Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.2322 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (73 mg, 0.357 mmol), 4 N HCl in dioxane (70 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and a solid precipitated out, which was filtered off. Purified solid with normal phase chromatography to yield a white solid (33.6 mg, 31%), 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. mp 295° C.; LCMS: m/z=465.41 (M+H+), 1H NMR (400 MHz, MeOD) δ 8.76 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 7.48 (m, 1H), 7.15 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 2.95 (s, 3H), 2.34 (m, 2H), 2.12 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH3:40]>>[NH2:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: N
Product: Nc1nccc(-c2sc(N3CCS(=O)(=O)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 38 %

Procedure:
Following a procedure analogous to Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.30 g, 0.487 mmol) and 7 M ammonia (20 mL) the title compound was obtained (0.11 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br. s., 1H), 7.85 (d, J=5.3 Hz, 1H), 7.63-7.75 (m, 1H), 7.42 (td, J=7.5, 1.7 Hz, 1H), 7.19-7.36 (m, 4H), 6.60 (br. s., 2H), 5.68 (d, J=5.1 Hz, 1H), 3.97 (br. s., 4H), 3.29 (br. s., 4H). m/z (ES+): 597 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 4-bromophenol (646, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10% ethyl acetate in hexanes) gave the desired compound as a colorless oil (647, 3.2 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:30][C:28]([O:27][CH:24]1[CH2:23][CH:12]2[CH2:13][O:14][C:15]3[C:20]([C:11]2([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:26][CH2:25]1)=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[O:29]
Reactant: O=C(Cl)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(O)CC1COc1c(F)ccc(F)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-ol (0.46 g, 1.11 mmole) was dissolved in 30 ml DCM. Phosgene (20% in toluene, 4 ml) and pyridine (1 ml) were added and the reaction was stirred at room temperature for 10 minutes. 20 ml DCM was added and the reaction was quenched by slowly adding 10 ml water. The organic layer washed with 50 ml 1N HCl solution, dried over sodium sulfate. After the solvent was removed, the residue was purified by column using EtOAc/Hex. as the solvent (gradient from 0/100 to 25/75 in 25 minutes). Yield: 0.37 g, 70%. 1H NMR (CDCl3 400 MHz) δ 7.62 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.06-7.13 (m, 1H), 6.40-6.47 (m, 1H), 5.28 (dd, 1H, J=11.7 and 2.9 Hz), 5.05 (s, 1H), 4.14 (d, 1H, J=11.7 Hz), 3.02 (dt, J=13.2 and 2.9 Hz, 1H), 2.31-2.49 (m, 2H), 2.01-2.16 (m, 2H), 1.66-1.75 (m, 1H), 1.30-1.40 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:35][N:36](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN>ClCCl.O1CCCC1>[OH:19][C@H:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][N:8]([CH:20]1[CH2:21][CH2:22][CH2:23][C:24]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH:36][CH3:35])=[CH:27][C:25]=2[CH2:26]1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(C(=O)O)cc2C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a mixture of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (0.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 1-hydroxybenzotriazole (0.11 g) in dichloromethane (6 ml) was added a solution of methylamine in tetrahydrofuran (2.0M, 0.40 ml). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (100:1 to 10:1) to afford N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-tert-butoxycarbonyl-(3-methylcarbamoyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.13 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH3:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:43]([NH:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)[CH2:42][CH2:41][CH2:40][CH3:39]
Reactant: CCCCCN
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 50 mmol), n-amylamine (45 ml, 650 mmol) and potassium carbonate (7.5 g, 50 mmol) in THF (45 mL) were stirred overnight at room temperature. The mixture was concentrated in vacuo, and then extracted with 1M aq. KOH (50 mL) and chloroform (3×200 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo to yield crude pentyl[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine, which was used without further purification. A solution of the crude material (30 g) in 4M HCl in 1,4-dioxane (300 mL) was stirred at room temperature. After 1 hour, the precipitate was filtered and washed with hexane to afford the title compound as the HCl salt (18.0 g). MS m/z: [M+H]+ calcd for C19H23N5, 321.20. found 322.5.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Br:15][C:16]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(Br)c(C=CC(=O)O)cc1OC
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3Br)nc2n(CC)c1=O
Yield: 49.2 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.78 g (17.2 mmol) of 2-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.34 g (yield 49%) of Compound 117 as pale yellow needles.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:20])[C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18]C.CN1C(=O)CC[C@H]1C(O)=O.C(N1C(=O)CC[C@H]1C(O)=O)C.FC1C=CC(CN)=C([C:51]([F:54])([F:53])[F:52])C=1.ClC1C=C(F)C=CC=1CN>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][NH:10][C:11](=[O:20])[C@@H:12]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[CH3:18])=[C:2]([C:51]([F:54])([F:53])[F:52])[CH:7]=1
Reactant: CCN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: NCc1ccc(F)cc1C(F)(F)F
Agent: CCN1C(=O)CC[C@H]1C(=O)O
Agent: CN1C(=O)CC[C@H]1C(=O)O
Agent: NCc1ccc(F)cc1Cl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1C(F)(F)F

Procedure:
N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-1-methyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxoprolinamide (Example 70) but 1-methyl-5-oxoproline (prepared as describe below) was substituted for 1-ethyl-5-oxoproline and {[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amine was substituted for 2-chloro-4-fluorobenzylamine.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[Mg].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH2:4][CH3:5]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(C)Br
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
Add slowly a solution of 2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirring mixture of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. Heat the mixture at reflux for 30 min. Cool the mixture to room temperature and add 4-bromo-benzaldehyde (5.36 g, 29 mmol). After stirring for 5 min, cool the mixture in an ice-bath and acidify with 3N aqueous HCl (50 mL). Dilute the mixture with water and extract twice with diethyl ether. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 20:1 and 1:1) to provide the desired intermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([NH:15][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14]=3[CH:12]([N:13]=2)[CH2:11][CH2:10][CH2:9]4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Solvent: O
Product: c1ccc(NC2=NC3CCCc4cccc(c43)N2)cc1

Procedure:
10.3 g (0.05 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine are introduced into 15 ml of aniline, whilst stirring. After the strongly exothermic reaction has subsided (temperature rises to 90° C.), water is added to the mixture and the crystals which have precipitated are isolated by filtration and washed several times with dilute aqueous ammonia solution. 2-Phenylamino-3a,4,5,6-tetrahydro-perimidine is obtained. Yield: 9.5 g (72% of theory) of melting point 233°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:37]O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[K+].[Br-].Cl>>[CH3:30][C:31]1([CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC1(CO)CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1(C)CCCCC1)(C(=O)OCC1(C)CCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclohexyl-methanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.84 (s, 6H, CH3, CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.1-1.4 (m, 20H, cyclohexyl), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (s, 1H, Ar--H), 7.09 (d, J=8.35 Hz, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 641 (M+); Analysis for: C36H48ClNO7 ×HCl: Calc'd: C, 63.71; H, 7.28; N, 2.06; Found: C, 63.72; H, 7.03; N, 1.91.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC(S(N)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH:70]1[C:74]([CH2:75][NH2:76])=[N:73][N:72]=[N:71]1>CN(C)C=O>[N:70]1[NH:71][N:72]=[N:73][C:74]=1[CH2:75][NH:76][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: NCc1nnn[nH]1
Agent: CC(C)(C)S(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(C(=O)NCc2nn[nH]n2)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
A 5 mL vial equipped with a stir bar was charged with 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (0.100 g, 0.233 mmol) as prepared in Example 1.1 using racemic 2-methylpropane-2-sulfinamide in Step B, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (133.0 mg, 0.350 mmol), N-methylmorpholine (118.0 mg, 1.167 mmol), N,N-dimethylformamide (1.2 mL). The mixture was purged with nitrogen, heated to 50° C. and stirred for 30 minutes. Then, (1H-tetrazol-5-yl)methanamine (39.9 mg, 0.233 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was purified by prep-HPLC to give (+/−)-N-((2H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamide (10 mg, 4.2%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.50 (d, 1H), 7.86 (dd, 1H), 7.80 (d, 2H), 7.72 (d, 2H), 7.64 (d, 2H), 7.50 (d2H), 6.58 (d, 1H), 5.11 (m, 1H), 4.82 (s, 2H), 1.89-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.68-1.62 (m, 1H), 1.03 (d, 3H), 1.00 (d, 3H) ppm. MS (M+1): 510.3
Reaction SMILES: [C:1]([O-])(=[O:4])[CH2:2]C.[Sc+3:6].[C:7]([O-])(=[O:10])[CH2:8]C.[C:12]([O-])(=[O:15])[CH2:13]C.C1C=CC=CC=1.[Li]>C(O)C>[O-:4][CH2:1][CH3:2].[Sc+3:6].[O-:10][CH2:7][CH3:8].[O-:15][CH2:12][CH3:13]
Reactant: CCC(=O)[O-]
Agent: [Li]
Agent: [Sc+3]
Solvent: CCO
Solvent: c1ccccc1
Product: CC[O-]
Yield: 118.4 %

Procedure:
Scandium propionate (0.03 mol.), benzene (50 ml) and ethanol (10 ml) were placed in a round-bottomed flask of 100 ml-capacity, to which was then added slowly 0.6 g (0.09 mol.) of metallic lithium under stirring. After the addition of the metallic lithium, the admixture in the flask was refluxed for 1 hour by heating with aid of a mantle heater, and then the reaction solution was processed in the same manner as in Example 1 to afford 6.4 g of scandium ethoxide as a white colored crystal. Yield 95.6%
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]([CH3:18])=[C:5]([C:19]([OH:21])=O)[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CN(C)C=O.[NH2:40][CH2:41][CH2:42][OH:43]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:6]([CH3:18])=[C:5]([C:19]([NH:40][CH2:41][CH2:42][OH:43])=[O:21])[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: NCCO
Reactant: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)O)C1c1ccc(C#N)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)NCCO)C1c1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 23.57 mg (0.05 mmol) of the compound of Example 60 in 100 μl dimethylformamide 16.22 mg (0.10 mmol) 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 12.22 mg (0.20 mmol) 2-aminoethanol are added. After stirring for 15 minutes, the reaction mixture is allowed to stand at room temperature for two days. The reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% triethylamine; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: ca 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:3](CSCCN)=[N:4]C=C[CH:7]=1.C(C=C(OC)OC)#N.[C:21]([CH:23]=[C:24](OC)[NH:25][CH2:26][CH2:27][S:28][CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=1)#[N:22].C(N)C#C>>[C:21]([CH:23]=[C:24]([NH:4][CH2:3][C:2]#[CH:7])[NH:25][CH2:26][CH2:27][S:28][CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=1)#[N:22]
Reactant: NCCSCc1ncccc1Cl
Reactant: COC(=CC#N)NCCSCc1ncccc1Cl
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
When 2-[(3-chloro-2-pyridyl)methylthio]ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene and the resultant 1-cyano-2-methoxy-2-{2-[(3-chloro-2-pyridyl)methylthio]ethylamino}ethylene is reacted with propargylamine according to the general procedure of Example 1 Step B the title compound is produced.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccccc1

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (1.6 g) was treated with benzoyl chloride (1.1 eq.) and triethylamine (1.5 eq) in methylene chloride (50 mL). The reaction mixture was washed with 1 N HCl, sat, NaHCO3, and sat NaCl and the solvent removed to give product. LC-MS showed the product had the expected M+H+ of 279.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[N:35]2[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].N1C=CC=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:35]1[CH:40]=[CH:41][CH:42]=[C:43]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:44]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cccnc1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cccnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyridin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (9%) as a colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40 (d, 1H), 7.29 (t, 2H), 7.18-7.08 (m, 2H), 7.00 (d, 1H), 6.81 (d, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10-2.90 (m, 2H); MS (ES+) m/z 448.5 (M+1).