Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CCO>[NH2:34][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 110 °C
Yield: 79.7 %

Procedure:
To a 20-mL vial was added (2S)-2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.235 g, 0.482 mmol), EtOH (3.0 mL), and ammonium hydroxide (30%, 3.0 mL, 23 mmol, J. T. Baker, Philipsburg, N.J.). The vial was sealed and heated at 110° C. for 20 h. The reaction mixture was cooled to rt and the solvent was removed in vacuo. The residue was partitioned between water (20 mL) and DCM (40 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford (2S)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.180 g) as a mixture of two isomers.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:21]1[CH2:22][CH2:23][N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CCCN1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CCCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 88.7 %

Procedure:
Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and 1.4 mL (9.3 mMol) 1-propyl-4-piperidone, 2.1 gm (88.2%) of the title compound were recovered as a yellow powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]#[N:33]>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[CH2:31][C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: N#CCCl
Product: COc1ccc(N2CCN(CC#N)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 21 %

Procedure:
Prepared using the same procedure described in Example 405 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and chloroacetonitrile to afford the title compound as a yellow solid (26 mg, 21%). LC/MS (Method B) 4.10 min, [M+1]+ 441.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]#[N:20])[C:10]2=[O:21])=[CH:4][C:3]=1[CH3:31].[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41](Cl)=[N:42][OH:43])[CH:36]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(OCC)C.C1COCC1.O.C(OCC)(=O)C>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:20]=[C:19]([CH2:18][N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([C:5]4[CH:4]=[C:3]([CH3:31])[C:2]([OH:1])=[C:7]([CH3:8])[CH:6]=4)([C:22]4[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=4)[C:10]3=[O:21])[O:43][N:42]=2)[CH:36]=1
Reactant: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(CC#N)c3ccccc32)cc(C)c1O
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2noc(CN3C(=O)C(c4cc(C)c(O)c(C)c4)(c4cc(C)c(O)c(C)c4)c4ccccc43)n2)c1
Yield: 8 %

Procedure:
Under an N2 atmosphere combine [3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-yl]-acetonitrile (0.501 g, 0.782 mmol), 3-[chloro(hydroxyimino)methyl]-benzoic acid methyl ester (1.17 g, 5.47 mmol), and diethyl ether (20 mL). Add a solution of triethylamine (0.84 mL, 6.02 mmol) in diethyl ether (10 mL) over 30 minutes. Stir the reaction at room temperature overnight. Dilute the reaction with ethyl acetate (200 mL) and water (200 mL). Separate the layers, and dry the organic layer with sodium sulfate. Concentrate in vacuo. Chromatograph on silica gel eluting with 20% ethyl acetate in hexanes and concentrate. Dissolve the resulting compound (0.124 g, 0.152 mmol) in THF (1 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.38 mL) and stir the reaction at room temperature for 30 minutes. Add 1N aqueous HCl(10 mL), ethyl acetate (50 mL), and water (40 mL). Separate the layers and wash the organic layer with brine (50 mL). Dry the ethyl acetate with sodium sulfate, and concentrate in vacuo. Chromatograph on silica gel eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.037 g of the title compound: mass spectrum (ion spray): m/z=590(M+1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 8.10-8.03 (m, 4H), 7.29-7.25 (m, 2H), 7.17 (d, 1H), 7.09 (t, 1H) 6.71 (s, 1H), 5.48 (s, 2H), 3.87 (s, 3H), 2.04 (s, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)COc1ccc(N)cc1
Yield: 53.4 %

Procedure:
2-(4-Nitrophenoxy)propionic acid 2-[2-(4-nitrophenoxy)acetoxy]-ethyl ester 38 (20 g, 50 mmol) was dissolved in dry dimethylformamide (150 ml) in a pressure vessel. Palladium on carbon (5%, 5 g) was added and the mixture stirred under an atmos-phere of hydrogen (4 kg) for 3 hrs. The catalyst was removed by filtration and ice water (1 L) added to the filtrate. Crude 39 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform:ethyl acetate (8:2) to give pure 39 (10 g, 58%) as a dark brown syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]1([CH3:26])[CH3:25])=[O:12])=[CH:5]2.[CH3:27][O:28][CH2:29][CH:30]=O>C1COCC1.C(Cl)Cl>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH:1][CH2:30][CH2:29][O:28][CH3:27])=[CH:10][CH:9]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: COCC=O
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNc1ccc2[nH]c(C(=O)N[C@H]3c4cc(C#N)ccc4CC3(C)C)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of (R)-5-amino-N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-1H-indole-2-carboxamide (66.0 mg, 0.192 mmol) (prepared as described in Example 9) and methoxyacetaldehyde (containing 13% water, 18.0 mg, 0.211 mmol) in 1:1 THF/CH2Cl2 (4 mL) was added NaB(Oac)3H at rt in one portion. The mixture was stirred at rt for 4 hr and the reaction was quenched with saturated with NaHCO3 solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The desired product (27.1 mg, 35% yield) was isolated as a pale yellow solid by prep. HPLC. LCMS (M+H)+=345.38. 1H NMR (500 MHz, DMSO-d6) δ: 11.1 (s, 1H), 8.34 (d, J=9.3 Hz, 1H, 7.69 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.03 (s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.61 (s, 1H), 5.36 (d, J=9.3 Hz, 1H), 5.00 (t, J=5.8 Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 3.28 (s, 3H), 3.16 (dt, J=11.5, 6.0 Hz, 2H), 2.86 (dd, J=23.0, 16.5 Hz, 2H), 1.20 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=O)=[CH:31][CH:30]=1.[CH:39]1[C:47]2[C:46]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:45]=3[O:44][C:43]=2[CH:42]=[CH:41][C:40]=1[NH2:54]>>[CH:39]1[C:47]2[C:46]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:45]=3[O:44][C:43]=2[CH:42]=[CH:41][C:40]=1[NH:54][C:36](=[O:38])[CH2:35][C:32]1[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: O=C(Cc1ccncc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 44.9 %

Procedure:
Following the procedure of Example 30, triethylamine (0.40 mL, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.33 g, 1.7 mmol), N-hydroxybenzotriazole (0.23 g, 1.7 mmol), 4-pyridylacetic acid(0.24 g, 1.4 mmol), and 6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-pyridin-4-ylacetamide (0.18 g). MS (ESI) m/z 335 ([M+H]+); MS (ESI) m/z 333 ([M−H]−).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[F:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[CH:43]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:2]1[N:3]=[C:4]3[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]3=[N:6][CH:7]=1)[N:44]=[CH:43]2
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Fc1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)ccc43)nc12
Temperature: 110 °C
Yield: 89.8 %

Procedure:
2-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 248 μmol) was dissolved in toluene (1.4 mL) and copper (I) iodide (2.49 mg, 27.8 μmol), sodium iodide (74.4 mg, 496 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (9.00 mg, 63.3 μmol) added. The mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h. 5-fluoro-1H-indazole (33.8 mg, 248 μmol) and potassium phosphate tribasic (111 mg 521 μmol) were added, the mixture degassed with nitrogen, and the mixture heated at in sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave 2-(5-Fluoro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (111 mg, 90%). 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.55 (dd, J=9.1, 4.2 Hz, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.49 (dd, J=8.1, 2.3 Hz, 1H), 7.28-7.33 (m, 1H), 5.73 (s, 2H), 3.81 (s, 2H), 3.53-3.66 (m, 2H), 1.54 (s, 6H), 0.91-1.01 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11]O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]2[CH2:10][CH2:11][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: OCCN(CCO)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(Br)cc1N1CCOCC1
Temperature: 160 °C

Procedure:
4-Bromo-2-bis(2-hydroxyethyl)aminophenol (2.5 g) was dissolved in 70% sulphuric acid (25 ml) and the solution heated to 160°C for 3 hours, allowed to cool, then neutralised with saturated sodium carbonate solution. Extraction with ether and evaporation of the extracts gave crude 4-bromo-2-morpholinophenol which was crystallised from ether gave the pure phenol (1.4 g, 60%, m.p. 128°C).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using morpholine instead of isopropylamine, to the title compound (45 mg, 70%) which was obtained as an off white foam. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:8]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from (S)-(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-3-phenylurea, prepared as described in Example 41A, and 3-chlorobenzaldehyde by procedures analogous to those described in Example 3A. HPLC (method B): retention time 7.2 min. MS (ES): m/z 417 [M+H]+. Chiral HPLC 100% e.e.; retention time=27.3 min; Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in hexanes for 60 min at 1 mL/min.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH2:14][S:15]([OH:18])(=O)=[O:16].C(Cl)(=O)C([Cl:22])=O>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH2:14][S:15]([Cl:22])(=[O:18])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C)c1CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CS(=O)(=O)Cl
Temperature: -20 °C
Yield: 84.5 %

Procedure:
Tetrahydrofuran (3.0 L), (2,6-dimethyl-phenyl)-methanesulfonic acid (300 g, containing 12% water by KF analysis, or 266 g corrected for water content), and N,N-dimethylformamide (15 g) were combined in a 5 L multi-necked flask equipped with overhead stirring. The reaction mixture was cooled to −20° C. and oxalyl chloride (655.5 g) was added slowly over 1 h. The reaction mixture was clarified by filtration and concentrated to a volume of 1 L. The filtrate was transferred to a flask equipped with overhead stirring and cooled to −40° C. Water (900 mL) was added over 30 minutes, maintaining an internal temperature of <−10° C. The product was collected by filtration, washed with water and heptane, and dried to give (2,6-dimethyl-phenyl)-methanesulfonic chloride (277 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.25-7.04 (m, 3H, ArH), 5.17 (s, CH2), and 2.50 (s, 6H, CH3).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[N:20]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C(Cl)CCc2ccccc2N1c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2ccccc2N(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A suspension of 5.0 g (0.0184 mole) of 3-chloro-1-phenyl-2,3,4,5-tetrahydro-1-benzoazepin-2(1H)-one and 1.8 g (0.0277 mole) of sodium azide suspended in 50 ml of dimethylformamide was stirred at a bath temperature of 80° C. overnight. Next, to the mixture was added 1.0 g (0.0154 mole) of sodium azide, and the mixture was stirred for 8 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the solvent was removed under reduced pressure to obtain a residue. The residue was recrystallized from ethyl acetate to obtain 3.58 g of the title compound as colorless crystals.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16]([N:18]([CH3:22])[N:19]([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][N:19]([CH3:20])[N:18]([CH3:22])[C:16](=[O:17])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reaction time: 0.5 h
Yield: 148 %

Procedure:
To a solution of N-methyl-N-[(1R)-2-phenyl-1-(N,N',N'-trimethylhydrazinocarbonyl)ethyl]carbamic acid tert-butyl ester (0.3 g, 0.89 mmol) in methylene chloride (1 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 30 min. The mixture was concentrated in vacuo, stripped three times with methylene chloride and suspended in methylene chloride:(methanol/ammonia) (1:1) (2 ml) and trifluoroammonium acetate precipitated. Then diethyl ether (10 ml) was added and the mixture was filtered and the filtrate was concentrated in vacuo to give 0.31 g of (2R)-2-methylamino-3-phenylpropionic acid trimethylhydrazide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20]CC4C=CC=CC=4)=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10](C(OC)=O)[C:9]=2[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.O1CCOCC1.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[CH:10][C:9]2([C:32]([O:34][CH3:35])=[O:33])[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)C1(C(=O)OC)C=Cc2cc(O)c(OC)cc2C1c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a suspension of 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6-benzyloxy-7-methoxynaphthalene (6.6 g) in a mixture of acetic acid and dioxane (1:1, 1000 ml) is added 10% palladium-carbon (2 g), and the mixture is subjected to medium-pressure catalytic hydrogenation at room temperature overnight with using, a Parr-reduction apparatus. To the reaction solution is added a mixture of acetic acid and dioxane (1000 ml), and thereto is added 10% palladium-carbon (2 g). The mixture is subjected to medium-pressure catalytic hydrogenation at room temperature for 18 hours with using a Parr-reduction apparatus. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from ethanol to give 1-(2-chloro4-pyridyl)-2,2-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (3.35 g, yield; 62%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:23]=[C:24]([Cl:26])[N:25]=2)[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])[CH2:5][CH2:4]1.[Cl:27][C:28]1[C:32]([Cl:33])=[C:31]([CH3:34])[NH:30][C:29]=1[C:35](NC1CCN(C2C=CC=C(Cl)N=2)CC1)=[O:36]>>[Cl:26][C:24]1[CH:23]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:35]([C:29]3[NH:30][C:31]([CH3:34])=[C:32]([Cl:33])[C:28]=3[Cl:27])=[O:36])[CH2:8][CH2:7]2)[N:25]=1)[C:12]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cccc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: NC1CCN(c2cc(C(=O)NCCN3CCOCC3)cc(Cl)n2)CC1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NCCN4CCOCC4)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 18 from 2-(4-aminopiperidin-1-yl)-6-chloro-N-(2-morpholin-4-ylethyl)isonicotinamide hydrochloride salt (Intermediate 218) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:40][CH2:41][O:42][C:43](Cl)=[O:44]>ClCCl>[C:24]([O:23][C:22]([NH:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7]([C:6]1[CH:29]=[CH:30][C:3]([CH2:2][NH:1][C:43](=[O:44])[O:42][CH2:41][Cl:40])=[CH:4][CH:5]=1)=[O:8])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN)cc1
Reactant: O=C(Cl)OCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCCl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
tert-butyl [2-{[4-(aminomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (2.0 g, 4.72 mmol) was suspended in dichloromethane (50 ml). Hunig's Base (1 ml, 5.73 mmol) was added. The solution was cooled to 0° C. Chlorocarbonic acid chloromethyl ester (0.5 ml, 5.68 mmol) was added slowly. The reaction was stirred for approximately 1-2 h. The mixture, while cold, was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane. MS: calc'd 417 (MH+-Boc), exp 417 (MH+-Boc).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH:6]1[C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[S:16]([O-:18])=[O:17])=[O:4].[Na+:23].[OH:24]O>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH:6]1[C:14]([F:22])([F:21])[C:15]([F:19])([F:20])[S:16]([O-:24])(=[O:18])=[O:17])=[O:4].[Na+:23]
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)(=O)[O-])C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged the aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate obtained as described above, and a catalytic amount of sodium tungstate (IV) dihydrate. Thereto, a 35% by mass hydrogen peroxide solution 3.00 g was added dropwise. After the mixture was stirred at room temperature for 5 hrs, the disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. After the completion of the reaction, 20 mL of water was further added thereto, and the aqueous layer was washed with 30 mL of dichloromethane five times to obtain an aqueous solution of sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfonate (precursor compound (a-5)) represented by the following formula (a-5), which was used for the following reaction.