Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C[Al](C)C.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20](OCC)=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:2][C:1]([NH:10][C:20]([C:16]1[S:15][CH:19]=[CH:18][N:17]=1)=[O:21])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)c1nccs1
Reactant: CC(C)(N)c1ccccc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)c1nccs1)c1ccccc1
Yield: 67.1 %

Procedure:
7.13 ml (50.0 mmol) of cumylamine and 156 ml of toluene are placed in a 1-liter three-necked flask with stirring and under an inert atmosphere. 24.8 ml (49.6 mmol) of trimethylaluminium are then added dropwise, and white fumes are evolved. After waiting until the medium has clarified, a solution of 3.9 g (24.8 mmol) of ethyl 2-thiazolecarboxylate (2) in 195 ml of toluene is added. The mixture is stirred for 15 minutes and then refluxed. After heating for 15 hours, the reaction medium is poured into 300 ml of 1M citric acid solution diluted with 200 ml of water and the whole is filtered through Celite®. The Celite® is washed with 100 ml of ethyl acetate and the aqueous phase is extracted with twice 100 ml of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, and after evaporating under reduced pressure, the residue is purified by flash chromatography (msilica=200 g; eluent: dichloromethane). 4.1 g of N-(1-methyl-1-phenylethyl)thiazole-2-carboxamide are obtained in the form of a brick-red solid. Rf(dichloromethane)=0.4.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C1COCC1>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)=[O:34]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 38.5 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with pivaloyl chloride (0.02 mL, 0.165 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 19 h. Obtained as a sand solid (26 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCBr
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ccc2cc[nH]c2c1
Reaction time: 18 h

Procedure:
6-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][NH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a 0° C. suspension of indole-2-carbonyl chloride (100 mg, 0.56 mmol) in CH2Cl2 was added a solution of TEA (235 μL, 1.67 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (156 mg, 0.84 mmol) in CH2Cl2. After 1.5 h at 0° C., the mixture was diluted with saturated aqueous (satd. aq.) NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with satd. aq. NaCl (20 mL), dried (Na2SO4), and concentrated to give a yellow liquid, which was purified by FCC to give a yellow solid (130 mg, 46%). 1H NMR (CDCl3): 9.37-9.17 (m, 1H), 7.70-7.64 (m, 1H), 7.47-7.41 (m, 1H), 7.35-7.28 (m, 1H), 7.19-7.10 (m, 1H), 6.86-6.78 (m, 1H), 5.13 (s, 1H), 4.77-4.50 (m, 1H), 4.02-3.80 (m, 1H), 3.80-3.39 (m, 2H), 2.08-1.88 (m, 2H), 1.54-1.35 (m, 9H).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=34)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:46]([C:49]1[CH:54]=[CH:53]C(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCC3COC4)N=2)=CC=1)=[C:47]=[O:48]>ClCCl.C(N(CC)CC)C>[CH:49]1([NH:46][C:47]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]4=[C:9]([N:8]4[CH:5]5[CH2:6][CH2:7][CH:1]4[CH2:2][O:3][CH2:4]5)[N:14]=3)=[CH:16][CH:17]=2)=[O:48])[CH2:54][CH2:53]1
Reactant: O=C=Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: NC1CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1)NC1CC1
Reaction time: 8 h
Yield: 41 %

Procedure:
A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (30 mg, 0.074 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.05 mL), followed by a solution of triphosgene (11 mg, 0.037 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (17 mg, 0.30 mmol)—was added to the 8-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Gemini 21 mm×100 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 60% or 75% acetonitrile over 30 minutes to provide 1-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (15 mg, 41%). MS (ES+): 488.2 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1.C(O)CCC>C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][N:23]([C:2]3[CH:11]=[C:10]([Cl:12])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=3)[CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1
Reactant: Brc1ccc2c(c1)CCCNC2
Reactant: Clc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Clc1ccc2nc(N3CCCc4cc(Br)ccc4C3)cc(Cl)c2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (291 mg, 1.29 mmol) and n-butanol (3 mL) was heated with stirring in a 10 mL microwave process vial for 1 hour at 160° C. under microwave irradiation. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), and then washed with water (10 mL). The organic layer was dried over sodium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel to give 222 mg of product as a white solid (yield was 41%). MS obsd. (ESI+) [(M+H)+] 421.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)C(NN)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:17]([NH:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:23][CH2:22][C:21]1[O:24][C:17]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:27]=[C:26]([Cl:28])[CH:25]=2)=[N:19][N:20]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a suspension of compound 5 (328 mg, 1.0 mmol) in DCM (10 ml) was added compound 6 (150 mg, 1.0 mmol), EDC (288 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and purified by chromatography to give compound 7 as a white solid (230 mg). Yield: 50%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1cnc(-c2ccc(F)cc2)o1
Product: O=C(NCCc1cnc(-c2ccc(F)cc2)o1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 20 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (28 mg, yield 20%). 1H NMR (400 MHz, MeOD) δ 8.56-8.55 (m, 1H), 8.30-8.28 (dq, J=7.8 Hz, 0.9 Hz, 1H), 8.06-8.04 (m, 1H), 8.00-7.96 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.71-7.69 (t, J=7.8 Hz, 1H), 7.21-7.17 (t, J=8.8 Hz, 2H), 7.03 (s, 1H), 3.78-3.75 (t, J=6.7 Hz, 2H), 3.15-3.12 (m, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O3: 446.10. found: 447.0 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[C:20]2[S:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH:25](OC)=[O:26].Cl>C1COCC1>[CH:25]([CH:13]1[CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[S:19][C:20]=2[C:12]1=[O:11])=[O:26]
Reactant: COC=O
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
LiHMDS solution (1 M, 27.7 mL) was added over 10 min to a suspension of N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage A.5, 2.0 g, 9.23 mmol) in dry THF (20 mL) cooled at −78° C. under an argon atm. The RM was then stirred at −78° C. for 2.5 h and methyl formate (2.308 mL, 36.9 mmol) added dropwise over 30 min. The RM was then warmed slowly to rt and was then stirred 18 h at rt. The RM was drown out into aqueous 1 M HCl (70 mL) and extracted 3× with DCM, dried over Na2SO4 and evaporated to give a the title compound as a solid. HPLC: tR 3.65 min (method D). MS: M−H=237. 1H-NMR in DMSO-d6 (400 MHz): 12.50 (s, br, 1H); 7.55 (s, 1H); 2.90-2.60 (m, 4H); 2.15 (s, 3H).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.[NH2:41][C:42]1[CH:47]=[C:46](Cl)[N:45]=[C:44]([CH3:49])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:46]4[N:45]=[C:44]([CH3:49])[N:43]=[C:42]([NH2:41])[CH:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: Cc1nc(N)cc(Cl)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1nc(N)cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-amino-6-chloro-2-methylpyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.
Reaction SMILES: [C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]([NH2:31])=O)[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1.[Cl-].[Na+].O>[C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29](=[S:41])[NH2:31])[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxamide (2.843 g, 7.029 mmol) in THF (50 mL) was treated with Lawesson's reagent (2.843 g, 7.029 mmol) at RT under nitrogen. The resulting yellow solution was allowed to heat at 80° C. for 4 hours and then treated with brine and extracted with EtOAc (2×). The organics were dried (Na2SO4), filtered, concentrated and purified by column chromatography (2% MeOH/DCM) to give the product as a yellow foam (quantitative yield). 1H NMR (DMSO, 400 MHz) δ 7.18-7.30 (16H, m), 8.28 (1H, m), 8.40 (1H, s), 10.34 (1H, br s); MS (ES+) 421.16
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20].CCN(CC)CC>CCOC(C)=O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-morpholinoethanamine (0.90 g, 6.91 mmol), 1,2-difluoro-4-nitrobenzene (1.10 g, 6.91 mmol) and Et3N (1.40 g, 13.82 mmol) in EtOAc (10 mL) was refluxed under N2 for 24 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.57 g, 84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1.[CH2:17](O)[CH3:18]>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:17][CH3:18])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1
Reactant: CCO
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1O
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1O
Yield: 98 %

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of 3-(4-chloro-2-hydroxybenzoyl)propionic acid (12.0 g, 0.053 mole) in dry ethanol (21.2 cc) until esterification was complete. The product crystallised from ether to give ethyl 3-(4-chloro-2-hydroxybenzoyl)propionate (13.29g, 98%, m.p. 68°-69°).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:45])([CH2:43][CH3:44])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[CH2:18][C:17]([F:20])([F:19])[CH2:16][N:15]1C(OC(C)(C)C)=O)=O>C(OCC)(=O)C.O>[CH3:45][C:7]([CH3:6])([CH2:43][CH3:44])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH2:18][C:17]([F:20])([F:19])[CH2:16][NH:15]2)[NH:11][CH:10]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CC(F)(F)CN2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (947 mg, 12.3 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (138 mg, 0.25 mmol) in xylenes (10 mL). After stirring in a sealed tube at 160° C. for 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to afford the title compound. (M+H) found: 443.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C.CN(C)C(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[N:24]([C:12]1[N:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[N+:25]=[N-:26]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(N=[N+]=[N-])ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 319.8 %

Procedure:
To an acetonitrile (70 ml) solution of 10 g (38.57 mmol) of methyl 3-benzyloxypicolinate N-oxide in a 200 ml round bottomed flask, 8.9 g (7.7 mmol) of trimethylsilylazide and 4.1 g (38.57 mmol) of N,N-dimethylcarbamoyl chloride were added, and the mixture was refluxed for 12 hours. Then, 4.4 g (38.5 mmol) of trimethylsilylazide and 2.1 g (19.3 mmol) of N,N-dimethylcarbamoyl chloride were further added, and the mixture was refluxed for 12 hours. After cooling, the reaction mixture was gradually added to an ice-cooled saturated sodium hydrogen carbonate aqueous solution. Formed crystals were collected by filtration, washed with water, then dissolved in dichloromethane, dried and concentrated, and then recrystallized from ethanol to obtain 7.0 g (yield: 64%) of the desired product.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[OH-].[Na+].O.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)=[CH:15][C:14]=1C>C(O)C>[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)=[C:17]([CH3:1])[CH:18]=1
Reactant: CSc1ccc(Oc2ccc(NC(C)=O)cc2)cc1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc(Oc2ccc(NC(C)=O)cc2)c(C)c1
Reaction time: 0.17 h

Procedure:
This solid was dissolved in ethanol and treated with first excess of acetic anhydride, and then, with stirring, with dilute aqueous sodium hydroxide solution until strongly alkaline. After about 10 minutes, the reaction was treated with water to faint turbidity and left to stand. Platelets of the product 4-(4-acetamidophenoxy)-2-methylphenyl methyl sulphide, come out of solution slowly, melting point 99.6° to 101° C. On recrystallisation from ethanol-water, analytical samples were obtained melting between 101.4° and 102.1° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCCCCC.CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)COc1ccc(C(=O)OCC)cc1

Procedure:
Sodium hydride (min. 60% parafflnic dispersion, 2.95 g, about 74 mmol) was washed with anhydrous hexane in a nitrogen stream and suspended in anhydrous dimethylformamide. The obtained suspension was stirred under cooling with ice, followed by the dropwise addition of a solution of ethyl 4-hydroxybenzoate (11.2 g, 67 mmol) in dimethylformamide. The obtained mixture was stirred at room temperature for 80 minutes and cooled with ice again, followed by the dropwise addition of a solution of ethyl bromoacetate (12.9 g, 77 mmol) in anhydrous dimethylformamide. The obtained mixture was stirred at room temperature to complete a reaction. The reaction mixture was filtered to remove insolubles and the filtrate was concentrated under a reduced pressure. The residue was dissolved in diethyl ether and the obtained solution was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of common salt, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography. Yield: 16.8 g.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][CH:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)[CH2:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2CC(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), and DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and acetyl chloride (11.9 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 12-1 as a pale yellow oil. MS m/z (M+H): calculated=371.2443; observed=371.2440.
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([CH3:23])[CH:10]=1>O>[Br:1][C:14]1[CH:13]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11]([CH3:23])=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: COc1ccc(Cc2ccc(C)cc2)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c(Cc2ccc(C)cc2)cc1Br
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Br2 was added dropwise to an acetic acid (35 mL) solution of 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene while cooled on ice. The reaction mixture was stirred at 110° C. for two hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with a saturated sodium bicarbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain a yellow oily title compound (4.21 g, 80%).