Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH2:19][O:20][CH3:21].[CH3:22]OCC1OC(C)=CC(=O)C=1OCC1C=CC=CC=1.C(N)C>>[ClH:1].[CH2:2]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]1[CH2:19][O:20][CH3:21])[CH3:22]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: COCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: CCN
Agent: Cl
Product: CCn1c(C)cc(=O)c(OCc2ccccc2)c1COC

Procedure:
The title compound was prepared by the method outlined for 1,6-dimethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one hydrochloride, using 6.5 g (25 mmol, 1 eq.) of 2-(1-methoxymethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one and 4.82 g (75 mmol, 3 eq.) of 70% aqueous ethylamine to yield the pure product 3.7 g (45.7%/) after recrystallisation from methanol/diethyl ether, as a white crystalline solid m.p. 114-116° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([CH:12]3[CH2:18][C:17](=[O:19])O[C:14](=[O:15])[CH2:13]3)[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH3:20][NH2:21].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:20][N:21]1[C:17](=[O:19])[CH2:18][CH:12]([C:10]2[CH:9]=[CH:8][C:5]3[C:6]([CH3:7])=[C:2]([CH3:1])[O:3][C:4]=3[CH:11]=2)[CH2:13][C:14]1=[O:15]
Reactant: Cc1oc2cc(C3CC(=O)OC(=O)C3)ccc2c1C
Reactant: CN
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1oc2cc(C3CC(=O)N(C)C(=O)C3)ccc2c1C
Temperature: 0 °C

Procedure:
3.87 g (0.015 mol) of 3-(2,3-dimethyl-6-benzofuranyl)-glutaric anhydride [c.f. Example (4a) to (e)] are dissolved in 12.5 ml of toluene and 12.5 ml of glacial acetic acid. 10 ml of a 1.88 molar solution of methylamine in toluene are added to this solution at room temperature and the reaction mixture is heated to the boiling point for 61/2 hours, using a water separator. The cooled reaction mixture is poured onto an ice-water mixture and extracted with ether and the organic phase is washed with sodium bicarbonate and saturated sodium chloride solution until neutral. The organic phase is then dried over sodium sulfate and evaporated in a rotary evaporator. N-Methyl-3-(2,3-dimethyl-6-benzofuranyl)-glutarimide thus obtained as sand-coloured crystals of melting point 182°-185° crystallises spontaneously.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.N1C=CC=CC=1.Cl[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>CCOC(C)=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([NH:22][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[CH:20][CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of di-tert-butyl(3-amino-6-phenylpyridin-2-yl)imidodicarbonate (351 mg, 0.910 mmol, theoretical yield from previous reaction), THF (1.82 mL) and methylene chloride (1.82 mL) was cooled 0° C. and pyridine (0.294 mL, 3.64 mmol) and benzyl chloroformate (0.256 mL, 1.82 mmol) were added dropwise. The reaction was stirred for 2 h, diluted with EtOAc and washed with 1M aq. HCl2×, sat. aq. NaHCO3, brine, dried (MgSO4) and concentrated to afford a residue purified via MPLC, silica cartridge, 5-20% EtOAc in heptanes to afford the product as a clear light orange oil. MS cal'd 520 (M+H)+, exp 520 (M+H)+.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][CH2:44][C:45]([OH:47])=[O:46]>>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)O
Yield: 70.2 %

Procedure:
Starting from 3-(9-octadecenoyloxy)-11-eicosenoic acid (2.6 g) prepared by the method described in Preparation 8 and glycine (1.2 g), N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycine (2 g) was obtained as powders in a similar manner to that of Example 6.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1)#C.NC1C=CC=CC=1[OH:23].C1(=O)OC(=O)C=C1.C(OC(=O)C)(=O)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.C(N(CC)CC)C.CC(C)=O>[OH:23][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C2=CC(=O)NC2=O)cc1
Reactant: Nc1ccccc1O
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C=C(c2ccc(O)cc2)C(=O)N1

Procedure:
4-hydroxyphenyl maleimide was prepared by the same procedure as for 4-ethynylphenyl maleimide with the following starting materials aminophenol (54.5 g, 0.50 mole), maleic anhydride (49.0 g, 0.50 mole), acetone (500 ml), triethylamine (11 ml), nickel (II) acetate (0.5 g, 43 mmol), and acetic anhydride (63.8 g, 0.625 mol).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:33]>CO>[NH2:33][CH2:28][C@H:26]([OH:27])[CH2:25][O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:31][CH3:32])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[N:16]=2)=[CH:18][C:19]=1[CH2:29][CH3:30]
Reactant: N
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H]1CO1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CN

Procedure:
A solution of 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg, 220 μmol) in 7 N NH3 in methanol (5 mL) is stirred at 65° C. for 24 h. The mixture is evaporated and dried to give crude (2S)-1-amino-3-{4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (101 mg) as a pale yellow oil; LC-MS**: tR=0.72 min, [M+H]+=453.27.
Reaction SMILES: ClC1C=C(C)N=C(NC2C=C(N[C@@H]3CCCC[C@@H]3NC(=O)[O:27]C(C)(C)C)C=NC=2C#N)C=1.[C:33]([C:36]1[N:41]=[CH:40][C:39]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]2[NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:38][C:37]=1[NH:57][C:58]1[CH:63]=[CH:62][C:61](O)=[C:60]([CH3:65])[N:59]=1)(=[O:35])[NH2:34]>>[C:33]([C:36]1[N:41]=[CH:40][C:39]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]2[NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:38][C:37]=1[NH:57][C:58]1[CH:63]=[C:62]([OH:27])[CH:61]=[C:60]([CH3:65])[N:59]=1)(=[O:35])[NH2:34]
Reactant: Cc1cc(Cl)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1O
Product: Cc1cc(O)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)n1

Procedure:
This example describes the conversion of (D13) to (E15) as shown in Scheme 3. tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4-hydroxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate was prepared from tert-butyl [(1S,2R)-2-({5-[(4-chloro-6-methylpyridin-2-yl)amino]-6-cyanopyridin-3-yl}amino)cyclohexyl]carbamate (PrepEx 1.7) using chemistry analogous to that described for the synthesis of tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(5-hydroxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (PrepEx 1.9). MS ESI calc'd. for C23H33N6O4 [M+H]+ 457. found 457.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[N:23][CH:22]=1>>[CH2:13]([C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][N:23]=[CH:24]3)[C:9](=[O:11])[C:8]=2[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1cc(Cc2ccccc2)sc1N=C=S
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc(Cc3ccccc3)cc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-benzylthiophene-3-carboxylate (0.10 g, 0.35 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH:6]([NH:16]C(=O)C)[CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2.Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH:6]([NH2:16])[CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2
Reactant: COc1ccc2cccc3c2c1CC(NC(C)=O)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cccc3c2c1CC(N)C3
Temperature: 90 °C
Yield: 79 %

Procedure:
N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)acetamide (5.95mmol; 1.52g) is dissolved in 20 cm3 of ethanol to which are added 54 cm3 of 10% HCl. The mixture is maintained at 90° C. for 20 h. After cooling, 10% NaOH solution is added until the pH is basic and the amine is extracted with CH2Cl2. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The title amine is thus isolated without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC1N2CCC(/C/1=[N:14]/[C:15]1[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=1)CC2>C1COCC1>[C:21]1([C:18]2[N:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1/C(=N\c2ccc(-c3ccccc3)nc2)C2CCN1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-methyl-1-aza-bicyclo[2.2.2]octan-3-one (1.33 g, 9.5 mmol), 6-phenyl-pyridin-3-ylamine (1.25 g, 7.3 mmol) and p-toluene sulfonic acid monohydrate (139 mg, 0.73 mmol) in toluene (40 ml) is heated under reflux for 18 hours using a Dean-Stark apparatus. The toluene is evaporated and the residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1) to afford [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine. A solution of LiAlH4 (1.03 ml, 1 M) in THF is added to a solution of [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine (300 mg, 1.02 mmol) in THF (10 ml). The resulting mixture is stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of sodium sulfate (1 ml). The solvents are removed by evaporation and the residue is redissolved in ethyl acetate and filtered. The filtrate is evaporated and purified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1) to afford Rac.-trans-2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine. MS (ES+): m/e=294.4 (MH+); preparative enantiomer separation (column: Chiralpak AD-H 10 um; (4.6×250 mm), eluent: n-hexane : EtOH 50:50, flow: 1.0 ml/min, detector: UV 210 nm): peak 1: 6.29 min; peak 2: 20.16 min.
Reaction SMILES: [C:1]1([C:13]2[NH:22][C:16]3[N:17]=[CH:18][N:19]=[C:20](O)[C:15]=3[CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:20]1[C:15]2[CH:14]=[C:13]([C:1]3[CH:6]=[CH:5][C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:3][CH:2]=3)[NH:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Oc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a protective gas, 430.5 mg (1.5 mmol) of 6-(biphen-4-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol in 6 ml of phosphorus oxychloride are heated at boiling for 4 hours. The reaction mixture is poured into ice-water and ethyl acetate. The aqueous phase is separated off and extracted with ethyl acetate. Concentrating the organic phases by evaporation and stirring the residue in hot THF/isopropanol yield the title compound; m.p. 295-300° C. (decomposition); FAB-MS: (M+H)+ =306.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[O:17]1[C:22]2[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[C:24]([O:27][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)[CH:25]=[CH:26][C:21]=2[NH:20][CH2:19][CH2:18]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Oc1ccc2c(c1)OCCN2
Product: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Yield: 74 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using Compound 83 (250 mg, 1.08 mmol) and 3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (328 mg, 2.17 mmol) to provide 218 (276 mg, 74% yield) as a tan solid. LC-MS (M+H=346, obsd.=346).
Reaction SMILES: FC1C=C(F)C(F)=CC=1C(O)=O.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17](O)=[O:18].S(Cl)([Cl:28])=O>>[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([Cl:28])=[O:18]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cc(F)c(F)cc1F
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acid leads to 3-chloro-2,4,5-trifluorobenzoic acid, which is reacted as the crude product with thionyl chloride to give 3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point 94°/18 mbar; nD20 =1.5164): ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH2:10][CH:11]=O)=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1
Reactant: COC(=O)c1c(CC=O)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(CCNc2ccc(C(C)(C)C)cc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the aldehyde (Step B, 0.51 g, 2.3 mmol, 1 eq) and CH2Cl2 (30 mL) was added 4-t-butyl-aniline (0.36 mL, 2.3 mmol, 1 eq) and NaBH(OAc)3 (1.5 g, 6.8 mmol, 3.0 eq). The mixture was stirred at RT for 18 h then quenched with H2O. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give an orange oil. Purification by silica flash chromatography gave the desired compound as a yellow-orange foam. MS m/e 357 (M+H)+. Calc'd for C20H24N2O4-356.42.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>N1CCCCC1.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>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:5]=[CH:6][C:7]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])=[CH:2][CH:3]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A mixture of 5 g (17 mmol) 1-iodo-3-trifluoromethoxy-benzene, 973 mg (1 mmol) Pd(PPh3)4 and 160 mg (1 mmol) cuprous iodide in 130 ml piperidine was stirred for 30 min at 50° C. under an argon atmosphere. 2.125 g (25 mmol) 4-Pentyn-1-ol was added within 60 min at 50° C. The temperature was raised to 80° C. and the mixture was stirred for 3 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of saturated aqueous 10% KHSO4/ice water 1/1 and extracted two times with tert butyl methyl ether. The combined extracts were washed with water and brine (two times) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 3.4 g of the title compound as orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](Br)[CH2:9][Br:10])[CH:5]=[CH:6][CH:7]=1.[I-].[K+].II.[OH2:16]>>[Br:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:16]
Reactant: O
Reactant: Clc1cccc(C(Br)CBr)c1
Agent: II
Agent: [I-]
Agent: [K+]
Product: OC(CBr)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To 996 g of 3-chloro-α,β-dibromoethylbenzene were added 10.8 g of potassium iodide and 3.5 l of water. The mixture was then heated under reflux for 49 hours while the released free iodine was being removed. After the termination of the reaction, the reaction solution was allowed to cool to room temperature. The oil phase separated was separated and then washed with water for neutralization to give 714 g of 2-bromo-1-(3-chlorophenyl)ethanol was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH2:21])=[N:18][C:17]=3[CH3:22])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:21][C:19]1[S:20][C:16]([C:8]2[CH:9]=[CH:10][C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=2)=[C:17]([CH3:22])[N:18]=1)=[O:26]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: O=C(Cl)CCl
Product: Cc1nc(NC(=O)CCl)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Temperature: 25 °C

Procedure:
5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) (0.537 g, 1.60 mmol) and chloroacetyl chloride (5 ml) are heated together for 2 hours. The reaction mixture is allowed to cool to room temperature and the solid filtered and washed with saturated sodium bicarbonate solution (3×100 ml) and water (2×50 ml) to yield the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([SH:12])[N:8]=2)=[CH:3][CH:2]=1.[CH3:13]C(C)([O-])C.[K+].CI>CN(C=O)C.O>[CH3:13][S:12][C:9]1[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[NH:11][N:10]=1
Reactant: Sc1n[nH]c(-c2ccncc2)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1n[nH]c(-c2ccncc2)n1
Temperature: 50 °C
Yield: 45.7 %

Procedure:
A suspension of 5-(4-pyridyl)-1H-1,2,4-triazole-3-thiol (Aldrich) (4 g, 22.4 mmol) and .potassium t-butoxide (2.89 g, 25.8 mmol) in DMF (30 mL) was stirred at room temperature under argon until a homogeneous solution resulted. Methyl iodide (1.48 mL 23.8 mmol) was added and the reaction mixture was heated to 50° C. in an oil bath for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, the organic extract was washed with water and dried (MgSO4). The solid obtained on concentration was filtered from hot ethyl acetate to obtain 3-methylthio-5-(4-pyridyl)-1H-1,2,4-triazole (1.97 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>CCOC(C)=O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:26](=[O:27])[CH2:25][Cl:24])[CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2c(c1)C(C1CCCCC1)NCC2
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccc(Cl)cc2C1C1CCCCC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
7-chloro-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (899 mg) was added to saturated aqueous sodium bicarbonate (15 mL), to which EtOAc (10 mL) was then further added. A solution of chloroacetyl chloride (390 mg) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes. The reaction liquid was stirred for 1 hour, extracted with EtOAc, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 7-chloro-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (888 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O.CC(C)=O>[CH2:24]([O:23][C:21]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CC(c2cccs2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 9.8 g of (±)-4,5-dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (see example 2B) and 13.8 g of potassium carbonate in 80 ml of water and 40 ml of acetone there is added slowly 9.3 g of benzyl chloroformate dissolved in 50 ml of acetone, maintaining the temperature of the mixture at 10°-15° C. with an ice bath. After stirring at room temperature for 2 hours, the mixture is diluted with an equal volume of water and washed twice with ether. The aqueous layer containing some solids, is adjusted to pH 3.0 with 6 N HCl and cooled and filtered to obtain the title compound.