Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:46](=[O:47])[CH2:45][N:42]3[C:43]([CH3:44])=[C:39]([Cl:38])[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41]3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Br)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.36 (d, 2H), 6.92 (d, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H), 3.14 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect=465.0, found=465.0.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][C@@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=1.P([O-])([O-])([O-])=O>CS(C)=O.C(OCC)(=O)C>[OH:1][C@@H:2]([CH2:24][C@@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=1
Reactant: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)OCC)cs1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of the compound 29 (142 mg) in dimethylsulfoxide (7.00 mL)/phosphate buffer (7.00 mL) was added esterase from porcine liver (0.850 mL) and the solution was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with an aqueous saturated ammonium sulfate solution, 1N hydrochloric acid, water and brine. The reaction solution was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate), to give the title compound (88.0 mg) having the following physical data.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:20])CC>C(Cl)Cl>[F:20][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCC(O)c1cccc(I)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C=CCCC(F)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(3-Iodo-phenyl)-pent-4-en-1-ol (0.51 g, 1.77 mmol), in dry methylene chloride (10 mL) at −78° C. and under a nitrogen atmosphere was added DAST (0.28 mL, 2.1 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 1 h, and then quenched with sat sodium bicarbonate (4 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo to a clear oil (0.46 g, 90%) and used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35](=[O:44])[C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:43])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH3:19])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35](=[O:44])[C:36]1[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)cyclohexylalaninyl]-3-amino -5-(2,6-dichlorobenzoyl)oxy-4-oxo-pentanoic acid, tert-butyl ester with TFA as described in Example 80 gave the titled product (54.2 mg) as a white powder. MS C35H41Cl2N3O7, [M+H]+=686, [M−H]−=684. TLC (CH2Cl2/MeOH , 90/10): Rf=0.30.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:11][O:12][CH2:13]Cl.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Sodium hydride (66%, 633 mg, 17.4 mmol) was added to an ice-cooled solution of 2-chloro-3-hydroxypyridine (2.05 g, 15.8 mmol) in tetrahydrofuran (30 ml) under nitrogen atmosphere, and this reaction mixture was stirred at that temperature for 15 minutes. Chloromethyl methyl ether (1.32 ml, 17.4 mmol) was added, and the resulting reaction mixture was stirred at that temperature for 30 minutes, then at room temperature for another 2 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.44 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[N:16][C:11]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 26, 35 mg) was dissolved in dry dichloromethane (3 mL). The reaction mixture was cooled down in an ice bath. Triethylamine (98 μl, 0.701 mmol) was added. Then a solution of triphosgene in dry dichloromethane (13.88 mg, 0.047 mmol dissolved in 1 mL of dichloromethane) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (4 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×5 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 2×4 g silica cartridges) with a gradient cyclohexane/ethylacetate from 100/0 to 50/50 during 10 min and 50/50 during 20 min. This afforded the title compound as a film (27 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:21](=[O:23])=[O:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:21]([OH:23])=[O:22])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Yield: 25 %

Procedure:
Reaction of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine (5.3 g, 25 mmol) sequentially with n-BuLi and CO2 as described in the following example gives 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine-4-carboxylic acid (1.60 g, 25%). 1H NMR (DMSO) δ 9.83 (1H, brs), 8.84 (1H, s), 7.49 (1H, d, J=2.9 Hz), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]([O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:22]([CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[C@H:21]2[C@H:12]1[C@:13]1([CH3:33])[C@@H:18]([CH2:19][CH2:20]2)[CH2:17][C@@H:16]2[O:32][C@@H:15]2[CH2:14]1)=[O:9])[CH3:6])[CH2:2][CH2:3][CH3:4].[BrH:34]>C(Cl)(Cl)Cl>[Br:34][C@H:15]1[CH2:14][C@@:13]2([CH3:33])[C@@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:12]2[C@@H:11]([O:10][C:8](=[O:9])[CH2:7][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:6])[CH2:30][C@@:29]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[CH2:17][C@@H:16]1[OH:32]
Reactant: Br
Reactant: CCCCN(C)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H]4O[C@@H]4C[C@]3(C)[C@H]21
Solvent: ClC(Cl)Cl
Product: CCCCN(C)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](Br)C[C@]3(C)[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11β-(N-butyl-N-methylaminoacetoxy)-2α,3α-epoxy-5α-pregnan-20-one (1.6 g) and aqueous 47% hydrobromic acid (2 ml) in chloroform (100 ml) was stirred at room temperature for 1 hour. The solution was washed with dilute sodium bicarbonate solution and water, dried and evaporated in vacuo to give a foam. Crystallization from ethyl acetate-petroleum ether afforded title compound, m.p. 108°-110°, [α]D +95° (1.303 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][C:14]([CH2:18][OH:19])([CH:16]=[CH2:17])[CH:13]([O:20]CC2C=CC=CC=2)[CH2:12]1.C(O)=O>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][C:14]([CH2:16][CH3:17])([CH2:18][OH:19])[CH:13]([OH:20])[CH2:12]1
Reactant: C=CC1(CO)OC(n2cnc3c(N)ncnc32)CC1OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCC1(CO)OC(n2cnc3c(N)ncnc32)CC1O
Yield: 63 %

Procedure:
[5-(6-Amino-purin-9-yl)-3-benzyloxy-2-vinyl-tetrahydro-furan-2-yl]-methanol was added to a flask. A 3.4% solution of HCOOH in methanol and Pd/C were added. The reaction was allowed to stir, was filtered and the solvent evaporated to provide the titled compound in 63% yield.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CCCOC(C)Cc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCOC(C)Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Then, 2.5 g (8 mM) of the thus-obtained (-)-4-acetoxy-4'-(2-propoxypropyl)biphenyl was dissolved in 30 ml of methanol, added with 20% NaOH aqueous solution, and sturred at room temperature for 2 hrs. After completion of the reaction, the reaction solution was added with 1N hydrochloric acid till pH 2-3, and then further added with 100 ml of ethyl acetate to subject extraction treatment. The resulting organic layer was water-washed and then concentrated under a reduced pressure to obtain 2.2 g of (-)-4-hydroxy-4'-(2-propoxypropyl)biphenyl (V-43) with 100% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:25])([F:24])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:19](OCC)=[O:20].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[F:24][C:3]1([F:25])[CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6]2[C:19](=[O:20])[NH:1][CH2:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of diethyl 1-(3-amino-2,2-difluoropropyl)-1H-indole-2,6-dicarboxylate (2.3 g) in ethanol (160 mL) are added triethylamine (2.7 mL, 19.0 mmol) and K2CO3 (1.3 g, 9.5 mmol). The mixture is heated at 80° C. for 16 h. Ethanol is removed under vacuum and water (100 mL) is added. The resulting light yellow solid is filtered and dried to afford the title compound (1.2 g, 70% for 3 steps).
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[C:13]([O:15]C)=[O:14]>CO>[CH3:12][O:11][C:9]([C:6]1[CH:7]=[CH:8][N:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=1)=[O:10]
Reactant: COC(=O)c1ccnc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccnc(C(=O)O)c1
Yield: 100.6 %

Procedure:
A mixture of methanol (800 mL), potassium hydroxide (44 g, 0.95 mol) and dimethyl pyridine-2,4-dicarboxylate (ChemPacific) (156 g, 0.79 mol) was refluxed for 0.5 hours and then evaporated in vacuo to afford 4-(methoxycarbonyl)picolinic acid (144 g) as a yellow solid.
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][C:17]#[N:18]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
Mix 4-bromophenol (1.4 mmol) in acetonitrile (5 ml) and water (2 ml), add K2CO3 (3 mmol) and bromoacetonitrile (1.5 mmol) at room temperature under inert atmosphere. Heat the mixture to 80° C. for 16 h. Analyze by LC/MS for final product. Evaporate the solvent and add water. Extract product with DCM (3×) and combine and evaporate organic phases to afford the title compound.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[CH3:13][C:12]1[C:7]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:33])([F:34])[F:23])=[CH:31][CH:30]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(OC(F)(F)F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [4-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.70 (d, J=3.6 Hz, 2H), 5.92 (bs, 1H), 6.44 (bs, 1H), 7.01-7.21 (m, 3H), 7.16 (bs, 1H), 7.44-7.61 (m, 3H), 8.58 (bs, 1H); MS (ESI) m/z 390.7 (M+1)+.
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]([NH:20][C:21](=[NH:30])[S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(OC)=[O:17]>ClCCCl>[CH:1]([N:4]1[S:5](=[O:7])(=[O:6])[NH:30][C:21]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20][C:16]1=[O:17])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(=N)SCc1ccccc1
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)N1C(=O)N=C(SCc2ccccc2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
37.9 parts of isopropylaminosulfonyl chloride and 26.3 parts of triethylamine were introduced simultaneously, through two feed lines, into a stirred mixture of 54 parts of N-carbomethoxy-S-benzyl-isothiourea and 740 parts of 1,2-dichloroethane, at from 5° to 10° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with 200 parts of water and twice with 100 parts, each time, of 0.5 N hydrochloric acid. After drying, and concentrating under reduced pressure, 79 parts of N-carbomethoxy-N'-isopropylsulfamyl-S-benzyl-isothiourea of nD25 =1.5598, were obtained. This material crystallized on trituration with hexane, and the crystalline product melted at 76°-78° C. 76 parts of this product were dissolved in a mixture of 44 parts of 50% strength by weight sodium hydroxide solution and 200 parts of water and the reaction mixture was stirred for 5 minutes at 85° C. It was then cooled and acidified with 15% strength hydrochloric acid, and the oil which precipitated was taken up in methylene chloride. This solution was dried over magnesium sulfate, filtered through neutral alumina and concentrated under reduced pressure, giving 59.5 parts of 6-isopropyl-3-benzylmercapto-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide (86.3% of theory), of melting point 124°-130° C. This constitutes active ingredient No. 2.
Reaction SMILES: [CH:1](Br)=[CH2:2].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1.BrBr.O>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)[CH:1]=[CH2:2]
Reactant: C=CBr
Reactant: O=Cc1ccc(O)cc1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A 2.5l sulfonation flask equipped with stirrer, thermometer, reflux condenser, addition funnel and bubble counter connected to an argon flask is charged with 92.2 g Mg turnings, (4.0 mol) and 150 ml THF. After the system has been flushed with argon one iodine crystal is added followed by 30 drops of a solution of 192.6 g vinyl bromide (1.8 mol) in 300 ml THF. Using an oil bath, the reaction flask is heated to 70° C. and one drop of bromine is added. After ignition of the Grignard-reaction the oil bath is removed and the vinyl bromide-THF solution is added steadily at ambient temperature over a period of 6 hours. Stirring is continued for another 30 minutes and the cloudy, black-grey mixture obtained is cooled to 0° with an ice bath. After dilution with 600 ml THF, a solution of 61.05 g 4-hydroxy-benzaldehyde (0.5 mol) in 150 ml THF is added under efficient cooling (ice bath) over a period of 30 minutes. The thick, but stirrable suspension obtained is stirred at room temperature overnight and then cooled to 0° C. Under vigorous stirring a solution of 133.7 g NH4Cl (2.5 mol) in 350 ml H2O is added very carefully over a period of 1.5 hours. The suspension obtained is stirred for another 1.5 hours, the precipitated solids are separated by filtration and the reaction vessel is rinsed several times with a total of 600 ml MTBE. The combined organic layers are washed 2× with 500 ml water, 2× with 500 ml aq. NaHSO3 (10%), 2× with 500 ml H2O, 1× with 500 ml saturated NaHCO3 and 2× with 500 ml brine/water ca 2:1. Each aqueous phase is extracted 1× with 500 ml MTBE, the combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel 60, Merck Flash; 30 cm column with 7.5 cm diameter; solvent: hexane/MTBE 1:1) to give 56.0 g (75%) 4-(1-hydroxyallyl)-phenol in the form of a yellowish, viscous oil that slowly crystallizes.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1cccc(CCl)c1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-methylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=7.1 Hz, 1H), 5.13 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63-2.60 (m, 2H), 2.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=O.[NH4+]=S.[CH:18]([C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)=O>>[CH3:8][N:7]1[C:2]2[NH:1][C:18]([C:20]3[CH:30]=[CH:29][C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)=[N:14][C:3]=2[C:4](=[O:13])[N:5]([CH2:10][CH2:11][CH3:12])[C:6]1=[O:9]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Product: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-1-methyl-3-propyl-2,4(1H,3Hpyrimidinedione was prepared freshly from 6-amino-1-methyl-5-nitroso-3-propyl-2,4(1H,3H)pyrimidinedione by ammonium sulfide reduction using the method of V. Papesch, M. Grove, and F. F. Schroeder (U.S. Pat. No. 2,602,795). This diamine (2.00 g, 10.0 mmol) was condensed with 4-formylcinnamic acid (1.76g, 10.0 mmol) by the procedure of Example 2 to give the title compound as an ivory powder, after crystallization from N,N-dimethylformamide-water; mp>300° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([Br:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([Br:13])[CH:3]=[C:2]([F:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1Cc2cc(Br)cc(F)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Br)cc(F)c3O2)cc1
Yield: 74.8 %

Procedure:
Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.