Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]#[N:10])[N:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[NH:17][C:9]([NH2:10])=[C:8]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: N#CC(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1nc2c(Cc3ccco3)c(N)[nH]c2c(=O)[nH]1
Temperature: 90 °C

Procedure:
To a solution of 2-Amino-α-(2-Furanylmethyl)-1,6-dihydro-5-nitro-6-oxo-4-pyrimidineacetonitrile (4.0 g) in 1N NaOH (250 mL) is added sodium dithionite (16 g) and the reaction mixture is heated at 90° C. for 30 min. The reaction mixture is cooled in an ice bath and neutralized with 4N HCl. The resulting precipitate is collected by filtration and purified by a series of acid/base reprecipitations. First the product is reprecipitated from 1N NaOH by acidifying (pH 2) with a saturated solution of oxalic acid. This NaOH/oxalic acid reprecipitation is repeated. Then it is reprecipitated from 1N NaOH by adjusting pH to 11 with 4N HCl. The product 2,6-Diamino-3,5-dihydro-7-(2-furanylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4one is dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@@H:28]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](O)CC4)c3C)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12

Procedure:
A solution of cis-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanol (140.0 mg, 0.2899 mmol), Dess-Martin periodinane (184.4 mg, 0.4348 mmol) and DCM (10 mL, 200 mmol) was stirred at rt for 1 h. The material was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 2-4% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a tan solid. MS (ES+): m/z=481.18/483.18 (100/50) [MH+]. HPLC: tR=1.49 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[C:33](=[O:47])[NH:34][C:35](=O)[C:36]=2[C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:24]1>C(COC)OC>[S:10]=[C:35]1[NH:34][C:33](=[O:47])[C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)=[C:36]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: O=C1NC(=S)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Yield: 8.7 %

Procedure:
820 mg of Lawesson's reagent was added to a solution of 330 mg of 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 50 ml of dimethoxyethane and the mixture was heated to reflux for 1 hour. 410 mg of Lawesson's reagent were then added and the mixture was heated to reflux for a further 1 hour. The solvent was evaporated and the residue was purified on silica gel with ethyl acetate/hexane (1:4). Recrystallization from diethyl ether/hexane gave 30 mg of 5-thioxo-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 254°-257° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](OC(F)(F)F)=[CH:24][CH:23]=3)[CH:17]=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:47][C:48]([F:64])([F:63])C1C=CC(C2C=C(CN)C=CN=2)=CC=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:48]([F:64])([F:63])[F:47])=[CH:24][CH:23]=3)[CH:17]=2)=[O:13])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded 100 mg of a beige solid. Yield=18.8% 1HNMR (DMSO, 200 MHz) δ 1.12 (3H, t, J=7 Hz), 3.47 (2H, q), 4.48 (2H, d, J=6.4 Hz), 5.41 (1H, s), 6.25 (1H, s), 7.34 (2H, m), 7.59 (1H, d, J=4 Hz), 7.84 (2H, d, J=8 Hz), 7.98 (1H, bs), 8.28 (2H, d, J=8 Hz), 8.63 (1H, d, J=5 Hz), 8.91 (1H, bt) [M+1] 530.1 (C22H19ClF3N3O3S2 requires 529.98).
Reaction SMILES: [CH3:1][C:2]1([CH:17]([CH3:19])[CH3:18])[C:6](=[O:7])[NH:5][C:4]2([CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:3]1.[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>C(O)CCCCC.Cl>[CH3:1][C:2]1([CH:17]([CH3:19])[CH3:18])[C:6](=[O:7])[NH:5][C:4]2([CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][OH:24])[C:11]([CH3:14])([CH3:13])[CH2:12]2)[O:3]1
Reactant: CC(C)C1(C)OC2(CC(C)(C)NC(C)(C)C2)NC1=O
Reactant: OCC1CO1
Agent: Cl
Solvent: CCCCCCO
Product: CC(C)C1(C)OC2(CC(C)(C)N(CC(O)CO)C(C)(C)C2)NC1=O

Procedure:
26.8 g (0.1 mole) of 2,7,7,9,9-pentamethyl-2-isopropyl-1-oxa-4,8-diaza-spiro[4.5]decan-3-one and 7.4 g (0.1 mole) of glycidol in 60 ml of hexanol were stirred for 65 hours at 140° C. in a stirring apparatus, using as catalyst 3 drops of concentrated HCl. The mixture was then evaporated on a rotary evaporator and the residue was recrystallized from xylene/methanol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH3:15])C1C=CC=CC=1.[C:16]([OH:19])(=[O:18])[CH3:17]>[Pd]>[C:16]([OH:19])(=[O:18])[CH3:17].[CH3:15][CH:9]1[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][NH:8]1
Reactant: CC1CC(=O)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CC(=O)CCN1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of the product of step B (3.8 g, 18.7 mmol) in acetic acid (20 mL) was added Pd/C 10% (380 mg) cautiously. The resulting mixture was hydrogenated at 50 psi H2 for 3 h. The reaction mixture was filtered through celite and washed with acetic acid (20 mL). The filtrate was concentrated in vacuo to yield 2-methylpiperidin-4-one acetate as a brown oil (2.98 g, >99%) which was sufficiently pure for the next step: 1H NMR (CD3OD, 400 MHz) δ 3.24-3.19 (m, 1H), 2.86-2.81 (m, 1H), 2.74-2.67 (m, 1H), 2.51-2.49 (m, 2H), 2.37-2.28 (m, 2H), 2.22-2.18 (m, 1H), 2.12-2.02 (m, 2H), 1.08 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([OH:14])(=[O:13])[CH:11]=O>CO>[NH2:4][C:3]1[C:5]([CH3:9])=[CH:6][C:7]([CH:11]([C:7]2[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[C:10]([OH:14])=[O:13])=[CH:8][C:2]=1[CH3:1]
Reactant: O=CC(=O)O
Reactant: Cc1cccc(C)c1N
Solvent: CO
Product: Cc1cc(C(C(=O)O)c2cc(C)c(N)c(C)c2)cc(C)c1N
Temperature: 25 °C

Procedure:
A mixture of 2,6-dimethylaniline (40 parts) and methanol (150 parts) was stirred at ambient temperature. Glyoxylic acid 50% w/v (24.5 parts) was added and the mixture was stirred for 24 hours at ambient temperature. The precipitated product was isolated by filtration, washed with methanol (30 parts) and dried to yield di(4-amino-3,5-dimethylphenyl)acetic acid (44.3 parts).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:37][C:36]6[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)c1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-methoxybenzaldehyde (63.1 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 21.2% yield, 25 mg.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5][N:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: C1CNCCNCCN1
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), ethyl bromoacetate and base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:9]=2[F:27])=[CH:4][CH:3]=1.ClN1C(C)(C)C(=O)N(Cl)C1=O>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([N:18]=[C:19]3[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]3)[C:9]=2[F:27])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(N=C2C=CC(=O)C=C2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of methyl 6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenyl)amino)-picolinate (0.155 g, 0.400 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.158 g, 0.800 mmol) in 1:1 CH3CN/H2O (5 mL) was stirred at room temperature. After 30 min the suspension of the solid ester dissolved giving a yellow/orange solution, then an orange solid began to form. After stirring at room temperature for 2 h, the reaction solution was decanted, and the orange solid was washed with 1:1 CH3CN/H2O (10 mL). The solid was dissolved in CH2Cl2 and dried (MgSO4), and the solvent was removed to give methyl 6-(4-chlorophenyl)-5-fluoro-4-((4-oxocyclohexa-2,5-dien-l-ylidene)amino)picolinate (0.13 g, 0.316 mmol, 79% yield) as an orange solid: mp 154-156° C.; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=7.3 Hz, 2H), 7.65 (d, J=5.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.36 (dd, J=10.1, 2.6 Hz, 1H), 6.87 (d, J=10.3 Hz, 1H), 6.77 (dd, J=10.1, 2.1 Hz, 1H), 6.61 (dd, J=10.2, 2.1 Hz, 1H), 4.02 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −145.68.
Reaction SMILES: [Mg].BrCC.[CH2:5]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:6]#[CH:7].[F:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=[O:23])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:5][C:6]#[C:7][CH:22]([OH:23])[CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([F:15])=[CH:17][CH:18]=1
Reactant: O=CCOc1ccc(F)cc1
Reactant: C#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCBr
Solvent: C1CCOC1
Product: OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the Grignard reagent prepared from magnesium (12.2 g., 0.5 mole) and bromoethane (54.5 g., 0.5 mole) in tetrahydrofuran (400 ml.) is added, dropwise, during 30 minutes, a solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (67.3 g., 0.5 mole) in tetrahydrofuran (50 ml.). The mixture is stirred at room temperature for 1 hour and then treated, dropwise, during 1 hour with 4-fluorophenoxyacetaldehyde (61.6 g., 0.4 mole). The resulting mixture is heated at reflux for 1 hour, then cooled and poured into an ice cold saturated solution of ammonium chloride in water.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37](O)=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH:43]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:45][CH2:44]1>>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:49][S:46]([CH:43]4[CH2:45][CH2:44]4)(=[O:48])=[O:47])=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: NS(=O)(=O)C1CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)C5CC5)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the procedure described in Example 315 using 1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and cyclopropanesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (40.8 mg, 0.144 mmol) was added NMP (0.5 ml), trans-4-aminocyclohexanol (41.5 mg, 0.360 mmol), Hunig's Base (0.101 ml, 0.576 mmol) and HATU (110 mg, 0.288 mmol) The reaction was stirred at room temperature for 6 hours, followed by LCMS. To the reaction was added 0.5 ml of NMP, filtered, purified by prep LC and lyophilized to give 33 mg of tert-butyl (S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate as the TFA Salt. LCMS m/z 381.1 (M+H)+, Rt 0.70 min.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Product: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylaniine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =546.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH2:6])[C:4]#[CH:5].[Cl:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>O>[CH2:3]([NH:6][S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)(=[O:16])=[O:15])[C:4]#[CH:5]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: C#CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCNS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Sodium hydroxide (0.60 g, 15 mmol) was dissolved in 10 ml of water and this solution was added to 0.66 g of propargylamine (12 mmol). Under ice-cooling, 2.11 g of 3-chlorobenzenesulfonyl chloride (10 mmol) was added dropwise to the mixture. The reaction temperature was raised again to room temperature and the mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain N-propargyl-3-chlorobenzenesulfonamide (2.20 g). NMR spectrum of this product was as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2.[CH:24]([N-]C(C)C)(C)[CH3:25].[Li+].C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]([CH2:24][CH3:25])[C:10]2[CH2:20][O:21][C:22](=[O:23])[C:9]1=2
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1=C(C)N(CC)C2=C(C(=O)OC2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mmol of ethyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in tetrahydrofuran, and 50 mmol of lithium diisopropylamide followed by 50 mmol of ethyl iodide are added at -78° C. The mixture is heated to room temperature and stirred for 1 hour, and is worked up analogously to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][F:12])[CH:3]=1.CO.[OH:15]S(O)(=O)=O>[CH3-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Au+].O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: FCCC#Cc1cccc(Br)c1
Agent: [Au+]
Agent: [CH3-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: O=C(CCCF)c1cccc(Br)c1
Temperature: 72 °C
Yield: 40 %

Procedure:
A mixture of 0.2 gm (0.89 mmol) of 1-bromo-3-(4-fluorobut-1-ynyl)benzene, 2 mL of MeOH, 1 mg of methyl(triphenylphosphine)gold (I), 25 μL of conc. H2SO4 and 0.44 mL of H2O was placed in a sealed tube, flushed with argon, heated to 72° C. for 2 h and was cooled. The reaction mixture was diluted with EtOAc, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of 0% to 20% EtOAc-hexanes gave 1-(3-bromophenyl)-4-fluorobutan-1-one as an oil, 0.086 gm (40% yield); 1H NMR (400 MHz, CDCl3) δ: 2.13 (m, 2H), 3.09 (t, 2H, J=7.1 Hz), 4.53 (dt, 2H, J=5.8, 47.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.66 (dq, 1H, J=1.0, 7.8 Hz), 7.55 (dq, 1H, J=1.0, 7.8 Hz), 8.07 (t, 1H, J=1.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24]([NH:8][C:5]2[C:4]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ncc(Cl)nc1OCc1cccnc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(Cl)nc1OCc1cccnc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (0.1 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.09 g). Yield 0.012 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br.[Na]>O1CCOCC1.CO>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: OC1CCOC1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccccc1COC1CCOC1
Temperature: 50 °C
Yield: 80 %

Procedure:
8.8 g (0.1 mole) of 3-hydroxy-tetrahydrofurane were added dropwise, whilst stirring, to a mixture of 2.8 g (0.12 mole) of sodium hydride (3.5 g of 80% strength sodium hydride in paraffin oil) in 100 ml of absolute dioxan at room temperature. The mixture was then heated for 30 minutes under reflux. After cooling to 50° C., 19 g (0.1 mol) of 2-fluorobenzyl bromide were added dropwise to the sodium salt thus obtained. The mixture was then heated for 3 hours under reflux and was allowed to cool to room temperature, 10 ml of methanol were added to destroy the excess sodium hydride, and the mixture was concentrated by distilling off the solvent in vacuo. The residue was taken up in 100 ml of water and extracted with methylene chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo. 15.7 g (80% of theory) of 3-(2-fluorobenzyloxy)-tetrahydrofurane of boiling point 89° C./0.1 mm Hg were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: OCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc(C3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.067 g) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222 mg) and the mixture was stirred at 20° for 15 min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157 g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5 h. Phosphate buffer solution (pH 6.5, 20 ml) and water (30 ml) were added. The mixture was extracted with EtOAc (2×20 ml) and the combined extracts were washed with water (30 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (1.42 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.