Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:15][C:16]([CH3:22])=[CH:17][C:18](OC)=[O:19]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:16]([CH3:22])([CH3:15])[CH2:17][C:18](=[O:19])[O:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OC(=O)CC2(C)C
Temperature: 130 °C
Yield: 39 %

Procedure:
A mixture of 3-methoxy-phenol (12 g, 96.5 mmol) and conc. sulfuric acid (0.5 ml) was heated at 130° C. with stirring, and methyl 3,3-dimethylacrylate (5.8 g, 51 mmol) was added. The mixture was stirred at 13° C. for 3 hours. After being cooled to ambient temperature, the organic layer was dissolved in ethyl acetate. The organic layer washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane= 1/9 to furnish 4.1 g (39% yield) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:25].[Na+].O1CCOCC1.O=O>[Pt].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][C@H:12]1[C:22]([OH:25])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OCc1ccccc1

Procedure:
To a mixture of (2S-trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g), sodium bicarbonate (0.5 g), dioxane (20 ml), and water (20 ml) was added freshly prepared platinum black (prepared by hydrogenating 0.3 g of platinum oxide). Oxygen was passed through the solution at room temperature for 16 hours with vigorous stirring. Filtration and acidification, followed by extractive work-up yielded (trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a glassy solid. This compound can be deprotected using catalytic hydrogenation as described in Method I.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCc1cccc2cc[nH]c12
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25](O)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:25]([O:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:26]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(O)c2o1
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cccc2cc(C(=O)c3c(-c4ccccc4)noc3C)oc12
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To a solution of (7-hydroxy-2-benzofuranyl)(5-methyl-3-phenyl-4-isoxazolyl)methanone (example 4) (100 mg, 0.31 mmol) in THF (3.1 mL) was added ethanol (19 mg, 24 μL, 0.42 mmol) and triphenylphosphine (109 mg, 0.42 mmoL) at room temperature. The resulting mixture was then cooled to 0° C. and diethyl azodicarboxylate (73 mg, 65 μL, 0.42 mmol) added. The resulting mixture was maintained at 0° C. for 30 min and then allowed to warm up to room temperature overnight. The mixture was then adsorbed onto SiO2 and purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 75:25) afforded the title compound (90 mg, 83%) as a white solid. MS m/e: 348.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.C([O-])([O-])=O.[Na+:36].[Na+].CCCCCCC>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([O-:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.[Na+:36]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)[O-])c2)n1
Reaction time: 15 h

Procedure:
A solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [540 mg, 1.17 mmol, Example 49(b)] in MeOH (60 mL) is treated with Na2CO3 (187 mg, 1.78 mmol) and the mixture is stirred for 15 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. To the residue is added a mixture of methanol, EtOAc and acetone. The insoluble material is filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. To the residue is added MeOH (1 mL) and EtOAc (5 mL), followed by heptane until the solution turned cloudy and a solid is formed slowly. Heptane is repeatedly added until the solution stay clear. The mixture is filtered affording sodium 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionate as a crystalline. LC/MS: RT=2.34 minutes, MS: 460 (M-Na+ 2H)+. 1H NMR [300 MHz, (CD3)2SO]: □ 7.97 (1H, br s), 7.24-7.7 (7H, m), 6.57 (1H, s), 3.86 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.4 (6H, s).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH:46]([N:48]=[C:49]=[O:50])=[CH2:47]>C(OCC)(=O)C>[CH:46]([NH:48][C:49]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:50])=[CH2:47]
Reactant: C=CN=C=O
Reactant: O=C1CCCCCN1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: C=CNC(=O)N1CCCCCC1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
113 parts of ε-caprolactam, 91 parts of ethyl acetate and 0.015% of dibutyl-tin dilaurate are initially taken in a reaction vessel and are heated at about 50° C. A mixture of 69 parts of vinyl isocyanate and 91 parts of ethyl acetate is added dropwise in the course of 1 hour, after which the mixture is allowed to continue reacting for a further 5 hours. A pale yellow clear solution is obtained. Content of blocked isocyanate groups: 11.5%. Preparation of component (C)
Reaction SMILES: [OH-].[Na+].[CH:3]1([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.CO>[CH:3]1([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)COC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of NaOH (4.89 g, 122 mmol) in a mixture of water (20 mL) and MeOH (20 mL) in an ice bath was added a solution of ethyl 2-(cyclohexyloxy)acetate (3.8 g, 20.4 mmol) in MeOH (10 mL) slowly and the mixture was stirred at rt for 2 h. It was then acidified to pH 4 with concentrated hydrochloric acid and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as pale yellow oil (2.7 g, 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.Cl.[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@H:29]1[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:25][CH:23]([F:24])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][O:33][C@@H:28]([CH3:27])[C@H:29]3[CH3:34])[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: C[C@@H]1NCCO[C@@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1OCCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine. (2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:12]Br>CC(O)=O>[Br:12][N:8]1[CH:3]2[C:2]([O:1][CH2:6][C:5](=[O:7])[NH:4]2)=[CH:11][CH:10]=[CH:9]1
Reactant: O=C1COc2cccnc2N1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1COC2=CC=CN(Br)C2N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.4 %

Procedure:
To a solution of 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (5.00 g, 33.3 mmole) in HOAc (100 mL) was added Br2 (2.6 mL, 50.0 mmole). After stirring for 48 hours at RT, the reaction solution was concentrated to an orange solid, which was suspended in 1N NaOH (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying under high vacuum gave the title compound (5.49 g, 72%) as a yellow solid: MS (ES) m/e 230 (M+H)+.
Reaction SMILES: CS[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1.[OH-].[NH3:19]>>[NH2:19][C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1
Reactant: N
Reactant: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Agent: [OH-]
Product: CCCCCn1c(N)nc(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol) was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. The mixture was stirred at 100° C. for 4 days. After cooling to room temperature, the solid was filtered and dried to yield the desired product (3.0 g, 68%). LCMS calculated for C10H16N5O (M+H): 222.1. Found: 222.1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-5-trifluoromethyl-pyridine (0.11 g, 0.6 mmol) and diisopropylethyl amine (0.21 mL, 1.2 mmol). The reaction mixture was stirred at 150° C. in a microwave for 180 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate in hexane to provide (4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 394 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (d, 1H), 7.61 (d, d 1H), 7.40-7.30 (m, 5H), 6.66 (d, 1H), 5.07 (s, 2H), 4.71-4.67 (m, 1H), 3.93 (m, 2H), 3.36 (m, 2H), 2.10 (m, 2H), 1.68 (m, 2H), 1.42 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])(=[O:7])=[O:6].N1C[CH2:20][O:19][CH2:18]C1>>[N:2]1([CH2:3][CH2:4][S:5]([C:8]2[CH:9]=[C:10]([NH:11][C:8]3[CH:9]=[CH:10][CH:12]=[CH:13][CH:14]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:6])[CH2:15][CH2:18][O:19][CH2:20][CH2:1]1
Reactant: CN(C)CCS(=O)(=O)c1cccc(N)c1
Reactant: C1COCCN1
Product: O=S(=O)(CCN1CCOCC1)c1cccc(Nc2ccccc2)c1
Yield: 98.7 %

Procedure:
This aniline was prepared with the same procedure described for the preparation of 3-(2-Dimethylaminoethylsulfonyl)-aniline, using morpholine instead of dimethylamine. 770 mg (2.137 mmol; 98.7% yield) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[CH3:11])[C:3]=1[OH:12].O[CH:14]([CH:27]=[CH2:28])[CH2:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][CH:14]([O:12][C:3]2[C:4](/[CH:9]=[CH:10]/[CH3:11])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:27]=[CH2:28])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: C/C=C/c1cc(F)cc(Br)c1O
Reactant: C=CC(O)COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CC(COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1/C=C/C
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenol (6.37 g, 0.0276 mol), toluene-4-sulfonic acid 2-hydroxy-but-3-enyl ester (8.8 g, 0.0363 mol) and triphenylphosphine (10.12 g, 0.0386 mol) in anhydrous toluene (200 mL) at 0° C. under nitrogen was added a solution of diethyl azodicarboxylate (6.72 g, 0.0386 mol) in anhydrous toluene (100 mL) over 10 minutes then the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of water (400 mL), stirred vigorously for 5 minutes and the resulting oily suspension extracted with diethyl ether (300 mL). The organic phase was separated, washed with water (2×500 mL), and saturated brine (400 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 2 to 10% ethyl acetate in hexane gave 12.11 g (96%) of 2-{2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenoxy}but-3-enyl 4-methylbenzenesulfonate as a colorless oil. HRMS: calcd for C20H20BrFO4S+NH4+, 472.05879. found (ESI, [M+NH4]+), 472.0581.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]Cl>CC(C)=O>[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][S:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: FC(F)(Cl)CCCCl
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(Cl)CCCSc1nccs1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Solid anhydrous potassium carbonate (9.33 g) was added in two portions to a stirred mixture of 2-mercaptothiazole (7.90 g), 1,4-dichloro-1,1-difluorobutane (9.70 g) and acetone (150 ml) under a nitrogen atmosphere, and the resultant mixture heated at the reflux temperature for 4 hours. After cooling to the ambient temperature the solid component was removed by filtration and washed with acetone (2×50 ml) and the combined washings and filtrate concentrated by evaporation of the solvent under reduced pressure. Diethyl ether (150 ml) was added to the residue and the resultant solution washed with aqueous potassium carbonate solution (2×100 ml) and with water (100 ml). After drying over anhydrous magnesium sulfate the solution was concentrated by removal of the solvent by evaporation under reduced pressure to yield 2-(4-chloro-4,4-difluorobutylthio)thiazole (13.98 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[CH:25]1([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:27]=[CH:26][C:25]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Temperature: 80 °C

Procedure:
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester compound was prepared following General Procedure D using (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (1.803 g, 4.38 mmol), 4-cyclohexyl-benzene boronic acid (1.61 g, 98%, 7.88 mmol), palladium tetrakis-triphenylphosphine (0.462 g, 0.4 mmol), and aqueous Na2CO3 (2.0 N, 16 mL, 32 mmol) in DME (32 mL). The mixture was heated at 80° C. for 14 h. Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave product as a red solid (2.01 g, 4.09 mmol, 93% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH2:2][C:3]2[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: COc1ccc(C(C)=O)cc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.7 %

Procedure:
A solution of 3'-chloromethyl-4'-methoxyacetophenone (10.0 g) in N,N-dimethylformamide (30 ml) was added slowly to a suspension of potassium phthalimide (9.4 g) in N,N-dimethylformamide (70 ml) at room temperature and then the mixture was stirred for 9 hours at room temperature. After removed of the insoluble material, the solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was extracted with ethyl acetate (300 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3'-phthalimidomethyl-4'-methoxyacetophenone (11.94 g).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 8639.2 %

Procedure:
The product from Example 247a (0.89 g, 2.63 mmol) was mixed with cesium carbonate (0.85 g, 2.63 mmol) and 4-benzyloxyphenol (0.53 g, 2.63 mmol) in DMF (10 mL) and stirred at room temperature a total of sixty hours. The reaction mixture was diluted with ethyl acetate (100 ml) and treated with 2N HCl (20 ml). The organic layer was separated and washed with 2N NaOH, 2, 10% sodium chloride and dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was evaporated under vacuum leaving the title compound as a yellow solid (118 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Fc1cccc(Br)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol), tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in DIPEA (1.83 g, 14.2 mmol) and ethanol (10 mL) was heated at 100° C. for 16 hours. After it was cooled, the solvent was removed under reduced pressure, and the residue was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:14]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[N:4]([CH3:14])[N:3]=1
Reactant: CC(C)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-iodo-5-isopropyl-1H-indazole (0.75 g, crude) in 50 mL of THF at 0° C. was added t-BuOK (0.59 g, 5.2 mmol) in one portion. The mixture was stirred at 0° C. for 30 minutes. CH3I (1.1 g, 7.7 mmol) was added and the solution was stirred at room temperature overnight. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure to give crude 3-iodo-5-isopropyl-1-methyl-1H-indazole which contained some N-2 alkylation isomer (0.7 g) as oil. LCMS: (M+H)+=301.