Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55](O)=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH2:54][C:55]([NH:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)=[O:56]
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Prepared using General Procedure 6. To a suspension of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 (60 mg, 0.104 mmol) and 2-(2,5-dimethoxyphenyl)acetic acid (20.48 mg, 0.104 mmol) stirring in DMF (2 mL) were added HATU (43.7 mg, 0.115 mmol) and TEA (36.4 μL, 0.261 mmol). After stirring at room temperature for 2 h the reaction mixture was diluted with EA (25 mL) and washed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL). The organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EA/hexanes) to afford 56 mg (71%) of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-65. LCMS-ESI (m/z) calculated for C45H44N4O7: 752; found 753 [M+H]+, tR=2.76 min (Method 10).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1.[CH3:22][N:23]=[C:24]=[S:25].CCOCC>CCCCCC>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:17][C:18]([F:21])([F:19])[F:20])[C:24]([NH:23][CH3:22])=[S:25])=[CH:11][CH:10]=1
Reactant: CN=C=S
Reactant: FC(F)(F)CNCc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CNC(=S)N(Cc1ccc(Cl)nc1)CC(F)(F)F
Yield: 55.3 %

Procedure:
In 35 m of toluene, 3,79 g (0.0169 mole) of N-(6-chloro-3-pyridylmethyl)-N-(2,2,2-trifluoroethyl)amine and 2.46 g of methyl isothiocyanate were stirred for 18 hours under reflux. The toluene was distilled off, and the residue was dissolved in 120 m of AcOEt, washed with 1N HC, (two ties) and aqueous sodium chloride solution in this order and dried over MgSO4. The AcOEt was distilled off to give oil. To this oily product were added Et2O and hexane, followed by cooling to give crystals. After addition of hexane to the mixture, the crystals were collected by filtration and dried to give 2.78 g of N-(6-chloro-3-pyridylmethyl)-N-(2,2,2-trifluoroethyl)-N'-methylthiourea as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][C:9]([NH2:12])=[N:8][C:7]=1[NH2:13])=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8][C:7]=1[NH2:13])[CH3:2]
Reactant: CCOC(=O)C1=C(N)N=C(N)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.7 %

Procedure:
To a solution of THF (300 mL) and 2,6-diamino-4,5-dihydro-pyridin-3-carboxylic acid ethyl ester (4.5 g) described in Manufacturing Example 10-2-2 was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.6 g), which was stirred for 40 minutes at room temperature. The solvent was evaporated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate), after which it was washed with hexane to obtain the titled compound (3.1 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[C:17](O)(=[O:20])[CH:18]=[CH2:19].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Yield: 58 %

Procedure:
The same procedures as in Example 1 were carried out from the compound obtained in Example 33 (3.3 g), acrylic acid (1.1 mL), DCC (3.4 g), triethylamine (9.5 mL, 68.2 mmol), and chloroform (140 mL), to give the captioned compound (2.1 g, 58%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](O)(=[O:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)C>[C:12]([C:10]1[O:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)(=[O:14])[CH3:13].[C:12]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][O:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: c1ccc(-c2ccoc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)C1(c2ccccc2)C=COC1
Product: CC(=O)c1cc(-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 64 h
Yield: 43 %
Yield: 13 %

Procedure:
3-Phenylfuran (4.3 g) was dissolved in 80 ml of acetonitrile under argon and treated while stirring with 8.6 g of the mixed anhydride from acetic acid and p-toluenesulphonic acid. The reaction solution was stirred at room temperature for 64 hours and subsequently stirred with 150 ml of saturated sodium hydrogen carbonate solution and 150 ml of diethyl ether 30 minutes. The phases were separated and the aqueous phase was extracted once with a further 100 ml of diethyl ether. The organic phases were combined, washed with 100 ml of water, dried over MgSO4 and freed from solvent. The residue was chromatographed on 200 g of silica gel with methylene chloride/hexane (1:1) as the eluent. There was obtained 0.7 g (13%) of 2-acetyl-4-phenylfuran besides 2.4 g (43%) of 3-acetyl-3-phenylfuran. The former was processed without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CC(C)=O>[CH2:18]([O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[CH3:19]
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc2cc[nH]c12
Reaction time: 16 h

Procedure:
To a stirred solution of 1H-indol-7-ol (500 mg, 3.75 mmol) in acetone (10 mL) at r.t. was added potassium carbonate (3.11 g, 22.5 mmol), followed by iodoethane (0.45 mL, 5.63 mol). The mixture was stirred at r.t for 16 h then solvent removed under reduced pressure. The crude product thus obtained was purified by chromatography over silica gel to afford 7-ethoxy-1H-indole: 1H NMR (400 MHz, MeOD) δ ppm 1.51 (t, J=6.95 Hz, 3H), 4.22 (q, J=6.91 Hz, 2H), 6.42 (d, J=3.03 Hz, 1H), 6.63 (d, J=7.58 Hz, 1H), 6.92 (t, J=7.83 Hz, 1H), 7.04-7.23 (m, 2H); MS (ES+): m/z 162.20 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: IC1CCCC1
Reactant: COc1ccc(CCN)cc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(CCNC2CCCC2)cc1
Temperature: 25 °C
Yield: 194.7 %

Procedure:
4-Methoxyphenethyl amine (0.8 mL, 6 mmol), and cyclopentyl iodide (0.22 mL, 2 mmol) in CH3CN (5 mL) were irradiated for 10 min in a microwave at 110° C. After cooling to room temperature the mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane as eluent and the product N-(4-methoxyphenethyl)cyclopentanamine (0.854 g, 65%) was obtained as a colorless liquid which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.10 (d, 2H, J=8.6 Hz), 6.78 (d, 2H, J=8.6 Hz), 3.74 (s, 3H), 3.69-3.65 (m, 1H), 3.08-3.07 (m, 4H), 1.84-1.83 (m, 2H), 1.82-1.81 (m, 2H), 1.66-1.56 (m, 4H). LC-MS (ESI) Calcd for: C14H21NO [M+H]+: 220.16. Found: 220.00.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:25][N:26]1[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=[C:27]1[CH2:39][C:40]([O-])=[O:41].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:40](=[O:41])[CH2:39][C:27]1[N:26]([CH3:25])[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1(C)CNc2cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CC(=O)N2CC(C)(C)c3c(Cl)cccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
20 mg of 4-chloro-3,3-dimethyl-2,3-dihydro-1H-indole [which can be prepared according to Tet. Let. (1987) (28), 5291-5294] and 34 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 30 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 0.5 ml of N,N-dimethylformamide and 0.5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 10 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with ethyl acetate, so as to give 12 mg of 2-[2-(4-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].CO.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2ccc(C=O)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnn(-c2ccc(CO)cc2)c1
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
A mixture of 1-(4-formylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (1.00 g), methanol (10 ml) and tetrahydrofuran (25 ml) was treated with sodium borohydride at 0° C. After 15 minutes, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated by evaporation to give 1-(4-hydroxymethylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (1.04 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[F:10][C:9]1[C:4]([CH2:3][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3([C:40]4[C:31](=[CH:32][C:33]5[O:38][CH2:37][CH2:36][O:35][C:34]=5[CH:39]=4)[O:30][CH2:29]3)[C:21]2=[O:41])=[N:5][CH:6]=[C:7]([F:11])[CH:8]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1cnc(CCl)c(F)c1
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncc(F)cc2F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3,5-difluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (64%) as a colorless solid: mp 220-222° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=1.7 Hz, 1H), 7.26-7.11 (m, 3H), 7.04-6.96 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.49-6.46 (m, 1H), 6.39-6.36 (m, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.00 (d, J=16.1 Hz, 1H), 4.95-4.90 (m, 1H), 4.68-4.63 (m, 1H), 4.20-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.7, 156.2, 155.3, 144.6, 142.0, 139.0, 138.9, 138.3, 133.8, 133.6, 132.5, 123.9, 123.4, 121.2, 112.0, 111.6, 108.9, 99.2, 80.1, 64.5, 63.9, 58.1, 40.3; MS (ES+) m/z 422.8 (M+1).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:7]1[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[N:6]=1
Reactant: BrBr
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
Bromine (4.72 g, 29.5 mmol) is added to a mixture of 2-methoxy-5-aminopyridine (3.66 g, 29.5 mmol) and sodium acetate (4.84 g, 7.32 mmol) in acetic acid (50 mL) and stirred at rt for 20 minutes. Acetic acid is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (40 mL), saturated sodium carbonate aqueous solution (20 mL), water (20 mL) and brine (20 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford 2-bromo-3-amino-6-methoxypyridine (4.35 g) as an oil. MS: 202 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.89 (s, 3H), 6.60(d, H), 7.07(d, H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.Cl[CH2:14][C:15](Cl)=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CN(C=O)C>[NH2:4][C:3]1[N:21]([CH:18]([CH3:20])[CH3:19])[CH2:14][C:15](=[O:16])[C:2]=1[C:1]#[N:5]
Reactant: CC(C)N
Reactant: N#CCC#N
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CC(=O)C(C#N)=C1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
99 g of malononitrile were dissolved in 150 ml of DMF and cooled to 0° C. While cooling, 306 g of triethylamine and 159 g of chloroacetyl chloride were simultaneously added dropwise to this. The reaction mixture was stirred at 10° C. for 10 minutes and subsequently added to a mixture of 1.5 kg of ice and 158 g of isopropylamine. The mixture was stirred at room temperature for 8 hours. The volatiles were then removed by distillation under atmospheric pressure at 100° C., and the distillation residue was cooled to 5° C. The precipitate was filtered off with suction, washed and dried. 105.6 g (43% of theory) of the compound of the formula ##STR24## of melting point 285° to 290° C. were obtained. The IR, NMR, UV and mass spectra and the elemental analysis are consistent with the structural formula.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[OH:8][C@H:9]([C:48]1[C:56]2[S:55][C:54](=[O:57])[NH:53][C:52]=2[C:51]([OH:58])=[CH:50][CH:49]=1)[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:47][CH2:46][C:32]3([O:37][CH2:36][CH2:35][N:34]([C:38]([C:40]4[CH:44]=[C:43]([CH3:45])[S:42][CH:41]=4)=[O:39])[CH2:33]3)[CH2:31][CH2:30]2)=[CH:22][CH:21]=1)C(=O)OC(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:3]([OH:5])=[O:4].[OH:58][C:51]1[C:52]2[NH:53][C:54](=[O:57])[S:55][C:56]=2[C:48]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:47][CH2:46][C:32]4([O:37][CH2:36][CH2:35][N:34]([C:38]([C:40]5[CH:44]=[C:43]([CH3:45])[S:42][CH:41]=5)=[O:39])[CH2:33]4)[CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:49][CH:50]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCOc4ccc(CNC[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)cc4)CC3)C2)cs1
Product: O=CO
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (1.2 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(4-(2-(4-(5-methylthiophene-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzyl)carbamate (example 104, step c) (0.33 g) in DCM (5 mL) and the resulting mixture stirred for 10 minutes. Toluene (20 mL) was added and the mixture was evaporated in vacuo. The residue was azeotroped with toluene (3×20 mL). Purification was by preparative HPLC (Phenomenex Gemini®, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to give the titled compound as a white solid. Yield 0.12 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](OCC)(OCC)OCC.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C([O-])(O)=O.[Na+].CCOC(C)=O>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[N:20]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:25]=[N:24][N:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Cn2nnnc2CCl)cc1
Temperature: 60 °C
Yield: 46.9 %

Procedure:
A solution of 9.55 g (48.6 mmol) 2-chloro-1,1,1-triethoxyethane and 3.9 ml (30 mmol) 4-methoxybenzylamine were heated at 40° C. for 15 min. Then a solution of 2.92 g (45 mmol) sodium azide in 60 ml acetic acid was added at RT and heated at 60° C. over night, 20h at 80° C. and 1h at 100° C. The reaction was neutralized with aqueous and solid NaHCO3/EtOAc (3×), washed with aqueous 10% NaCl. The organic phase was dried over Na2SO4, evaporated and purified by flash-chromatography on silicagel (hexane/EtOAc 1:1) to give 3.36 g (47%) 5-Chloromethyl-1-(4-methoxy-benzyl)-1H-tetrazole, MS: 238 (M). [Y. Satoh, S. De Lombaert, N. Marcopulos, J. Moliterni, M. Moskal, J. Tan, E. Wallace, Synthesis of tetrazole analogs of alpha-amino acids by alkylation of a Schiff base of alpha-aminomethyltetrazole. Tetrahedron Lett. (1998), 39(21), 3367-3370].
Reaction SMILES: Cl[C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6](C=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CCO)CCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH2:6][CH:5]2[CH2:2][CH2:3][CH2:4]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCCC1CCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cyclobutylethanol, the title compound was obtained as a colorless solid (0.12 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.22 (d, J=12.4 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 2.87 (s, 6H), 2.47-2.40 (m, 1H), 2.10-1.99 (m, 2H), 1.89-1.63 (m, 6H); MS (ES−) m/z 377.2, 379.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29]>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)([OH:32])[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Reactant: C#CC(C)(O)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ccccn3)ccc12
Temperature: 35 °C

Procedure:
To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (150 mg, 0.36 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (16.8 mg, 0.02 mmol), copper(I) iodide (2.8 mg, 0.02 mmol) and 2-(pyridin-2-yl)but-3-yn-2-ol (112 mg, 0.73 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Biotage, DCM containing a 1-10% MeOH gradient) to furnish the title compound as a brown oil: 1H NMR (500 MHz, CDCl3) delta 1.78 (6H, s), 1.94 (3H, s), 2.84 (1H, br. s.), 5.18 (2H, br. s.), 5.80 (1H, br. s.), 7.19-7.39 (1H, m), 7.74 (1H, d, J=7.88 Hz), 7.82 (1H, td, J=7.72, 1.58 Hz), 7.90 (1H, d, J=8.35 Hz), 8.29 (1H, d, J=5.36 Hz), 8.58 (1H, d, J=4.73 Hz), 8.89 (1 H, s); LCMS: m/z=+415.05 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:6]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[O:5]
Reactant: NC(=O)c1cc(F)ccc1Br
Reactant: COC(C)(OC)N(C)C
Solvent: CO
Product: CC(=NC(=O)c1cc(F)ccc1Br)N(C)C
Temperature: 120 °C
Yield: 75 %

Procedure:
A mixture of 2-bromo-5-fluorobenzamide (9.57 g, 43.89 mmol) and N,N-dimethylacetamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylacetamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (30 ml) and hexane (50 ml) to give 9.51 g (75% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.43 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.19 (3H, s, NCH3), 6.90-6.97 (1H, m, aromatic), 7.46 (1H, dd, J=3.1 Hz and J=9.1 Hz, aromatic), 7.53 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic). MS (ESI+) m/e 287 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>ClCCl>[C:28]([O:14][C@H:12]1[CH2:13][C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C@@H:11]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1OC(=O)c1ccccc1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (234 mg, 0.859 mmol) prepared in Example 98a and triethylamine (0.40 mL, 2.87 mmol) in dichloromethane (4.0 mL), benzoyl chloride (0.260 mL, 2.24 mmol) was added, and the reaction solution was stirred for 5 hours. To the reaction solution, water (50 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=3:2) to yield the title compound (297 mg, 92%) as a colorless oil.