Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([OH:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C=O)C>[C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([Cl:26])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Yield: 88.2 %

Procedure:
To a solution of the pyridinium salt of 4-benzoylamino-napthalene-1-sulfonic acid (2.4 g, 5.9 mmol) in DMF (10 mL), was added thionyl chloride (0.6 mL, 8.8 mmol). The resultant solution was stirred at 25° C. for 3 hours. The reaction mixture was quenched by pouring into ice water and filtered to give the title compound (1.8 g) a pale white solid. This material was used without further purification.1H NMR (300 MHz, DMSO) δ 8.88 (d, 1H), 8.09 (d, 2H), 7.97 (d, 2H), 7.55 (m, 6H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.CO[C:13]1[CH:19]=CC(O)=[CH:15][CH:14]=1>C(O)CCC>[C:1]([O:5][CH2:19][CH2:13][CH2:14][CH3:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: COc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: C=CC(=O)OCCCC
Reaction time: 2.5 h

Procedure:
For comparison, a known esterification process was carried out using only one reaction region. In this Comparative Example, 4 mol/h of acrylic acid, 4 mol/h of fresh butanol and 1.6 mol/h of recycled butanol (distillate from the butanol recovery) were fed to a circulation evaporator (2.5 l, level of fill 2 l). The residence time was 2.5 h. The esterification was carried out in the presence of 9.7% by weight (based on the reaction mixture) of sulfuric acid at 126° C. The reactor was connected to a bubble-cap column (30 trays), which was stabilized with 15 ml/h of hydroquinone monomethyl ether (MeHQ) in butanol. Butyl acrylate formed was removed via the top by adding 340 ml/h of water as a reflux (azeotropic entraining agent) to the column. In addition, 175 ml/h of organic reflux were added to the column in order to suppress the acrylic acid.
Reaction SMILES: Cl.S(Cl)(Cl)(=O)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=O)=[CH:21][CH:20]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1

Procedure:
The sulphonyl chloride hydrochloride derivative of the sulphonic acid or part (a) was used to sulphonylate N,N-diethylethylenediamine using a similar procedure to Example 8. The crude product obtained after evaporation of solvent from the chloroform layer was a brown solid which was purified by column chromatography (basic alumina: 1% ethanol/chloroform) to give a creamy white solid. Recrystallisation from ethanol/water gave the title compound hemihydrate, m.p. 110°-113° C. Analysis: Calculated for C20H24ClNSO2S.1/2H2O C, 54.2%; H, 5.69%; N, 15.8%. Found C, 54.3%; H, 5.64%; N, 16.1%.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:4].O.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[C:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:14][NH:15][C:3]=1[NH2:4]
Reactant: CC(C#N)C(=O)c1cccnc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c(-c2cccnc2)n[nH]c1N
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-3-oxo-3-(pyridin-3-yl) propanenitrile (1.5 g, 9.4 mmol) in EtOH (20 mL) was added 85% hydrazine hydrate (2 mL). The resulting mixture was heated to reflux for 2 hours. After cooling to rt, the solvent was removed in vacuo and the crude product purified by column chromatography (DCM:MeOH=10:1) to give the desired product: MS (m/z): 175.0 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.71 (d, 1H, J=2.0 Hz), 8.50-8.51 (m, 1H), 7.99 (d, 1H, J=8.0 Hz), 7.50-7.55 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:4](ON1C(=O)CCC1=O)=[O:5])[CH3:3].[NH2:31][C@H:32]([C:52]([OH:54])=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:50]([CH3:51])=[C:48]([CH3:49])[C:45]([O:46][CH3:47])=[CH:44][C:42]=1[CH3:43])(=[O:40])=[O:39].C(=O)(O)[O-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.O.O.COCCOC>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@H:2]([C:4]([NH:31][C@H:32]([C:52]([OH:54])=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:50]([CH3:51])=[C:48]([CH3:49])[C:45]([O:46][CH3:47])=[CH:44][C:42]=1[CH3:43])(=[O:40])=[O:39])=[O:5])[CH3:3]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C

Procedure:
A solution of Fmoc-Ala-OSu 7c (15.31 mmol) in DME (100 mL) was added to a stirred solution of Lys(Mtr) 2 (6.4080 g, 1 equiv) and potassium bicarbonate (1.5331 mg, 1 equiv) in 2:1 water/DME (150 mL). After 16 h the DME was removed in vacuo and the resulting suspension was treated with citric acid (3.22 g, 1.1 equiv) in water (25 mL). The mixture was extracted with ethyl acetate. The organic phase was washed with water (2×) and brine, dried over sodium sulfate, and concentrated in vacuo, giving a yellow foam which was carried on without further purification. 1H-NMR (CDCl3/CD3OD) δ 1.25 (m, 2H), 1.32 (d, 3H), 1.57 (m, 3H), 1.73 (m, 1H), 2.41 (brt, 2H), 3.72 (s, 3H), 4.14 (m, 1H), 4.29 (m, 4H), 6.79 (d, 2H), 7.22 (m, 16H), 7.38 (d, 4H), 7.52 (m, 2H), 7.72 (d, 2H). MS (FAB) 712.2 (MH)+, 750.2 (M+K)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]2[CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:1]=[C:2]2[CH:11]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc2nc(N)cc(OC)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(cc(OC)c3cc(OC)c(OC)cc32)n1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To 50 ml. of N,N-dimethylformamide was added 5.2 g. (0.022 mole) of 2-amino-4,6,7-trimethoxyquinoline, and 3.38 g. (0.0244 mole) potassium carbonate. To the resulting slurry was added dropwise over 15 minutes 4.76 g. (0.0244 mole) ethyl bromopyruvate. The reaction mixture was stirred at room temperature 1.75 hours, during which the mixture became orange and a solid precipitated. Upon pouring onto 400 ml. of cold water a solid material formed which was filtered, dried, then dissolved in the minimum amount of chloroform. The solution was charged onto a column made up of 100 g. of silica gel in chloroform and elution with chloroform started. After 200 ml. of eluate was collected, elution with chloroform/ethanol (98:2 v/v) was started and 200 ml. fractions were collected. Fractions 1 through 4 were combined and evaporated to dryness to afford 3.0 g. of product. Recrystallization from benzene/cyclohexane yielded 2.7 g. of colorless solid, M.P. 195°-197° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[C:43](=[O:44])[CH2:42][C:36]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35][C:34]=2[OH:45])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:14][CH:13]=1)#[N:11].C(N(CC)C(C)C)(C)C>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:33]2[C:34](=[O:45])[CH2:35][C:36]3([CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH2:42][C:43]=2[O:44][CH3:6])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:16][CH:17]=1)#[N:11]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC3(CCOCC3)CC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyloxonium tetrafluoroborate (320 mg, 2.16 mmol) is added to a solution of 1-((4-cyanophenyl)(8-hydroxy-10-oxo-3-oxaspiro[5.5]undec-8-en-9-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 10, 712 mg, 1.43 mmol) and N,N-diisopropylethylamine (490 μL, 2.81 mmol) in dichloromethane (20 mL). The mixture is stirred at room temperature for 30 min and washed with water. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 380 mg; ESI mass spectrum [M+H]+=514, Retention time HPLC: 1.18 min (V012_S01).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:15][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1I
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a 20 mL scintillation vial, 5-bromo-3-iodo-2-methoxypyridine (Alfa Aesar, 2.02 g, 6.43 mmol), methanesulfonamide (Fluka, 0.645 g, 6.78 mmol), copper (I) iodide (Strem, 0.122 g, 0.643 mmol), cesium carbonate (Aldrich, 5.27 g, 16.1 mmol) and water (0.60 ml, 33.3 mmol) were mixed into DMF (6 mL). The reaction mixture was stirred at 105° C. for overnight. Then the mixture was heated in a microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between Tris-HCl buffer (1 M, pH 7.0) (20 mL) and EtOAc (20 mL). The aq phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aq NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 0% to 50%) to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (1.06 g, 59% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (d, J=2.19 Hz, 1H) 7.90 (d, J=2.19 Hz, 1H) 6.72 (br. s., 1H) 4.00 (s, 3H) 3.04 (s, 3H). m/z (ESI, positive ion): 280.8, 282.8 [M+1, M+3].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:23])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nc3occn3c2I)cc1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of 6-(4-fluorophenyl)imidazo[2,1-b]oxazole (4.92 g, 24.3 mmol; prepared according to WO2004110990A2, Example 1, Steps 1-3), NIS (5.75 g, 25.6 mmol), and DMF (100 mL) was stirred at ambient temperature. After about 3 h, the reaction was poured into water (300 mL) and the resulting precipitate was filtered, washing with additional water, and dried in a vacuum oven at about 55-65° C. to give the title compound (7.21 g, 89%): LC/MS (Table 1, Method b) Rt, =2.09 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: C([NH:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Yield: 98.9 %

Procedure:
A solution of the intermediate (5.4 g, 18.5 mmol) of step B, Pd(OH)2/C (0.3 g) in MeOH (200 mL) was stirred under hydrogen at 55 psi overnight. The catalyst was filtered off and the filtrate was concentrated to give 3.7 g of the desired product as a solid. MS calculated (M+H)+ 203. found 203.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:41]=[CH:40][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:21](=[O:38])[C:20]2=[O:39])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.[ClH:42]>C(OCC)(=O)C.O1CCOCC1>[ClH:42].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:21](=[O:38])[C:20]2=[O:39])=[CH:40][CH:41]=1)(=[NH:8])[NH2:10]
Reactant: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C(=N)N)cc2)C(=O)C1=O

Procedure:
In 2 ml of ethyl acetate was dissolved 0.45 g of ethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)-propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionate, followed by adding thereto 4 ml of a 2.4N solution of hydrochloric acid in dioxane, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the resulting residue was purified by a reversed phase column chromatography (eluent: a 15% aqueous acetonitrile solution) to obtain 0.20 g of ethyl 3-[4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate hydrochloride as a white solid.
Reaction SMILES: F[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].O>CO>[F:10][C:3]1[CH:2]=[CH:9][CH:8]=[C:7]([O:12][CH3:11])[C:4]=1[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1cccc(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(F)c1C#N
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
640.5 g (4.6 mol) of difluorobenzonitrile were dissolved in 3.5 l of methanol and then cooled to 0-5° C. 828.8 g of 30% strength sodium methoxide solution were added dropwise in this temperature range, and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was added to 20 l of water and the precipitate was filtered off with suction and washed twice with water and twice with heptane. The solid was dried in vacuo at 50° C. Yield: 740 g (99% of theory) of a white solid with a purity of >95% according to GC. 1H NMR (in CDCl3): δ=3.95 ppm (s, 3H, O—CH3), 6.85 ppm (m, 2H, arom. H), 7.5 ppm (q, 1H, arom. H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]2C(OCC)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:10]2)[CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C(=O)OCC)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)CC(=O)C(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 2.74 g ethyl 8-ethoxycarbonyl-2-methyl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate in 10 ml N,N-dimethylformamide, were added 512 mg sodium chloride and 315 μl water, and the mixture was heated with stirring for two hours in an oil bath held at 140°-150° C. The reaction mixture was poured into 30 ml ice water, the resulting mixure was extracted with chloroform, and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent from the dried solution, the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of n-hexane/ethyl acetate (1:1 by volume), giving 1.54 g of 8-ethoxycarbonyl-2-methyl-1-oxa-8-azaspiro[4,5]- decane-3-one as oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])[NH2:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:55]3[CH:56]=[CH:57][C:52]([C:49](=[O:51])[NH2:50])=[CH:53][CH:54]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C(N)=O)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-carbamoylphenylboronic acid to give 34 on a 0.1 mmol scale via General Procedure H (62 mg, 49%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.82 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.39 (s, 2H, CH2), 5.03 (s, 2H, CH2), 5.34 (s, 2H, CH2), 5.91 (s, 1H, NH2), 6.44 (s, 1H, NH), 6.65 (s, 1H, CH2), 6.68 (d, 1H, CH), 7.19 (d, J=6.0 Hz, 2H, CH), 7.24-7.35 (m, 4H, CH), 7.38-7.41 (m, 2H, CH), 7.44-7.50 (m, 6H, CH), 7.53 (d, J=4.8 Hz, 1H, CH), 7.59 (s, 2H, CH), 7.61 (s, 2H, CH), 7.64 (d, J=5.4 Hz, 2H, CH), 7.68 (d, J=5.4 Hz, 2H, CH), 7.83 (d, J=6.3 Hz, 1H, CH), 7.89 (d, J=6.0 Hz, 2H, CH); δC (100 MHz, CDCl3) 21.3, 35.9, 51.3, 52.7, 66.9, 70.6, 113.9, 119.9, 120.8, 126.8, 126.9, 127.1, 127.3, 127.9, 128.1, 128.1, 128.3, 128.4, 128.4, 129.4, 131.8, 131.8, 131.8, 131.9, 132.0, 132.8, 133.0, 135.1, 135.5, 135.6, 136.3, 139.1, 143.2, 143.8, 144.8, 158.7, 165.2, 167.0, 168.8; LRMS (ES+) calcd for [C45H41N3O7S+H] 768.27 found 768.27.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Yield: 80 %

Procedure:
A solution of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.7 g, 23 mmol, Example 165) and 4-amino-1N-Boc-piperidine (6.8 g, 34 mmol, Astatech) in 30 mL of 1-methyl-2-pyrrolidinone was heated at 70° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was chromatographed on silica gel. Elution with 3:2 ethyl acetate/hexane provided 80% yield of 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 114 dec., identical to material prepared in Example 106. Mass Spectrum (LR-ES) M+: 463.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives -2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:2].CI.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:19])[CH3:2]
Reactant: CCOC(=O)Cc1ccnn1-c1nccs1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccnn1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester (100 mg, 0.42 mmol), methyl iodide (66 mg, 0.46 mmol) and cesium carbonate (151 mg, 0.46 mmol) in DMF (6 mL) is stirred at room temperature overnight. The reaction is quenched with NH4Cl (aq.) (6 mL) and ethyl acetate (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×30 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (hexane/ethyl acetate 3:1) to give 2-(2-thiazol-2-yl-2H-pyrazol-3-yl)-propionic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: Clc1ccc(-c2nsc3cc(C#CCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Piperidine were converted to yield 3-(4-Chloro-phenyl)-6-(5-piperidin-1-yl-pent-1-ynyl)-benzo[d]isothiazole, MS: 395 (MH+).