Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[O-:11][C:12]#[N:13].[K+].[Cl-].[NH4+].Cl>O>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8]([OH:10])=[N:13][C:12]=1[OH:11]
Reactant: Nc1cccnc1C(=O)O
Reactant: N#C[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Oc1nc(O)c2ncccc2n1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
3-Aminopicolinic acid (B-1) (1.0 g, 7.24 mmol, 1.0 eq), potassium cyanate (2.94 g, 36.2 mmol, 5.0 eq) and ammonium chloride (3.87 g, 72.4 mmol, 10.0 eq) were suspended in water (40 mL). The slurry was heated to 160° C. and mixed manually for 2 h as water vapor was expelled from the reaction vessel. The reaction temperature was then increased to 200° C. and stirred for 40 min. After cooling to 90° C., hot water was added and then the mixture was allowed to cool to RT. The mixture was acidified with concentrated HCl to pH=3-4. The precipitate was collected by filtration, rinsed with water (2×10 mL) and dried in vacuo to afford the product pyrido[3,2-d]pyrimidine-2,4-diol 235.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[C:44](=[O:45])[N:43]([CH2:46][CH2:47][CH2:48][C:49]([F:52])([F:51])[F:50])[N:42]=[CH:41]2)[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[C:44](=[O:45])[N:43]([CH2:46][CH2:47][CH2:48][C:49]([F:52])([F:51])[F:50])[N:42]=[CH:41]2)[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(-n2cnn(CCCC(F)(F)F)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Product: Cc1nc(-n2cnn(CCCC(F)(F)F)c2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(5-oxo-1-(4,4,4-trifluorobutyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: MS (ES−) m/z 335.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][C:10]([F:12])([F:11])[F:13])=[CH:4][C:5]([NH2:8])=[C:6]([Cl:14])[CH:7]=1
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc:hexanes) to produce the desired product as an orange-ish colored oil (1.4 g, 64% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)[CH:5]=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:18][C:4]1[CH:5]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O[C@@H]2CCN(S(C)(=O)=O)C2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
Methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 11d (71 mg, 0.13 mmol) was dissolved in 10 mL of methanol, followed by addition of 2M aqueous sodium hydroxide solution (0.5 mL, 1 mmol). The reaction solution was stirred for 2 hours. To the resulting solution, 1M citric acid was added dropwise to adjust the pH to 4˜5. The organic phase was dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 11 (70 mg, yield 100%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH:5]([CH2:9][NH2:10])[N:4]1CC1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH:5]([CH2:9][NH2:10])[NH:4]1
Reactant: NCC1COCC(CN)N1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCC1COCC(CN)N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,5-Bis--aminomethyl--4-benzylmorpholine (1.3 g, 5.5 mmol) was dissolved in methanol (50 ml) . Ammoniumformiate (1.4 g, 22 mmol) and palladium on activated carbon (10 % , 5 g) were added. The reaction mixture was stirred at 50 ° C. under nitrogen for 3 hours. The catalyst was then filtered off and washed with several small portions of methanol and the solution evaporated to dryness. The tri-amine was used direcly in the next reaction step. FAB/MS: 146 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[CH3:14][C:10]1([CH3:15])[CH2:9][CH:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:13][CH2:12][O:11]1
Reactant: CC1(C)CC(NC(=O)NCCCl)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(N2CCNC2=O)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A −20° C. solution of 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (0.700 g, 2.98 mmol) in THF (15 mL), under Ar, was treated with NaH (60% in mineral oil, 0.298 g, 7.46 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was cooled to 0° C., quenched with saturated NH4Cl, warmed to RT, treatd with brine, extracted with EtOAc (2×) and the combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one as a white solid (155 mg, 26%). 1H NMR (400 MHz, DMSO-d6): δ 6.24 (s, 1 H), 3.85 (m, 1 H), 3.67-3.54 (m, 2 H), 3.26-3.13 (m, 4 H), 1.53-1.37 (m, 4 H), 1.14 (d, J=10.2 Hz, 6 H); MS (ESI) m/z: 199.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.O>C(Cl)Cl>[OH:4][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: NC[C@@H](O)c1cccnc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Solvent: ClCCl
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@@H](O)c4cccnc4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1S)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example 130) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp:>88° C. decomposed; 1H NMR (400 MHz, DMSO-d6) δ 1.38–1.50 (m, 2 H), 1.90–1.98 (m, 2 H), 2.63–2.71 (t, 2 H), 2.78–2.96 (m, 4 H), 3.23–3.27 (m, 1 H), 3.62–3.65 (m, 2 H), 4.62–4.67 (m, 1 H), 4.76–4.79 (m, 1 H), 6.83–6.86 (d, 2 H), 7.03–7.05 (d, 2 H), 7.36–7.38 (m, 1 H), 7.76–7.79 (m, 1 H), 8.46–8.48 (m, 1 H), 8.57–8.58 (m, 1 H); MS (ES) m/z: 427 (MH+); Anal. Calcd. for C22H36N4O2×0.3 H2O×0.3 CH2Cl2: C, 55.87; H, 5.51; N, 11.69. Found: C, 55.92; H, 5.80; N, 11.45.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCCCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (4.64 g, 7.5 mmol) dissolved in THF:methanol (50:150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.35 g (76%); off white solid; mp 180° C.; MS: 295.9 (M+2H)2+ 590.9 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24]>>[CH2:23]([C:24]1[O:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:20][N:21]=1)[CH3:22]
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc(-c2ccc3occ(-c4ccc(SC)cc4)c3c2)o1
Yield: 9 %

Procedure:
In the same manner as in Example 239 and using 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide instead of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide and using triethyl orthopropionate instead of triethyl orthoacetate, the title compound (yield 9%) was obtained as colorless crystals.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[NH2:6][CH:7]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[Cl:40])[CH2:8][NH:9][C:10](=[O:32])[CH2:11][N:12]1[C:16](=[O:17])[N:15]([CH2:18][C@H:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:14]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:13]1.O.CO>CS(C)=O>[C:2]([NH:6][CH:7]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[Cl:40])[CH2:8][NH:9][C:10](=[O:32])[CH2:11][N:12]1[C:16](=[O:17])[N:15]([CH2:18][C@H:19]([OH:24])[C:20]([F:21])([F:23])[F:22])[C:14]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:13]1)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
12 mg of potassium cyanate (153 μmol) were added to a mixture of 30 mg (51 μmol) of the compound of Example 54A, 1 ml of water and 1 ml of methanol, and the mixture was stirred at 40° C. for 1.5 h. An additional 6 mg (75 μmol) of potassium cyanate were added, and stirring of the reaction mixture was continued at RT overnight. A few ml of DMSO were added, and the entire solution was separated by preparative HPLC [Method 8]. The product fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 17 mg (56% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.FC(F)CO[C:15]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>O.CC#N>[CH3:25][NH:24][C:22]1[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([N:6]2[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]2)[N:23]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-trifluoromethyl-piperidine (330 mg, 2.2 mmol), TEA (1.00 mL, 7.2 mmol), 2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinic acid (500 mg, 1.8 mmol, prepared according to WO2010/34799), DMF (5 mL) and MeCN (5 mL) is stirred for 3 h at rt. Then Cs2CO3 (1.5 g, 4.6 mmol) is added and it is stirred overnight at rt and for 6 h at 70° C. Water is added and the mixture is concentrated i.vac. The residue is diluted with water, HCOOH is added and the resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [O:1]1[C@H:3]2[C@H:4]([OH:29])[CH2:5][C:6]3[C@:26]([CH3:27])([C@@H:2]12)[C@@H:25]1[C:9]([C@H:10]2[C@:22]([CH3:28])([CH2:23][CH2:24]1)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]2)=[CH:8][CH:7]=3.[CH2:30]([OH:34])[CH2:31][CH2:32][OH:33].CC(C)([O-])C.[K+]>O>[OH:33][CH2:32][CH2:31][CH2:30][O:34][C@H:3]1[C@H:2]([OH:1])[C@@:26]2([CH3:27])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@H:4]1[OH:29]
Reactant: OCCCO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H](OCCCO)[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 69.9 %

Procedure:
A mixture of 275 mg (6.9×10-4 mol) of 1α,2α-epoxy-3β-hydroxy-5,7-cholestadiene, 4 ml (5.5×10-2 mol) of 1,3-propanediol, and 258 mg (2.1×10-3 mol) of potassium t-butoxide was stirred in an argon atmosphere at 110° C. (bath temperature) for 4.5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted twice with diethyl ether and washed three times with water. Sodium chloride was added to the aqueous layer, and the mixture was extracted twice with ethyl acetate and washed once with a saturated aqueous sodium chloride solution. After drying the combined organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel:dichloro-methane:ethanol=10:1) to obtain 229 mg (70% yield) of the titled compound as a white powder.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[N+:28]([C:31]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:32]=1[NH2:33])([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:33][C:32]1[CH:34]=[CH:35][C:36]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:27])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:37][C:31]=1[N+:28]([O-:30])=[O:29]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 92.5 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (1.0 g, 2.46 mmol) in DME (10 mL) was added 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.97 g, 3.69 mmol), Pd(PPh3)4 (90 mg, 0.12 mmol), Na2CO3 (781 mg, 7.38 mmol) and water (2 mL) with stirring for 40 minutes at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 2-(4-amino-3-nitrophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (900 mg, 93%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:32])[NH:12][C:13]2[S:17][C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[N:15][C:14]=2[C:29](=[O:31])[NH2:30])=[CH:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:12][C:13]2[S:17][C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[N:15][C:14]=2[C:29]([NH2:30])=[O:31])=[O:32])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(O)cc1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of 4-{[4-carbamoyl-2-(naphthalen-2-ylamino)thiazol-5-yl]carbamoyl}phenyl acetate (100 mg, 0.22 mmol) in MeOH (10 mL) was added K2CO3 (93 mg, 0.67 mmol) at rt, and the mixture was stirred for 1 h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solids were collected by filtration and washed with MeOH to give 60 mg (68% yield) of the titled compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@H:4]5[CH2:3][C@H:2]([O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a partial suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide (85 mg, 0.16 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (33 μL, 0.24 mmol) followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give methanesulfonic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as an off-white foam which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:12][CH2:13][CH3:14])=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].Cl>C1COCC1>[CH2:13]([S:12][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[CH:9][N:8]=1)[CH3:14]
Reactant: CCOC(=O)c1cncnc1SCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1ncncc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of 2.40 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid ethyl ester, 12 ml of a 2 M aqueous potassium hydroxide solution and 8 ml of THF was stirred at room temperature for 1 hour. Concentrated hydrochloric acid was poured to the reaction mixture and neutralized, then the mixture was concentrated under reduced pressure, and THF was distilled. Concentrated hydrochloric acid was further added to the reaction mixture to adjust pH of the reaction mixture at 5, and the precipitated crystal was filtered. The resulting solid was washed with water and n-hexane and dried to obtain 1.89 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulphonylbenzoic acid (6.0 g) and thionyl chloride were stirred and heated at reflux for 2 hours. The mixture was cooled and evaporated to dryness. Toluene was added and the solvent re-evaporated to give 2-fluoro-4-methylsulphonylbenzoyl chloride (6.5 g) as a brown solid which was not further purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(C)C)(C)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:12][C:25]([NH:24][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[S:26])[CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: COc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (357 mg) in acetone (5 ml) was added benzoyl isothiocyanate (0.252 ml), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added diisopropyl ether, and the precipitate was collected by filtration and dried to give N-(3-(4-methoxypyridin-2-yl)phenyl)-N′-benzoylthiourea (462 mg).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Yield: 79.3 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.7749 g, 1.35 mmol), benzyl bromide (0.4618 g, 0.321 ml, 2.7 mmol), 18-crown-6 (0.714 g, 2.7 mmol) and sodium hydride (0.1037 g, 4.32 mmol) in THF (6 ml) were heated at 60° C. for 1 hour. The mixture was diluted with water and extracted into ethyl acetate. The organics were collected and dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 15% ethyl acetate/iso-hexane, to afford the title compound as a clear oil (712 mg, 79%).