Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH3:2].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9](O)[CH:8]=[CH:7]2.[C:15](=[O:18])([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH2:15][CH3:2])[CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2cc(Br)ccc2c1

Procedure:
This experimental procedure is an O-alkylation. A solution of bromomethane (48.90 g, 0.45 mol) is added dropwise to a stirred refluxing mixture of 6-Bromo-2-naphthol (40.00 g, 0.18 mol) and potassium carbonate (63.00 g, 0.46 mol) in acetone. The stirred mixture is heated under reflux for 24 hours (ie until glc analysis reveals a complete reaction). The potassium carbonate is filtered off, water is added to filtrate and the product is recrystallised from ethanol to give a yield of 43.92 g (97%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Cl>CO.O>[OH:17][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol (0.033 g, 0.3 mmol) in MeOH: H2O (1.8:0.2 mL; v/v) was shaken in a sealed tube at 100° C. for 24 h (or 80° C. for 3 days), cooled to room temperature, diluted with water (15 mL), acidified with 2N HCl (pH>2). Upon saturation with sodium chloride it was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate and solvent was removed. The resulting residue was filtered through a pad of silica gel (200-400 mesh) using CH2Cl2->1>10% MeOH in CH2Cl2 to obtain the desired N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218). If the reaction scale is large enough, solid of the resulting product can be isolated by filtration. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=5.1 Hz), 7.12-6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd, 1H, J=1.2 and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS (m/e): 313 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CCO.C1COCC1>O>[CH3:1][C:2]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)c1cc(C2(C)OCCO2)on1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(c2cc(CO)no2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of the dioxolane 318 (3.14 g, 13.8 mmol) in a 1:2 mixture of EtOH-THF (45 mL) NaBH4 (0.68 g, 18.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, treated with water and the organic solvents were evaporated. The aqueous phase was extracted with EtOAc and combined organic layers were successively washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to afford the title compound as oil (2.39 g, 93% yield) which was used for next step without further purification. 1H NMR (DMSO-d6) δ (ppm): 6.43 (s, 1H), 5.47 (t, J=5.9 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.06-4.02 (m, 2H), 3.94-3.90 (m, 2H), 1.66 (s, 3H). MS (m/z): 185.18 (calc) 186.1 (MH+) (found).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:35])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:16]=1[CH3:43])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:35])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:16]=1[CH3:43])#[N:14]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCc3ccccc3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CCc3ccccc3)nc2c1C#N
Reaction time: 1.17 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (110 μl, 871 μmol) was added at 150° C. to a dimethyl sulfoxide (12 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-N-(2-phenylethyl)-1,3-benzoxazole-2-carboxamide (I-120) (300 mg, 726 μmol) and triethylamine (132 μl, 944 μmol), followed by stirring at the same temperature for 70 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (161 mg, 44%) as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)(Cl)Cl.C(OCC)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](COc3ccc(F)cc3)CC[C@@H]2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc(OC[C@H]2CC[C@@H]3CNCCN3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.1 %

Procedure:
A solution of 0.44 g (1.2 mmol) of (7S,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 25 mL of chloroform was treated with excess HCl(g) in ethyl ether and stirred at ambient temperature for 2 h. The solvent was evaporated to give 0.40 g of title compound as the dihydrochloride salt which was used for subsequent reactions without purification.
Reaction SMILES: ClC1C=CC([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=CC=1.[NH:41]1CCCC[CH2:42]1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=2)C1)C1C=CC=CC=1.C(C1C=CC(O)=CC=1)#N.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:69][C:66]1[CH:67]=[CH:68][C:63]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:42]#[N:41])=[CH:21][CH:22]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:9]2)=[CH:64][CH:65]=1
Reactant: C1CCNCC1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: N#Cc1ccc(O)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(C#N)cc1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-cyano-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 554.3 [(M+H)+].
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C(Cl)Cl>[OH:17][C@:18]1([C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1cccc(-c2cccc(Br)c2)c1
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cccc(-c2cccc([C@]3(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Magnesium (0.513 g, 21.11 mmol) was stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 3-bromo-3′-vinylbiphenyl (5.21 g, 20.10 mmol) in THF (100 mL), was added in dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (5.78 g, 20.11 mmol) in DCM (110 mL) at 0° C. and stirred for 1 hr and then quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.9 g, 6.20 mmol, 31% yield) as a yellow foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 0.05 (d, J=2.44 Hz, 9H) 0.99 (dd, J=9.77, 7.32 Hz, 1H) 1.04 (dd, J=9.61, 7.17 Hz, 1H) 1.27 (t, J=7.17 Hz, 1H) 2.38-2.53 (m, 1H) 2.66-2.82 (m, 1H) 3.67-3.83 (m, 1H) 3.82-3.89 (m, 3H) 3.96-4.09 (m, 1H) 4.17-4.32 (m, 2H) 4.52-4.69 (m, 1H) 5.32 (d, J=10.99 Hz, 1H) 5.83 (d, J=17.40 Hz, 1H) 6.80 (dd, J=17.55, 10.83 Hz, 1H) 7.39-7.46 (m, 2H) 7.46-7.52 (m, 3H) 7.55 (ddd, J=4.58, 2.14, 1.83 Hz, 1H) 7.61 (br. s., 1H) 7.73 (s, 1H). LCMS: rt=2.32 min. [M+H]+=468; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 54.7 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (S)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.08 g, 53%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: CI
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1H-Indole-3-carboxylic acid (960 mg) was dissolved in N,N-dimethylformamide (15 ml) and cooled to 0° C. Sodiumhydride (720 mg) was added in two divided portions thereto, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled again to 0° C., and a solution of methyl iodide (0.67 ml) in N,N-dimethylformamide (5 ml) was added slowly dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C., then ice was added thereto, water (50 ml) was further added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (910 mg, Y.:87%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:34]([NH2:36])=[O:35])=[N:4][C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2S(C1C=CC=CC=1)(=O)=O.NC1C(C(OC)=O)=NC(C2C=CC=[C:65]([OH:69])C=2)=NC=1NC1C=CC=C2C=1C=CN2S(C1C=CC=CC=1)(=O)=O>N.CO>[OH:33][C:29]1[CH:28]=[C:27]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:65](=[O:69])[N:8]3[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH:11]=[CH:12][NH:13]4)=[C:3]([C:34]([NH2:36])=[O:35])[N:4]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc(Nc2cccc3c2ccn3S(=O)(=O)c2ccccc2)c1N
Reactant: NC(=O)c1nc(-c2cccc(O)c2)nc(Nc2cccc3c2ccn3S(=O)(=O)c2ccccc2)c1N
Agent: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2-c1cccc2[nH]ccc12

Procedure:
5-Amino-2-(3-hydroxyphenyl)-6-(1-(phenylsulfonyl)-1H-indol-4-ylamino)pyrimidine-4-carboxamide. Methyl 5-amino-2-(3-hydroxyphenyl)-6-(1-(phenylsulfonyl)-1H-indol-4-ylamino)pyrimidine-4-carboxylate (0.1 g, 0.19 mmol) was stirred in 7N NH3/MeOH (20 mL) at 55° C. for 24 h. LCMS shows only the desired product. The mixture was concentrated to afford the title compound, 50 mg, 0.1 mmol, 50%. MS (ESI) m/z 501.5[M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:17][CH2:18][Cl:19])(=O)=O)=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:17][CH2:18][Cl:19])=[C:24]([Cl:29])[CH:23]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (8.29 g, 60 mmol, 3.0 eq.) and 2-chloroethyl p-toluenesulfonate (5.16 g, 22 mmol, 1.1 eq.) were added in sequence to a solution of 4-bromo-2-chlorophenol (4.19 g, 20 mmol, 1.0 eq.) in DMF (25 mL). The resulting mixture was heated up to 60° C. and stirred at that temperature for 4 hours. The mixture was allowed to cool down to r.t. and was partitioned between AcOEt (290 mL) and water (120 mL). The layers were separated. The org. phase was washed with water (4×120 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 4-bromo-2-chloro-1-(2-chloro-ethoxy)-benzene as a colorless oil that solidified upon standing. The product was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[OH:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>ClCCl.ClCCCl>[OH:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([Cl:3])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1O
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
20 ml (270 mmol) of thionyl chloride and 1 ml of dimethylformamide are added respectively to 12.5 g (90 mmol) of 2-hydroxynicotinic acid in suspension in a mixture of 80 ml of dichloromethane and 20 ml of 1,2-dichloroethane. The suspension is stirred at reflux for 2.5 hours. The reaction mixture is cooled to room temperature and the precipitate formed is filtered to yield (11.98 g) of 2-hydroxynicotinic chloride. The solid is suspended in 150 ml of dichloromethane, and then 7.42 g (76 mmol) of N,O-dimethylhydroxylamine hydrochloride and 21.37 ml (152 mmol) of triethylamine are added successively. The reaction mixture is stirred for 2 hours at room temperature, the solvent is evaporated, and then the solid is taken up in a minimum of ethyl acetate (70 ml). The solid is filtered (triethylamine salt) and the filtrate is concentrated to yield after purification by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) 10.5 g (64%) of N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(O)c(C#N)c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 14.9 grams (0.10 mole) of 3-cyano-2-hydroxy-4,6-dimethylpyridine is cooled in an ice bath, and a solution of 18.1 grams (0.10 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide is added dropwise during a 15 minute period. Upon completion of addition the reaction mixture is stirred at ambient temperature for about 72 hours. After this time, the reaction mixture is diluted to 1000 mL with water and filtered to collect a solid. The solid is dried under vacuum at about 60° C., yielding 22.2 grams of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine, mp 254-262° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][CH:23]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: FC(F)c1ccc(CBr)cc1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(C(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 94.8 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (0.45 g, 1.50 mmol), 1-bromomethyl-4-difluoromethyl-benzene (0.66 g, 3.00 mmol), potassium carbonate (2.09 g, 15.0 mmol) and potassium iodide (0.05 g, 0.20 mmol) in 15 ml dimethylformamide were stirred at 65° C. for 5 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane (90/10 to 1/0) yielded 0.63 g (94%) 4-chloro-N-(4-difluoromethyl-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=443.0 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:79])[C@H:71]([CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])[NH2:72]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:72][CH:71]([CH2:73][CH2:74][C:75]([O:77][CH3:78])=[O:76])[C:70]([O:69][CH3:68])=[O:79])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.34 mmol) in 10 ml of anhydrous DMF were added HATU (156 mg, 0.41 mmol) and N,N-diisopropylethylamine (175 mg, 1.36 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (108 mg, 0.51 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as white solid. Yield: 120 mg, 59%.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:9]=2)=[C:4]([CH3:16])[N:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:13]1([C:10]2[N:9]=[C:8]([C:5]3[N:6]([CH3:7])[C:2]([C:24]#[C:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:3][C:4]=3[CH3:16])[O:12][N:11]=2)[CH2:15][CH2:14]1
Reactant: Cc1nc(Br)n(C)c1-c1nc(C2CC2)no1
Reactant: C#Cc1ccccc1
Product: Cc1nc(C#Cc2ccccc2)n(C)c1-c1nc(C2CC2)no1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=305.2 (M+H+), was prepared from 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-cyclopropyl-[1,2,4]oxadiazole and phenylacetylene in accordance with the general procedure of example 12c.
Reaction SMILES: BrC[CH2:3][C:4]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)OCCO1.[C:17](=O)([O-:19])[O-:18].[Ca+2].C(N)=O>O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH3:3])[C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(C2(CCBr)OCCO2)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: NC=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of 2-(bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (2.87 g; 10 mmol), calcium carbonate (1.2 g; 12 mmol), formamide (44 ml) and water (4 ml) is heated at 120° C., under stirring, for 6 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.67 g; 8.3 mmol; yield 83%), m.p. 55°-57° C.
Reaction SMILES: [NH2:1][OH:2].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([O:21]C)=O)[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>CO>[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([NH:1][OH:2])=[O:21])[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: CO
Product: CC(=O)N1CCC(O[C@@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H](C(=O)NO)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 M of H2NOH in MeOH (0.75 ml) was added inTo a solution of methyl(1S,2S,5R)-5-[(1-acetylpiperidin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.1 mmol, 0.0001 mol) in 0.5 ml of MeOH. It was stirred at rt for 2 hrs. It was purified by Prep-HPLC. LCMS: (M+H)+=473.1.