Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][PH:2][CH2:3][C:4]([OH:6])=O.Cl.C[O:9][C:10](=[O:30])[C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[N:12]([I:14])[I:13]>>[CH3:1][PH:2][CH2:3][C:4]([C@@:11]([C:10]([OH:30])=[O:9])([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)[N:12]([I:13])[I:14])=[O:6]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(O)cc2)cc1)N(I)I
Reactant: CPCC(=O)O
Agent: Cl
Product: CPCC(=O)[C@](Cc1ccc(Oc2ccc(O)cc2)cc1)(C(=O)O)N(I)I

Procedure:
The compound was prepared analogously to the procedure described in examples (2) and (3). Methylphosphinoacetic acid was used in place of methylphosphinopropionic acid and diiodothyronine methyl ester hydrochloride was used in place of triiodothyronine methyl ester hydrochloride. The final product was purified by inverse phase column chromatography on silica gel RP 18 using 75% strength methanol as eluent. The unary substance of the main fraction, differing in the TLC from the starting materials, was identified by mass spectrometry as the title compound.
Reaction SMILES: [O:1]=[C:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15])[CH:3]=[CH2:4].[C:17]([OH:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([S:24][CH2:4][CH2:3][C:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15])=[O:1])(=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=CC(=O)N1c2ccccc2CC1C(=O)O
Solvent: ClCCl
Product: O=C(SCCC(=O)N1c2ccccc2CC1C(=O)O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirring mixture of 2,3-dihydro-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid (6.52 g.) and methylene chloride (160 ml.) was added dropwise thiobenzoic acid (95%, 4.36 g.) dissolved in a small amount of methylene chloride. During the addition, the reaction mixture was chilled in ice. The ice bath was removed in 10 minutes after the completion of the addition, but the stirring was continued for 1 hour. The reaction mixture was then immersed in an oil bath maintained at 80° for 2.5 hours. The reaction mixture was concentrated on a rotary evaporator under reduced pressure to ca. 30 ml., and kept in a refrigerator for 1 day. A precipitate was collected on a filter and washed with methylene chloride to give the titled compound which melted at 173°-175°, and weighed 11.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([NH2:14])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].COC(=O)C1C=C([C:24]#[N:25])C=C([N+]([O-])=O)C=1N>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([NH2:14])=[N:10][C:9]=2[CH:8]=[C:7]([C:24]#[N:25])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(N)[nH]c12
Reactant: COC(=O)c1cc(C#N)cc([N+](=O)[O-])c1N
Product: COC(=O)c1cc(C#N)cc2nc(N)[nH]c12
Yield: 50 %

Procedure:
0.28 g (50% overall yield) of 2-Amino-6-cyano-3H-benzoimidazole-4-carboxylic acid methyl ester was synthesized according to procedures described for the synthesis of 2-Amino-3H-benzoimidazole-4-carboxylic acid methyl ester starting from 1.0 g of 2-amino-5-cyano-3-nitro-benzoic acid methyl ester. LCMS: 269 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:20][CH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:21][C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=3)[N:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:23]=2)=[O:8])=[CH:4][N:3]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a stirred solution of 6-chloronicotinic acid (183 mg, 1.16 mmol) and N,N-diisopropylethylamine (409 mg, 552 μL, 3.16 mmol) in methylene chloride was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphonate (BOP) (559 mg, 1.26 mmol). After 15 min., 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (300 mg, 1.05 mmol) was added. After 1.5 hr., the suspension was diluted with CH2Cl2 and washed with water followed by citric acid solution (5%) and finally potassium carbonate solution. The organic layer was dried, filtered and concentrated to afford 6-chloro-N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-nicotinamide (340 mg, 76%). The product was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5](CBr)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][OH:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][O:24][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CCCCN1Cc1ccccc1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(OCC2CCCCN2Cc2ccccc2)cc1

Procedure:
Following the procedure for Example 139, 4-fluorobenzylbromide and 1-benzyl-2-(hydroxymethyl)-piperidine were reacted to give 1-benzyl-2-(4'-fluorophenoxymethyl) piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1
Product: CCCCCCCCCCCC(=O)Nc1ccccc1
Yield: 84 %

Procedure:
N-dodecanoylaminobenzene was prepared by acylation of aminobenzene with lauroyl chloride by a procedure similar to that of Example 1(a). After crystallization from hexane, a yield of 84% of white crystalline plates m.p. 76.3°-76.8° C. was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][S:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:25])([F:24])[C:18]([NH:20][CH2:21][C:22]#[CH:23])=[O:19]>>[CH:7]1([S:6][CH2:5][C:4]2[CH:3]=[C:2]([C:23]#[C:22][CH2:21][NH:20][C:18](=[O:19])[C:17]([F:25])([F:24])[F:16])[CH:15]=[CH:14][CH:13]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: Brc1cccc(CSC2CCCCC2)c1
Product: O=C(NCC#Cc1cccc(CSC2CCCCC2)c1)C(F)(F)F

Procedure:
Sonogashira coupling between (3-bromobenzyl)(cyclohexyl)sulfane and 2,2,2-trifluoro-N-(prop-2-ynyl)acetamide following the method used in Example 139 gave N-(3-(3-(cyclohexylthiomethyl)phenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide as a yellow oil. Yield (0.70 g, 35%); 1H NMR (400 MHz, DMSO-d6) δ 10.0 (br t, 1H), 7.24-7.37 (m, 4H), 4.25 (d, J=5.5 Hz, 2H), 3.72 (s, 2H), 2.48-2.53 (m, 1H), 1.79-1.87 (m, 2H), 1.58-1.65 (m, 2H), 1.45-1.52 (m, 1H), 1.12-1.27 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cc(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 60 %

Procedure:
To a mixture of methyl 5-methyl-2-valerylaminobenzoate (12.8 g) in acetic anhydride (5.9 g) was added dropwise, while stirring under ice-cooling, fuming nitric acid (6.7 ml), followed by stirring for 3 hours. To the reaction mixture was added ice water, which was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and water, which was then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel. Crystals thus obtained were recrystallized from isopropyl ether gave colorless crystals (8.5 g, 60%), m.p. 59-60° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (370 mg, 1.04 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (321 mg, 1.04 mmol) according to general procedure II. Obtained as an orange solid (164 mg, 27%). MS (ISN) 581 [(M−H)−]; mp 201–204° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][OH:15])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][O:15][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)CN(CCO)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: C=C(C)CN(CCOS(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)glycine tert-butyl ester was reacted with 3-bromo-2-methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2methylprop-2-enyl)-1,3-oxazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The compound of step 1 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. This mixture was stirred for 30 min at room temperature, poured on a mixture of 2 N hydrochloric acid and diethyl ether, filtered and washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (21 g).
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:27])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C@H:6]([CH3:27])[CH2:5][NH:4][CH3:1])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 56 %

Procedure:
The procedure described in Example 2.3 (preparation of starting materials) was repeated using chlorotris(triphenylphosphine)rhodium (I) and 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-methylphenol to give 2-methyl-4-({5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-yl}amino)-phenol as a brown foam in 56% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.15 (s, 3H), 2.33 (s, H), 2.87 (m, 2H), 4.85 (m, 1H), 6.77 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.43 (s, 1H), 7.46 (d, 1H), 7.64 (t, 1H), 8.38 (s, 1H), 9.14 (s, 1H), 10.35 (s, 1H); Mass spectrum MH+ 339.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[N:8][CH:9]=[N:10]2
Reactant: Oc1cccc2cncnc12
Reactant: O=C1CCC(=O)N1Br
Product: Oc1ccc(Br)c2cncnc12

Procedure:
Bromination of 8-hydroxy-quinazoline (A1) with N-bromosuccimide, according to the method previously described by Gerson and McNeil,15 gave 5-bromo-8-hydroxy-quinazoline (A139).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CCCCOc1ccc(F)cc1CCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ccc(F)cc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 4.4 %

Procedure:
A solution of 3-(2-butoxy-5-fluoro-phenyl)-propionic acid (300 mg, 1.37 mmoles) and benzoic acid N′-isopropyl-hydrazide (203 mg, 1.14 mmoles) in DMF (3 mL) was treated with diisopropylethylamine (0.50 mL, 2.85 mmoles), and PyBroP (800 mg, 1.71 mmoles) at room temperature for 16 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (20 mg, 5%). LC-MS m/e 401.28 (M+H+)
Reaction SMILES: C[O-].[Na+].[CH:4](=[O:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(P([CH:20]([CH3:23])[C:21]#[N:22])(CC)=O)C.O>CO.C(O)(=O)C>[CH3:23][C:20](=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([CH:4]=[O:13])=[CH:6][CH:7]=1)[C:21]#[N:22]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCP(=O)(CC)C(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C#N)=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.5 %

Procedure:
360 g of a 30% solution of sodium methylate in methanol are added dropwise to a suspension of 134 g of terephthalaldehyde in 500 ml of methanol at 20°-25° C. 191 g of 2-(diethylphosphoryl)-propionitrile [prepared by the method of M. L. Raggio and D. S. Watt, J. Org. Chem. 41, 1873 (1976)] are now slowly added dropwise to the resulting reaction solution at 20°-25° C. The reaction mixture is stirred at room temperature for 6 hours and then poured onto 1,000 ml of water, and the aqueous suspension is adjusted to a pH value of 7 with acetic acid. The product which has precipitated is filtered off, dried and then chromatographed on silica gel. 35 g (20.5% of theory) of 2-methyl-3-(4-formylphenyl)-2-propenonitrile of the formula ##STR32## and then obtained in the form of colourless crystals having a melting point of 63°-64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([Br:8])[CH:7]=1>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Solvent: CC(=O)O
Product: Nc1cc(Br)cc(Br)c1
Yield: 85.7 %

Procedure:
In a scale up reaction using the same procedure as described above, 5 g (17.9 mmol) of 3,5-dibromonitrobenzene (262), 30 mL of TiCl3 (30% wt. in 2.0 N aqueous HCl) and AcOH (125 mL) were used. After 4 h reaction and subsequent work-up, 3.85 g (85.7% yield) of 3,5-dibromoaniline (273) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH2:19][CH2:20][CH3:21])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: CCCC(=O)CC
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 3-hexanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then recrystallized from methanol, and the precipitate was collected by filtration. This yellow solid contained methanol, so it was stirred in ethyl acetate (5.0 mL) for 30 min at 70° C. After cooling, the precipitate was collected by filtration to afford the title compound (0.0334 g, 22%) as a yellow solid:
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1H-7-azaindole (less polar isomer) (10 mg, 0.0415 mmol), benzenesulfonyl chloride (10 μL, 0.0784 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37](Cl)=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5ccccc5Cl)noc4C(C)C)cc3)cc2cn1
Temperature: 50 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
A mixture of 174 mg (0.62 mmol) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate, 285 mg (0.92 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 260 mg (1.83 mmol) of K2CO3 in 2 mL of DMF was stirred at 50° C. for 20 hr. EtOAc was added then the mixture washed with three portions of H2O, then brine. The organics were dried over Na2SO4 then evaporated and the residue purified by silica gel chromatography (40 g of silica gel eluting with 0-70% EtOAc in hexanes over 45 minutes) to give 196 mg (58%) of methyl 7-[4-({[3-(2-chlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate as white solid. 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 7.99 (m, 2H), 7.60 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.33 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.80 (s, 2H), 4.06 (s, 3H), 3.36 (septet, 1H, J=7 Hz), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[NH2:10][CH2:9][C:4]1([NH:3][CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCNC1(C#N)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCNC1(CN)CCCC1

Procedure:
This material was obtained in analogy to example 65 step a, from 1-ethylamino-cyclopentanecarbonitrile (7.5 g), synthesis described in: J. Med. Chem.; 1969; 473, by reduction with diisobutylaluminiumhydride (20% in toluene, 282.6 mL) as an oil (6.55 g) and directly used in the next reaction step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: Cl.FC1C=C(CCN)C=CC=1C(F)(F)F.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C1COCC1>>[ClH:16].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: NCCc1ccc(C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was synthesized in analogy to 2-(3-fluoro-4-trifluoromethyl-phenyl)-ethylamine hydrochloride (described in example S1-B) from 3.188 g of crude (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (14.5 mmol) and 76 ml of a 1M borane-THF complex solution in THF (76 mmol). The product was obtained as a white solid (1.52 g, 40%). MS (ISP) 224.1 (M+H)+.