.9 mmol) and trans-crotyl alcohol (manufactured by Fluka, 2.37 g, 32.9 mmol) to give 5.78 g of the title compound (white powder, yield: 91%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13](=[O:22])[CH2:14][C:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:22])[CH2:14][C:15]1([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)CC1(N)CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CC1(Nc2ccccc2[N+](=O)[O-])CCCCC1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (450 □L, 4.3 mmol) and (1-amino-cyclohexyl)-acetic acid methyl ester (880 mg, 5.2 mmol) in DMF (5 mL) was added DIPEA (1.0 mL, 5.7 mmol). The mixture was heated at 90° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desired [1-(2-nitro-phenylamino)-cyclohexyl]-acetic acid methyl ester (230 mg, 19%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:10])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH2:16][OH:17].C(Cl)C#C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:10][C:8]#[CH:7])[CH2:16][OH:17]
Reactant: CC(C)=O
Reactant: COc1cc(CO)ccc1O
Agent: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCOc1ccc(CO)cc1OC
Yield: 94 %

Procedure:
Finely powdered K2CO3, 10.4 grams (0.075 moles), and KI, 9.1 grams (0.060 moles), were placed in a 300 mL round-bottomed flask equipped with a magnetic stir bar, and 150 mL acetone was added. 3-methoxy-4-hydroxybenzyl alcohol, 7.71 grams (0.050 moles), and propargyl chloride, 4.10 grams (0.055 moles), were then added, and the mixture stirred and refluxed for approximately 48 hours. The results from thin layer chromatography showed no starting material (3-methoxy-4-hydroxybenzyl alcohol) as well as the presence of a new compound. The solution was then filtered. The acetone of the resulting filtrate was removed by rotary evaporation, leaving an oily residue. The oily residue was dissolved in 50 mL dichloromethane and washed with water (30 mL×2) and then dried over anhydrous potassium carbonate. After filtering the organic phase, the solvents were removed by rotary evaporation, leaving a liquid product. 9 grams of product was obtained, which corresponds to a 94% yield.
Reaction SMILES: C([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C:10]([NH:21][CH2:22][C:23](=[O:43])[NH:24][CH:25]2[CH2:28][N:27]([CH:29]3[CH2:34][CH2:33][CH:32]([O:35][Si](C(C)(C)C)(C)C)[CH2:31][CH2:30]3)[CH2:26]2)=[N:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:35][CH:32]1[CH2:31][CH2:30][CH:29]([N:27]2[CH2:26][CH:25]([NH:24][C:23]([CH2:22][NH:21][C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=4)[N:8]([C:6]([NH2:5])=[O:7])[N:9]=3)=[O:43])[CH2:28]2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from de-protection of 3-[({1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butylamide (as prepared in Example 84) with TFA using the procedure described in Example 81.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CC(=O)NCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OCC(F)(F)F)=N[C@@H](c3ccc(Cl)cc3)[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 718.5 [(M+H)+]
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[N:38]=[C:39]([C:41]1[C:42]2[CH2:43][CH2:44][CH:45]([OH:50])[C:46]=2[CH:47]=[CH:48][CH:49]=1)[NH2:40].[Na+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:10][N:40]=[C:39]([C:41]3[CH:49]=[CH:48][CH:47]=[C:46]4[C:42]=3[CH2:43][CH2:44][CH:45]4[OH:50])[N:38]=2)=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=NO)c1cccc2c1CCC2O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
In a microwave vial, a stirring solution of 4-ethoxy-3-nitrobenzoic acid (200 mg, 0.947 mmol) in DMF was treated with HOBt (167 mg, 1.231 mmol) and EDCI (236 mg, 1.23 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of N′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (200 mg, 1.04 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as pale yellow solid in 40% yield (150 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:23]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1ccccc1CN1Cc2ccccc2N=C1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1CN1Cc2ccccc2N=C1N1CCNCC1

Procedure:
Splitting off the Boc group starting from 5.16 g tert-butyl-4-[3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2-yl]piperazine 1-carboxylate with 4N HCl in dioxane and basic workup yielded the desired product: 3.24 g.