Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:23])([F:22])[F:24])[C:28]([O:27][CH3:26])=[O:36]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([NH:33][C:34](=[O:35])[O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)c1ccc(Cl)cc1
Agent: NC(=O)[O-]
Product: CCn1c(COC(=O)NC(=O)c2ccc(Cl)cc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 25 %

Procedure:
The compound 19 (69 mg, 0.2 mmol) was converted to the carbamate with 4-chlorobenzoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 86 (26 mg, 25%) as crystals. Mp. 82-83° C. Rf 0.13 (1:2 EtOAc - hexane).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=1>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]2[C:7]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]([O:15][CH3:16])=[O:14])[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])=[CH:24][CH:23]=1)([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 97.6 %

Procedure:
2-n-Propyl-4,5-dicarbomethoxyimidazole (2.00 g, 8.8 mmol, 1 eq.) was alkylated with 4'-bromomethyl-2-carbomethoxybiphenyl (2.70 g, 8.8 mmol, 1 eq.) by the procedure described in Example 1, Part A. Obtained 3.87 g of a yellow oil which was suitable for further transformation. NMR (DMSO-d6): δ7.84-7.22 (m, 4H); 7.22 (d, 2H, J=9 Hz); 7.13 (d, 2H, J=9 Hz); 5.50 (s, 2H); 3.77 (s, 3H); 3.75 (s, 3H); 3.55 (s, 3H); 2.67 (t, 2H, J=7 Hz); 1.67 (t of q, 2H, J=7,7 Hz); 0.88 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[CH:5]1[O:7][CH2:6]1.[CH2:16]([CH2:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH2:23][NH:24][CH2:6][CH:5]([C:4]1[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[OH:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C1CO1
Reactant: NCCc1ccccc1
Product: COc1ccc(S(N)(=O)=O)cc1C(O)CNCCc1ccccc1

Procedure:
2-Methoxy-5-sulphamoylstyrene oxide obtained in step 1 of Example 5, treated with benzylmethylamine under the conditions described in step 2 of Example 5, gives α-benzylmethylaminomethyl-2-methoxy-5-sulphamoylbenzenemethanol in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]#[CH:12].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CCNc1ccc(C#N)cc1

Procedure:
A solution of 23.6 g (0.20 mol) of 4-amino-benzonitrile, 16.6 ml (0.22 mol) of propargyl bromide and 38.3 ml (0.22 mol) of diisopropylethylamine is heated to 90° C. in 500 ml of toluene for 27 hours. It is then diluted with ethyl acetate, washed 3× with H2O and dried over MgSO4. After removal of the solvent by distillation the crude product is purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=20:80 to 75:25).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[F:14].[C:15]([CH:17]1[CH2:19][CH:18]1[C:20](N(OC)C)=[O:21])#[N:16].O>CCCCCC.C1COCC1>[F:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[C:20]([CH:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:21]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CC2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
16.5 ml (26.5 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 5.00 g (26.5 mmol) of 4-bromo-3-fluorotoluene in 40 ml of THF at −78° C., and the mixture was stirred for 0.5 h. Then, at −78° C., a solution of 2.72 g (17.6 mmol) of the compound from Example 73A in 10 ml of THF was added, and the mixture was allowed to warm to RT and was stirred at RT for 2 h. Water was added, the mixture was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 300 mg (9% of theory) of the title compound were obtained.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:20]1[N:21]=[C:22]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][CH:24]=1)\[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl[CH2:46][C:47]#[N:48]>>[C:47]([CH2:46][O:1]/[N:2]=[C:3](/[C:20]1[N:21]=[C:22]([NH:25][C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:23][CH:24]=1)\[C:4]([O:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])#[N:48]
Reactant: N#CCCl
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 77 %

Procedure:
Diphenylmethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (1.5 g) was alkylated with chloroacetonitrile (0.38 g) as described in Example 5a to give the title compound as a white solid (1.23 g); νmax (CH2Cl2) 3400, 1740, 1535 and 1490 cm-1 ; δH (CDCl3) 4.82 (2H, s), 6.45 (1H, s), 6.98 (1H, broad s), 7.17 (1H, s) and 7.26-7.52 (25H, m). [Mass spectrum: +ve ion (3NOBA) MH+ (635) and (3NOBA/Na+) MNa+ (657)]
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH2:35])[CH2:27][O:26]1>>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH:35][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][O:26]1
Reactant: NC1COCc2ccccc21
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2COCc3ccccc32)cn1
Yield: 96 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using rac-3,4-dihydro-1H-isochromen-4-amine hydrochloride instead of methylamine, to the title compound (136 mg, 96%) which was obtained as an off white solid. MS: m/e=442.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][C@@H:17]3[CH2:21][O:20][CH2:19][C@@H:18]3CC([O-])=O)=[CH:11][C:10]=2[CH3:26])[CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+].C[C:30]([CH3:32])=[O:31].C[OH:34]>>[C:30]([O:34][C@@H:18]1[C@@H:17]([O:16][C:12]2[CH:13]=[C:14]([CH3:15])[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][OH:2])[CH:4]=3)=[C:10]([CH3:26])[CH:11]=2)[CH2:21][O:20][CH2:19]1)(=[O:31])[CH3:32]
Reactant: CO
Reactant: CC(C)=O
Reactant: Cc1cc(O[C@@H]2COC[C@@H]2CC(=O)[O-])cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)O[C@H]1COC[C@@H]1Oc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
(3R,4R)-4-((3′-Formyl-2,6-dimethylbiphenyl-4-yl)oxy)tetrahydrofuran-3-yl acetate 13c (280 mg, 0.79 mmol) was dissolved in 5 mL of methanol. The reaction mixture was cooled down to 0° C., followed by addition of sodium borohydride (45 mg, 1.20 mmol), then warmed up to room temperature and stirred for 30 minutes. The resulting mixture was mixed with 5 mL of acetone, and concentrated under reduced pressure. The residue was mixed with 10 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL×3), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (3R,4R)/(3S,4S)-4-((3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl)oxy)tetrahydrofuran-3-yl acetate 13d (200 mg, yield 70.9%) as a colorless slime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:4][C:3]=1[O:23]C(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[CH:4][C:3]=1[OH:23]
Reactant: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(O)c2)n2cnnc2)cc1
Temperature: 25 °C

Procedure:
A solution of benzoic acid 2-chloro-5-{[(4-cyano-phenyl)-[1,2,4]triazol-4-yl-amino]methyl}-phenyl ester (CAB02139, 1.13 g, 2.63 mmol) and sodium methoxide (500 mg) in methanol (20 mL) and water (5 mL) was heated to reflux for 30 minutes. After cooling to room temperature most of the solvent was removed under reduced pressure and concentrated sodium bicarbonate solution (20 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, dried over sodium sulphate and the solvent was removed under reduced pressure. The resulting white powder was refluxed in ethyl acetate (10 mL, product did not dissolve completely). After cooling to room temperature the product was filtered off and dried under high vacuum. Yield: 412 mg (48%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=4.97 (s, 2H), 6.71-6.75 (m, 3H), 6.84 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.75 (d, J=9.0 Hz, 2H), 8.76 (s, 2H), 10.21 (s, 1H, —OH). LRMS (FAB+): 326.1 (100, [M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=O)=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O1CCOCC1>[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7])=[CH:33][CH:32]=1)#[N:27]
Reactant: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(N)=O)cc1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
In a mixture of 5 ml of pyridine and 50 ml of dioxane was suspended 2.5 g of (E)-2-[2-[4-(2-heptenyloxy)benzoylamino]phenylthio]benzamide followed by dropwise addition of 2.2 g of trifluoroacetic anhydride with ice-cooling and stirring.. After completion of dropwise addition, the mixture was stirred at room temperature for an additional 3 hours. Then, ice-water was added and the crystals separated out therefrom were collected by filtration, washed with water and dried to give 2.4 g of the title compound as white crystals.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1>C(O)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[N:4]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: N
Solvent: CCO
Product: Nc1nc(F)cc(F)n1
Yield: 54.9 %

Procedure:
This entailed, in the first stage of the synthesis, absolute ethanol being saturated with ammonia at 0° C., and a solution of 2,4,6-trifluoropyrimidine (II) and ethanol then being added to the solution obtained in this way. It was possible, after elaborate separation of the isomers, to isolate 2-amino-4,6-difluoropyrimidine IVa' in 54.9% yield.
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[O:10][CH2:9][CH2:8]1)=[N+]=[N-].CP(C)C.O>C1COCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2([CH3:18])[NH2:4]
Reactant: CC1(N=[N+]=[N-])CCOc2ccc(I)cc21
Agent: CP(C)C
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(N)CCOc2ccc(I)cc21
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a mixture of 6-iodo-4-methylchroman-4-ol (1.0 g, 3.4 mmol) and NaN3 (0.7 g, 10.3 mmol) in CHCl3 (15 ml), at 0° C., was added TFA (1.3 ml, 17.2 mmol) as a solution in 10 ml of CHCl3 dropwise via addition funnel. The addition was carried out over 2 h and stirring continued for an additional 2 h at 0° C. The mixture was warmed to r.t. and stirred over night. The mixture was diluted with 30 ml of water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 4-azido-6-iodo-4-methylchroman as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=2.07 Hz, 1 H), 7.50 (dd, J=8.71, 2.07 Hz, 1 H), 6.66 (d, J=8.71 Hz, 1 H), 4.27 (m, 2 H), 2.06 (m, 2 H), 1.68 (s, 3 H). MS (ESI+) for C10H10IN3O m/z 273.0 (M+H)+ loss of azide. The crude azide was dissolved in THF (15 ml) followed by the addition of trimethylphosphine (4 ml, 1.0 M in THF) at r.t. After 15 min. 3 ml of water was added and stirring continued at r.t. for 2 h until complete as indicated by LC/MS. The solvent was removed in vacuo and the residue diluted with water (75 ml) and extracted with CH2Cl2 (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacou to yield 6-iodo-4-methylchroman-4-amine (0.900 g, 91%) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.07 Hz, 1 H), 7.40 (dd, J=8.60, 2.18 Hz, 1 H), 6.59 (d, J=8.50 Hz, 1 H), 4.25 (m, 2 H), 2.01 (m, 2 H), 1.53 (s, 3 H). MS (ESI+) for C10H12INO m/z 273.2 (M+H)+ loss of NH3.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl.[OH2:16]>CC(C)=O>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:1]=[C:9]2[CH:10]=[O:16]
Reactant: O=N[O-]
Reactant: O
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=Cc1n[nH]c2ccc(Br)cc12
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of NaNO2 (110.4 g, 1.6 mol, 8 eq) in water (200 mL) was added dropwise to a solution of 5-bromoindole (IX) (39.2 g, 0.2 mol, 1 eq) in acetone (1000 mL) stirred at −10→0° C., while adding NaNO2 the solution temperature was maintained below 20° C. An aqueous 2N HCl solution (480 mL) was added slowly to the solution with vigorously stirring while keeping the internal temperature between 0 and 20° C. The solution was further stirred at 20° C. for 3 h after the addition. The solution was concentrated under reduced pressure to remove acetone while keeping the temperature below 35° C. The solid was collected by filtration and transferred to a flask. Cold (−10° C.) DCM (200 mL) was added and stirred for 30 min at −5° C., the solids were filtered and dried under vacuum at 40° C. to get 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151 mmol, 76% yield) as a brown solid. ESIMS found for C8H5BrN2Om/z 225 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:19][C:20]([CH3:22])=[O:21]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 50 g (0.2 mol) of 4-benzyloxybenzaldehyde in 500 mL of acetone was diluted with 500 mL of water. To the cloudy emulsion which formed was added 20 mL of 1N sodium hydroxide and the mixture stirred at room temperature for 20 hours. The solids which precipitated were recovered by filtration. Recrystallizaton from methanol gave the above named product, as a tan flasky solid, in a yield of 51 g (87 percent of theoretical). The product melted at 102°-109° C.; 1H NMR (CDCl3): δ 2.29 (s, 3H, CH3 --), 5.04 (s, 2H, --CH2 --), 6.48-7.52 (m, 11H, ArH's and --CH=CH--).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27]Br)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)Oc1cccc(C(=O)N2CCC(CCBr)(c3ccc(C(F)(F)F)cc3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(C(F)(F)F)cc3)C2)c1

Procedure:
Combine 2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin -3-yl]-ethyl-bromide (8 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol), K2CO3 (36 mmol), KI (0.8 mmol), and THF/H2O (3/1, 80 mL). Heat at reflux for 72 h. Concentrate in vacuo to remove THF and extract with dichloromethane (2×50 mL). Extract the combined organic layers using water (50 mL). Dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)[C:30]2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:30]=[CH:29][N:28]=[CH:27][CH:23]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccncc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)pyridine hydrobromide and isolated as orange solid (4.1 mg, 27%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[C:9][N:10]([CH3:22])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>N1C=CC=CC=1>[C:1]1([CH2:7]/[CH:8]=[CH:9]\[N:10]([CH3:22])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: [H][H]
Reactant: CN(C#CCC1=CCCCC1)Cc1cccc2ccccc12
Solvent: c1ccncc1
Product: CN(/C=C\CC1=CCCCC1)Cc1cccc2ccccc12

Procedure:
5 g of N-(3cyclohex-1-en-1-yl-propynyl)-N-methyl-N-(1-naphthylmethyl)amine are hydrogenated in absolute pyridine using 750 mg Pd/BaSO4 as catalyst at room temperature and normal pressure, until the calculated amount of hydrogen is taken up. The reaction mixture is filtered and the pyridine removed in a vacuum. The residue is chromatographed on silica-gel using benzene/ethylacetate (9:1) to yield the title compound in free base form as an oil after evaoporating the appropriate fractions,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH:41]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:47][S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), 4-dimethylaminopyridine (46 mg, 0.38 mmol), cyclopropane sulfonamide (91 mg, 0.75 mmol) in dichloromethane (3 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (37.8 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 504.1, observed: 504.2.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[C:11]1([CH3:17])[CH:16]=CC=[CH:13][CH:12]=1>COC1C=CC(O)=CC=1>[CH:3]12[CH2:17][CH:11]([CH:12]=[CH:13]1)[CH2:16][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: Cc1ccccc1
Reactant: C=CC(=O)O
Agent: C1=CCC=C1
Agent: COc1ccc(O)cc1
Product: O=C(O)C1CC2C=CC1C2

Procedure:
To a four-necked flask having a capacity of 1 L and equipped with a stirrer, a thermometer, and a dropping funnel, 0.40 g of p-methoxyphenol, 108.1 g (1.50 mol) of acrylic acid, and 300 mL of toluene were added, and 109.1 g (1.65 mol) of cyclopentadiene was added dropwise to the flask from the dropping funnel at 40° C. or lower over 2 hours. After completion of the addition, the resultant mixture was stirred at room temperature for 10 hours, and then concentrated under reduced pressure, to thereby obtain 167.3 g (1.21 mol) of 5-norbornene-2-carboxylic acid.