Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Na][Na].[SH:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[C:18]([OH:20])=[O:19]>C(O)CCC>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:16][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:21])[C:18]([OH:20])=[O:19])[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CC(S)(C(=O)O)c1ccccc1
Reactant: CCOc1ccc2nc(Cl)sc2c1
Agent: [Na][Na]
Solvent: CCCCO
Product: CCOc1ccc2nc(SC(C)(C(=O)O)c3ccccc3)sc2c1
Reaction time: 4 h

Procedure:
A mixture of 21.4 g of 2-chloro-6-ethoxybenzothiazole, 22.6 g of the disodium salt of 2-mercapto-2-phenylpropionic acid and 200 ml of n-butanol is boiled for 4 hours and is evaporated and worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid, m.p. 152°-153°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15](=[O:20])[NH:16][CH:17]2[CH2:19][CH2:18]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[NH:7][C:6]=2[CH:14]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:15](=[O:20])[NH:16][CH:17]2[CH2:18][CH2:19]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[NH:7][C:6]=2[CH:14]=1
Reactant: COC(=O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Reaction time: 14 h
Yield: 84.4 %

Procedure:
To a solution of methyl 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylate (2.1 g, 7.2 mmol) in tetrahydrofuran (50 ml) was added dropwise, at 0° C., a solution of lithium hydroxide monohydrate (0.6 g, 14.3 mmol) in water (25 ml). The reaction mixture was stirred at this temperature for 14 h. After removing the tetrahydrofuran under reduced pressure, the aqueous solution was acidified with hydrochloric acid (2 M). The precipitated solid was filtered off with suction. 1.7 g (81% of theory) of 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylic acid were obtained.
Reaction SMILES: C[N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:28]([O:27][C:25]([N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 712 mg of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine in 5 ml toluene is added 1.2 g of ethyl chloroformate and the reaction mixture is heated at reflux temperature with stirring for 8 hours. On cooling to room temperature the reaction mixture is diluted with 50 ml of diethyl ether and the resulting precipitate collected by filtration and washed well with ether. The filtrate is evaporated to dryness under reduced pressure to yield 1,3,4,16b-tetrahydro-2-ethoxycarbonyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine as an oil which is used in the next step without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)CS(C)(=O)=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CN)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfonyl)propan-2-yl]carbamate (10.0 g, 26.2 mmol) in ethanol (150 mL) was added dropwise hydrazine hydrate (15.7 g, 262 mmol) at 0° C., and the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was heated to reflux. After two hours, the reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford tert-butyl [1-amino-3-(methylsulfonyl)propan-2-yl]carbamate. MS ESI calc'd. for C9H21N2O4S [M+H]+ 253. found 253. 1H NMR (400 MHz, CD3OD) δ 4.06-4.00 (m, 1H), 3.30-3.27 (m, 2H), 3.00 (s, 3H), 2.82-2.69 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]2[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:7]=2[S:8][C:9]=1[CH3:10].CO.[OH-].[Na+]>O1CCCC1>[C:15]([C:13]1[CH:12]=[CH:11][C:7]2[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])[C:6]=2[CH:14]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo-[b]thiophene (0.52 g, 1.42 mmol), methanol (5 ml), tetrahydrofuran (5 ml) and 2 ml aqueous sodium hydroxide solution (7 ml) was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. Then, the mixture was acidified with 3N hydrochloric acid and the precipitate was extracted from hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was ffitered off, and the filtrate was concentrated under reduced pressure to give the objective compound (0.45 g, 90% by two steps) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH:5]=[CH:6][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Nc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C

Procedure:
3.8 g (13 mmol) of (3-bromophenyl)-(2-nitrophenyl)amine was dissolved in 30 mL of tetrahydrofuran. A solution of 11 g (64 mmol) of sodium hydrosulfite in 30 mL of water was added dropwise to the solution while stirring the solution at room temperature in an argon atmosphere. After stirring the mixture for 5 hours, 20 mL of ethyl acetate was added to the mixture. A solution of 2.2 g (26 mmol) of sodium hydrogencarbonate in 20 mL of water was then added to the mixture. After the dropwise addition of a solution of 2.5 g (18 mmol) of benzoyl chloride in 10 mL of ethyl acetate, the mixture was stirred at room temperature for 1 hour. The mixture was then extracted with ethyl acetate, washed with a 10% potassium carbonate aqueous solution, water, and a saturated sodium chloride solution sequentially, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to obtain N-[2-(3-bromophenylamino)phenyl]benzamide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.CS(O[CH2:31][C@H:32](OC1CCCCO1)[CH3:33])(=O)=O.[CH3:41][NH2:42].O1CCCC1>>[CH3:41][NH:42][C@H:32]([CH3:33])[CH2:31][O:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:24][CH:23]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: CN
Reactant: C[C@H](COS(C)(=O)=O)OC1CCCCO1
Solvent: C1CCOC1
Product: CN[C@H](C)COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1

Procedure:
Using 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol obtained in Example 6-3), (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate and 2 M methylamine/tetrahydrofuran solution, and in the same manner as in Example 26 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (6 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1[CH:45]=CC(N)=C[CH:40]=1>>[CH2:1]([N:5]1[CH:9]=[C:8]([C:20]2[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]4[CH:35]=[CH:36][N:37]=[C:31]4[CH:30]=3)=[O:26])=[CH:22][CH:21]=2)[CH:7]=[N:6]1)[C:2]1[CH:3]=[CH:45][CH:39]=[CH:40][CH:4]=1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)o1
Reactant: Nc1ccc(Br)cc1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(-c2cnn(Cc3ccccc3)c2)o1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)furan-2-carboxamide for 4-bromoaniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (t, J=6.1 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 8.27 (d, J=0.7 Hz, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.89 (t, J=0.9 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41-7.23 (m, 6H), 7.17 (d, J=3.5 Hz, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 6.68 (d, J=3.5 Hz, 1H), 5.39 (s, 2H), 4.49 (d, J=6.1 Hz, 2H); MS (ESI(+)) m/e 398 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:15]([N:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:49]1N=NC2C=[CH:53][CH:54]=[CH:55][C:50]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[N:49]2[CH2:50][CH2:55][CH2:54][CH2:53]2)[CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)c2ccccc2F)c1)c1ccncc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)N2CCCC2)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino)-butyric acid (0.025 g), TBTU (0.028 g) and HOBt (0.012 g) in DMF (1 ml) was added DIPEA (0.015 ml) followed by pyrrolidine (0.007 ml) after 10 min. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.025 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:31])=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH:19]([CH2:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:17]=3[CH:30]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:32](OCC)(=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[C:24]1([CH2:23][CH2:22][CH2:21][CH:19]2[CH2:18][C:17]3[CH:30]=[C:13]([C:11]([NH:10][C:6]4[C:5]5[O:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:2][C:1](=[O:3])[C:4]=5[CH:9]=[CH:8][CH:7]=4)=[O:12])[CH:14]=[CH:15][C:16]=3[O:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[CH2:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CC(CCCc2ccccc2)O3)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCO
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(CCCc3ccccc3)O4)c2o1
Yield: 67 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-2-hydroxyphenyl)-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by crystallization in hot ethanol (67% yield).
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.[NH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].C(NCC(O)=O)(=O)C.CN(CC(O)=O)CC(O)=O>COCCOC>[C:1]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(O)CNCC(=O)O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: CN(CC(=O)O)CC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 100 °C
Yield: 95 %

Procedure:
The regenerated catalyst precursor was transferred, under CO:H2 pressure, into the autoclave containing CO:H2 (95:5) at 800 psi (5517 kPa), acetamide (VII)(29.5 g, 0.5 mole), 95% paraformaldehyde (34.0 g, 1.08 mole), water (32.2 g, 1.79 mole), and DME (650 mL). A CO:H2 (95:5) atmosphere at 1500 psi (10,345 kPa) was immediately established. This mixture was heated to 100° C. The reaction warmed to 125° C. and was maintained at this temperature for one hour. HPLC analysis of this stream gave a 95% yield of (XVI), 2% (XIV), 2.5% (XVIII), and 0.5% N-methyliminodiacetic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1.C([O-])(O)=O.[Na+].[Cl:22][C:23]1[C:31]([C:32]2[CH:33]=[N:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=2)=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.[C:42](#[N:44])C>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[O:28])=[CH:30][C:31]=1[C:32]1[CH:33]=[N:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][C:37]=1[C:42]#[N:44]
Reactant: CC#N
Reactant: O=C(Cl)c1ccc(Cl)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: CNc1ccccc1OCCc1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCc1nnn[nH]1
Reaction time: 2 h

Procedure:
The stirring aqueous solution of methyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine was basified with sat. NaHCO3 and diluted with acetonitrile (40 mL). 4-Chloro-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride (Step 39A, 2.9 g, 8.8 mmol) in acetonitrile (20 mL) was added dropwise. The mixture was stirred for 2 hrs, acidified, and concentrated to remove acetonitrile. The concentrated mixture was extracted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with 2% MeOH in DCM and then further purified via silica gel flash column chromatography eluting with 50% ethyl acetate in hexane to produce 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide 45-1 (3.2 g). [M+H]+528.2; tR=3.43 min (method 3).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([OH:19])=[CH:17][C:16]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]5)=[N:24][CH:25]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:38])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.CI>[Cl-].[NH4+].CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([O:19][CH3:39])=[CH:17][C:16]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:38])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(OC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-hydroxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (533 mg, 0.593 mmol), dicesium carbonate (390 mg, 1.19 mmol) and N,N-dimethylformamide (10 mL) at 0° C. was added MeI (55 μL, 0.89 mmol) and the reaction mixture was allowed to warm to rt before stirring for 1 hr. A further portion of MeI (110 μL, 1.78 mmol) was added and the mixture stirred at rt for a further 18 hrs. The reaction was diluted with ammonium chloride solution (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer washed with further portions of EtOAc (2×50 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give crude product mixture followed by flash chromatography (12 g silica column), eluting with 0-100% EtOAc gradient in n-heptane to give the desired product (226 mg, light brown solid). 1H NMR (CDCl3) δ 8.63 (s, 2H), 7.51 (d, J=1.3 Hz, 1H), 6.82 (d, J=1.3 Hz, 1H), 5.23 (s, 2H), 4.42 (dt, J=13.6, 4.0 Hz, 2H), 4.35 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 3.56-3.50 (m, 2H), 3.43-3.34 (m, 2H), 2.70 (s, 3H), 2.25 (d, J=13.6 Hz, 2H), 1.58-1.48 (m, 2H), 1.38-1.24 (m, 9H). MS: 554.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]([Cl:9])[Cl:8])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].O.C(Cl)(Cl)(Cl)[Cl:16]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])([Cl:8])[Cl:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(Cl)Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(Cl)(Cl)Cl)cc1
Yield: 88.7 %

Procedure:
22.7 gms of 4-ethyl benzal chloride dissolved in 100 gms of carbon tetrachloride was charged into a reaction vessel with 2.0 gms of Aliquot 4. 150 ml of 50% sodium hydroxide was added and the mixture heated to reflux for a period of about 1 hour. After the completion of the reaction, water was added to the mixture and the organic layer separated by phase separation. The organic solvent was stripped on a rotovac and product distilled on Krughrohr to give 23.8 gms of pale yellow liquid. (Yield 89%). [Pot temperature 90° -100° C. (at 0.15 mm/Hg - 0.2×105 pascals)]. Elemental analysis for C9H9Cl3 :
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].C([Li])CCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>O1CCCC1>[OH:16][C:17]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([OH:10])[CH3:9])[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2C(C)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)ethanol (step 1, 5.4 g, 25.1 mmol) in tetrahydrofuran (25 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (33 mL, 51.5 mmol) at −78° C. for 20 min and the mixture was stirred for 2 h at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidine-1-carboxylate (4.73 g, 27.6 mmol) in tetrahydrofuran (10 mL) at −78° C. for 15 min. This resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (2/1), then hexane/ethyl acetate (1/1) to afford 1.37 g (19%) of the title compound as a slight yellow syrup:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=O.[C:35]1([C:41]2[CH:45]=[N:44][NH:43][C:42]=2[C:46]2[C:54]3[C:49](=[N+:50]([O-])[CH:51]=[CH:52][CH:53]=3)[NH:48][CH:47]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Si:56]([O:63][CH2:64][CH2:65][NH2:66])([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]>>[CH2:29]([N:66]([CH2:65][CH2:64][O:63][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C:51]1[N:50]=[C:49]2[NH:48][CH:47]=[C:46]([C:42]3[NH:43][N:44]=[CH:45][C:41]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:54]2=[CH:53][CH:52]=1)[C:28]1[CH:32]=[CH:33][CH:34]=[CH:26][CH:27]=1
Reactant: [O-][n+]1cccc2c(-c3[nH]ncc3-c3ccccc3)c[nH]c21
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)c1ccc2c(-c3[nH]ncc3-c3ccccc3)c[nH]c2n1

Procedure:
This material was synthesized by the PyBrOP mediated amination of 3-(4-phenyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine 7-oxide meta-chlorobenzoate salt with 2-((tert-butyldimethylsilyl)oxy)ethylamine as described in Step 2 of Example 4. The crude product obtained was used directly in Step 2 below.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([CH3:34])[NH:19][C:18]=1[CH3:35])=[O:16])[CH3:13].C([O-])(=O)C.[Na+]>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:21]1[CH:22]([C:23]2[CH:24]=[N+:25]([O-:9])[CH:26]=[CH:27][CH:28]=2)[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:18]([CH3:35])[NH:19][C:20]=1[CH3:34])=[O:30])[CH3:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.1 g of 3-chloroperbenzoic acid in 40 ml of methylene chloride is added dropwise to a mixture of 3.3 g of 2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 1.4 g of sodium acetate in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 20 hours and extracted with a 2N aqueous sodium carbonate solution and then twice with an aqueous iron(II) sulphate solution. The organic solution is dried and concentrated by evaporation under reduced pressure. The residue is chromatographed over 400 g of silica gel, there being used as liquid phase a 95:5 mixture of chloroform and methanol and the chromatograph being effected by means of thin layer chromatography (silica gel; mobile phase: chloroform/methanol 95:5). The eluate, which contains the main portion of the desired compound, is concentrated by evaporation, and the residue is crystallised from acetonitrile. In this manner, 2,6-dimethyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained, which melts at 191°-193° and is identical to the product obtainable in accordance with the process of Example 2.