Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([O:13][CH3:14])=[C:2]([CH2:21][C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: COc1c(Br)cc(Br)c2ccccc12
Product: COc1c(Cc2ccc(Cl)s2)cc(Br)c2ccccc12

Procedure:
2,4-Dibromo-1-methoxynaphthalene (see Org. Lett. (2003) 5, 831) and 5-chloro-2-thiophenecarboxaldehyde were treated in a manner similar to Reference Example 1 to give 4-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15]2>O1CCOCC1.ClCCl>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH2:15]2
Reactant: O=C(N1CCc2c(cccc2OC2CCCCO2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc2c(c(OC3CCCCO3)c1)CCNC2
Reaction time: 8 h

Procedure:
Excess of 2 mol L-1 aqueous sodium hydroxide was added to a solution of 5-(tetrahydropyran-2-yloxy)-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Example 3) (4.1 g, 12.4 mmol) in dioxane. The mixture was stirred overnight, diluted with dichloromethane, washed with water and aqueous sodium chloride and evaporated. Yield 2.77 g, 96% 1H NMR (CDCl3, 400 MHz): 7.07 (1H, t, 8.1 Hz), 6.92 (1H, d, 8.3 Hz), 6.66 (1H, d, 7.6 Hz), 5.43 (1H, t, 3.2 Hz), 3.99 (2H, s), 3.76 (1H, m), 3.61 (1H, m), 3.14 (2H, t, 6.1 Hz), 2,73 (2H, m), 1.5-2.1 (6H, m); 13C NMR (CDCl3, 100 MHz): 154.6, 137.2, 126.0, 124.3, 119.1, 111.2, 95.8, 61.9, 48.3, 43.7, 30.5, 25.2, 23.5, 18.9; MS (EI, 70 eV): 233 (M+, 8%), 148 (92%), 132 (23%), 120 (47%), 91 (16%), 85 (100%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:25][CH2:24][C@:23]4([CH3:28])[C@H:26]([CH3:27])[C@H:19]3[CH2:20][C:21]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:22]=34)=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1>CN(C)C=O.O.CC#N>[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:18]3[CH2:25][CH2:24][C@:23]4([CH3:28])[C@H:26]([CH3:27])[C@H:19]3[CH2:20][C:21]3[CH:32]=[CH:31][C:30]([C:33]5[NH:34][N:3]=[N:2][N:1]=5)=[CH:29][C:22]=34)=[O:17])=[CH:15][C:10]=2[NH:9][CH:8]=1
Reactant: C[C@@H]1[C@H]2Cc3ccc(C#N)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2Cc3ccc(-c4nnn[nH]4)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of sodium azide (105 mg), NH4Cl (87 mg), and (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile (0.30 g) in dimethylformamide (3 mL) is stirred at 100° C. overnight. Then, another portion of NaN3 (50 mg) and NH4Cl (40 mg) is added and the mixture is stirred at 110° C. for additional 14 h. After cooling to ambient temperature, the mixture is diluted with water and MeCN and purified by HPLC on reversed phase (MeCN/H2O/NH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol) in MeOH was added K2CO3 (1.82 g, 13.2 mmol). After stirring for 5 h, the reaction was filtered then concentrated. The residue was diluted with EtOAc then washed with H2O. The aqueous phase was back-extracted with EtOAc two times then the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (5-10% MeOH—CH2Cl2 gradient) to afford (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.62 g, 6.6 mmol, quantitative yield). LCMS-ESI+: calc'd for C22H27N4O3: 395.2 (M+H+). Found: 395.2 (M+H+).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>CO>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[NH:32][C:33](=[O:34])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of (R)-aminocarnitine (35 mg, 0.22 mmol) and diisopropylethylamine (0.11 mL, 0.65 mmol) in MeOH (2 mL) was added 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (67 uL, 0.44 mmol) and the reaction stirred at room temperature overnight. The MeOH was removed in vacuo and the residue titurated several times with 1:1 ether/EtOAc, the resulting solid was filtered and dried to give the title compound as a white powder (15 mg, 18%). NMR (300 MHz, CD3OD) δ 8.37 (m, 1H), 7.68 (m, 1H), 7.53 (m, 1H), 4.29 (m, 1H), 3.78-3.48 (m, 2H), 3.25 (s, 9H), 2.70-2.49 (m, 2H); MS ESI 382.1 [M+H]+, calcd for [C15H19ClF3N3O3+H]+ 382.78.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:7]=[C:2]([I:1])[C:3]([NH2:13])=[N:4][CH:5]=2)=[N:9]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Nc1ncc(-c2nn[nH]n2)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridin-2-amine (0.61 g, 2.12 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.66 mL, 1.3 eq), and potassium carbonate (0.44 g, 1.5 eq) in anhydrous dimethylformamide (8 mL) was stirred and heated at 80° C. under nitrogen atmosphere for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. A gradient column chromatography [Hexane to EtOAc-Hex (1:2)] rendered 5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-3-iodopyridin-2-amine as a white solid in the amount of 797 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(OCC)(=O)C.O>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
4-Nitrobenzylbromide (21.6 g, 0.1 mol) was added to a rapidly stirred suspension of 1,2,4-triazole sodium salt (9.1 g, 0.1 mol) in anhydrous DMF (100 ml) and the mixture stirred at room temperature for 16 h. Ethyl acetate (400 ml) was added followed by water (250 ml) and the layers separated. The organic phase was washed with water (3×250 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate to give the title-product (10.6 g, 52%); m.p. 98°-100° C. δ (360 MHz, CDCl3) 5.47 (2H, s, CH2) 7.40 (2H, d, J=9 Hz, Ar--H), 8.02 (1H, s, Ar--H), 8.18 (1H, s, Ar--H), 8.23 (2H, d, J=9 Hz, Ar--H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:1][CH2:2][CH2:3][CH2:4]3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: NCc1ccc2c(c1)CCCN2
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)CCCN2

Procedure:
Prepared according to the described general procedure 6 (GP6) with (1,2,3,4-tetrahydroquinolin-6-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.53 min.; [M+H]+: 381.15 g/mol.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:3][C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: OC1(c2ccccn2)CN2CCC1CC2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: ClC1(c2ccccn2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Thionyl chloride (0.74 ml, 10.2 mmol) was added dropwise to a solution of 3-hydroxy-3-(2-pyridinyl)-1-azabicyclo[2.2.2]octane (1.04 g, 5.09 mmol, prepared as in Description 1) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 1 h, poured into saturated aqueous potassium carbonate (30 ml) and extracted with dichloromethane. The organic extract was dried over magnesium sulphate and then concentrated to a brown oil. The crude product was chromatographed through silica-gel using dichloromethane/methanol/ammonia (94.5:5:0.5) as eluent to give first 0.28 g of 3-chloro-3-(2-pyridinyl)-1-azabicyclo[2.2.2]octane followed by 0.39 g of 3-(2-pyridinyl)-1-azabicyclo[2.2.2]oct-2-ene.
Reaction SMILES: [N:1]([C@H:4]([CH3:21])[CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7]1)=[N+]=[N-]>C(O)C.[Pt]=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[CH2:11][CH2:10][C:9]3[CH:8]=[CH:7][N:6]([CH2:5][C@H:4]([NH2:1])[CH3:21])[C:14]=3[C:13]=2[CH:15]=1
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N=[N+]=[N-])CC2
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N)CC2
Yield: 95.1 %

Procedure:
1.9 g of (R)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indole dissolved in 100 ml of anhydrous ethanol were hydrogenated on 190 mg of platinum oxide for 16 hours. The catalyst was subsequently filtered off, rinsed with ethonal and the solvent was drawn off in a vacuum. There were obtained 1.64 g (95%) of (R)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine as a colorless oil, of which 440 mg were dissolved in 70 ml of anhydrous ether, filtered and treated while stirring with a solution of 200 mg of fumaric acid in 20 ml of methanol the mixture was stirred at room temperature for 2 hours and the white crystals were subsequently filtered off. 450 mg (70%) of (R)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 194° were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[3-(1H-indol-3-yl)propyl]acetamide (742 mg, 1.78 mmol) was dissolved in ethyl methyl ketone (25 ml), and chlorotrimethylsilane (0.34 ml, 2.7 mmol) was added. After 2 h the hydrochloride was isolated as a beige-coloured solid with an m.p. of 165-173° C. in a yield of 75% (606 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:19]1[Se:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([NH2:27])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)(C)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:27][C:21]1[CH:20]=[C:19]([C:15]([CH3:18])([CH3:16])[CH3:17])[Se:23][C:22]=1[C:24]([NH2:26])=[O:25])([O-:14])=[O:13]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c(C(N)=O)[se]1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 4-chloro-6-nitroquinazoline (1.1 g, 5.2 mmol) in isopropanol (10 mL) was added 5-tert-butyl-3-amino-selenophene-2-carboxamide (2.58 g, 10.50 mmol) at rt and the mixture was stirred for 30 min. The mixture was poured into ice cold water and stirred for 15 min The precipitated solid was filtered, washed with water and dried to give the product as a pale yellow color solid (2.1 g, 95%), mp 280-282° C. 1H NMR (400 MHz, DMSO-d6): δ 13.23 (1H, br s), 9.05 (1H, br s), 8.85 (1H, s), 8.56-8.60 (2H, m), 7.98 (1H, d, J=9.2 Hz), 7.80 (2H, br s), 1.43 (9H, s); LC-MS (negative ion mode): m/z 416, 418 (M−H)−.
Reaction SMILES: [CH2:1]([N:12]([CH2:16][C:17]([O-:19])=[O:18])[CH2:13][CH2:14][OH:15])[CH2:2][N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([O-:7])=[O:6].[Na+].[Na+].[Na+].C(C(CCCC)COP(=O)(O)OCC(CC)CCCC)C>O>[CH2:1]([N:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:14][OH:15])[CH2:2][N:3]([CH2:4][C:5]([OH:7])=[O:6])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C([O-])CN(CCO)CCN(CC(=O)[O-])CC(=O)[O-]
Agent: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Agent: [Na+]
Solvent: O
Product: O=C(O)CN(CCO)CCN(CC(=O)O)CC(=O)O

Procedure:
A carboxylic acid is prepared by contacting an aqueous solution of the alkali metal or ammonium carboxylate with a liquid cation exchange agent dissolved in an organic solvent in which the carboxylic acid is substantially water immiscible. As an example, an aqueous solution of trisodium N-(2-hydroxyethyl)ethylenediaminetriacetate is contacted with di(2-ethylhexyl)phosphoric acid in kerosene to thereby form N-(2-hydroxyethyl)ethylenediaminetriacetic acid in the aqueous solution.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[CH3:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=1.[Cl-].[NH4+]>N1C=CC=CC=1>[C:15]1([N:14]2[C:10]([CH3:9])=[C:11]([C:21]3[CH2:22][CH2:23][N:24]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:25][CH:26]=3)[N:12]=[N:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(C2=CCNCC2)nnn1-c1ccccc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: Cc1c(C2=CCN(C(=O)OC(C)C)CC2)nnn1-c1ccccc1

Procedure:
Pyridine (0.5 ml) and 0.01 ml of isopropyl chloroformate were added to 4-(5-methyl-1-phenyl-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine hydrochloride prepared in the above 1) and the mixture was stirred for one night. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/2) to give 3.5 mg of the title compound as a white solid.
Reaction SMILES: C1(C)C(C(O)=O)=CC=CC=1.[C:11]1([CH:17]2[O:23][CH2:22][CH2:21][CH:20]=[CH:19][O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH:17]2[CH:20]([CH:19]=[O:18])[CH2:21][CH2:22][O:23]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1=COC(c2ccccc2)OCC1
Agent: Cc1ccccc1C(=O)O
Product: O=CC1CCOC1c1ccccc1
Temperature: 150 °C

Procedure:
3 g of o-toluic acid were added to 44 g (0.25 mol) of 2-phenyl-4,5-dihydro-1,3-dioxepine and the mixture was heated at 150° C. for 3 hours, while stirring. The 2-phenyltetrahydrofuran-3-aldehyde which had formed (a mixture of the cis and trans isomers) was then distilled under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:61]([N:60]([CH3:59])[C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)=[O:25])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (150 mg, 0.378 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (145 mg, 0.756 mmol), and 1-Hydroxybenzotriazole (102 mg, 0.756 mmol) were dissolved in 2.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (132 μL, 0.756 mmol) and N-methyl-1-phenylmethanamine (45.8 mg, 0.378 mmol) were added as a 1.0 mL DCM solution. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with 1N HCl followed by saturated sodium bicarbonate then saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with methanol and filtered under vacuum to obtain pure product as a white solid. Yield: 63.7 mg (White solid)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[N:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:44])([F:45])[F:46])[CH:37]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(F)c(C(F)(F)F)c3)c(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(F)c(C(F)(F)F)c3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.28 mL, 0.84 mmol) was added to a THF solution (0.9 mL) of ethyl 3-(5-(2-(((2-chloro-4′-fluoro-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-4,5-difluorophenyl)picolinamido)propanoate (100 mg, 0.17 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via HPLC to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]3[NH:19][C:18]4[CH2:17][CH2:16][C:15]5(OCC[O:20]5)[CH2:14][C:13]=4[C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>CO>[C:1]1([C:7]2[N:8]=[CH:9][C:10]3[NH:19][C:18]4[CH2:17][CH2:16][C:15](=[O:20])[CH2:14][C:13]=4[C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc3[nH]c4c(c3n2)CC2(CC4)OCCO2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2[nH]c3cnc(-c4ccccc4)nc3c2C1
Reaction time: 48 h

Procedure:
A mixture of 2'-Phenyl-6',7',8',9'-tetrahydro-spiro[(1,3)dioxolane2,8'(5H)-indolo[3,2-d]-pyrimidine] (200 mg), 3N sulfuric acid (1.5 mL) and methanol (1.5 mL) was kept at room temperature for 2 days. The reaction mixture was neutralized with 2N ammonium hydroxide and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was remov ed in vacuo and the residue was crystallized froom ether/hexane to afford 2-Phenyl-5,6,7,9-tetrahydro-8H-indolo[3,2-d]pyrimidin-8-one (Compound 30) melting at 246°-247° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]([NH2:35])([CH3:34])[CH3:33].[BH4-].[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH:32]([CH3:34])[CH3:33])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)N
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(C)C)c4)cc23)CC1
Yield: 52.9 %

Procedure:
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), isopropylamine (23 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (11.5 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(=O)O)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.29 g (1.1 mmol) methyl 2-chloro-6-methanesulphonylamino-isonicotinate in 5.0 mL tetrahydrofuran and 1 mL water were mixed with 79 mg (3.3 mmol) lithium hydroxide and stirred overnight at RT. The reaction mixture was acidified with 1M aqueous hydrochloric acid and evaporated down. The product was reacted without further purification.