Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C.ClCCl>[CH:36]1([NH:39][CH2:1][C:3]2[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[N:27]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:12]=3)[CH:8]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: Cc1ccc(C=O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(CNC2CC2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture of N-(5-formyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide (250 mg, 0.546 mmol), cyclopropylamine (238 μL, 3.44 mmol), dichloromethane (10 m:), tetrahydrofuran (2 drops) and acetic acid (2 drops) was stirred at rt for 1 h. Sodium triacetoxyborohydride (275 mg, 1.30 mmol) was added and the mixture was stirred overnight. The crude reaction was diluted with dichloromethane, washed with saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. The solution was concentrated on a rotary evaporator and purified by HPLC to give a yellow solid (143 mg, 52%).
Reaction SMILES: N1(CC(N)=O)C=CC=N1.[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([O:30]CC)=O)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C>>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([NH:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:30])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: NCCN1CCCC1
Agent: NC(=O)Cn1cccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCN1CCCC1

Procedure:
By a procedure substantially similar to that of Example 18, 6.67 g of 4,5-diphenyl-N-2-(1-pyrrolidinyl)ethyl-]1H-pyrazole-1-acetamide, mp 80°-84° C., was prepared from 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 9 mL (0.072 mol) of N-(2-aminoethyl)pyrrolidine and 62 mL (0.36 mol) of diisopropylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([C:39]1[CH:44]=[CH:43]C(O)=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:44][C:39]([CH2:35][CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1ccc(OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 81.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-butylphenol (77 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 75%).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:14]Cl>C1(C)C=CC=CC=1.O>[Cl:14][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: ClCl
Reactant: CC(=O)CC(=O)Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(Cl)C(=O)Nc1ccccc1
Temperature: 6 °C
Yield: 63.9 %

Procedure:
A suspension of 177 g (1.0 mole) of acetoacetanilide in 1440 ml of toluene and 167 ml of water, in a chlorinator (2000 ml 3-neck flask), was cooled to approximately 6° C. and chlorine gas was added at about the rate of 1.5 g/minute, while maintaining the temperature at 6° C. until 82.6 g (1.16 moles) of chlorine had been added (about 56 minutes). The resultant mixture was stirred for an additional 36 minutes and then heated to 70° C. for 15 minutes. The mixture was then cooled and the product was precipitated. The precipitate was filtered from the toluene/aqueous HCl mixture to give 134.8 g (63.9%) of α-chloroacetoacetanilide, mp 132°-134° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]1>>[OH:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:24]1
Reactant: O[C@H]1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](O)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-3-ol (1.2 equiv) to give 172 (14.1 mg, M+1 397.1)
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC([N:35]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=1)[C:36](=[O:38])[O-:37])(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:44]3[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][NH:35][C:36]([O:37][C:16]([CH3:11])([CH3:7])[CH3:15])=[O:38])=[CH:46][CH:45]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)N(CCc1ccc(Br)cc1)C(=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N1c2ccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (125 mg, 0.300 mmol), 1,1-dimethylethyl[2-(4-bromophenyl)ethyl]carbamate (90 mg, 0.300 mmol), potassium carbonate (104 mg, 0.751 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.35 mg, 0.015 mmol) was degassed under house vacuum for 15 min and quenched several times with nitrogen, then was then stirred at 100° C. under nitrogen for 50 min before being cooled to room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between AcOEt (20 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 75% AcOEt in Hexanes) gave 1-methylethyl((2S,4R)-1-acetyl-6-{4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]phenyl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (50 mg, 0.093 mmol, 31%) as a colourless oil.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Sc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CSc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of phenacyl bromide (1 g), 4-chlorothiophenol (1.37 g), and benzyl triethyl ammonium chloride (78 mg) in dichloromethane (20 ml) NaOH (0.61 g) in water (2 ml) was added. The mixture was stirred vigorously at rt for 16 h. After dilution with water (50 ml) the organic layer was separated, washed with brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by column chromatography on silica gel (petrol ether/ethyl acetate 12:1) to provide 2-(4-chlorophenylthio)-1-phenylethanone (0.74 g) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH2:39][CH2:40][N:41]([CH3:47])[CH2:42]2.Cl>CN(C=O)C.CO.ClCCl>[ClH:11].[CH3:47][N:41]1[CH2:40][CH2:39][C:38]2[C:43](=[CH:44][CH:45]=[CH:46][C:37]=2[NH:36][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=2[O:12][CH3:13])[CH2:42]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (2.08 g, 11.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g 9.24 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.24 mmol) were dissolved in dry DMF (40 ml) and stirred at room temperature under argon for 0.5h before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.5 g, 9.24 mmol) was added. The mixture was then stirred for 18 h under argon at room temperature. The DMF was removed in vacuo and the residue taken up into ethyl acethate and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a yellow solid. This was then passed through a short pad of silica eluting with dichloromethane to afford a white solid which was then taken up into methanol and treated with hydrogen chloride (1M in ether, 1 equivalent). The solvent was removed in vacuo and the residue recrystallised from methanol and ethyl acethate to afford the title compound as a white solid (0.775 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([CH:31](OC)[O:32]C)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(Cl)(Cl)Cl.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(OC)c1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mL of water and 21 mL of trifluoroacetic acid are added to a suspension of 9.8 g (24.02 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-dimethoxymethylphenyl)acrylamide in 280 mL of chloroform and the reaction mixture is stirred for 8 hours at ambient temperature. It is diluted with chloroform and water, the organic phase is separated off and extracted with water. The organic phase is dried, filtered through silica gel, and the solvent is distilled off. Yield: 5.5 g; C22H16ClNO2 (M=361.83); calc.: molecular ion peak (M+H)+: 362/364; found: molecular ion peak (M+H)+: 362/364; Rf value: 0.6 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[N:28]1CCCCC1.CC[O:36][CH2:37]C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][O:36][CH3:37])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: CCOCC
Reactant: CN1CCCCC1
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)NOC)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (500 mg, 1.41 mmol) and N,N′-carbonyldiimidazole (250 mg, 1.54 mmol) in methylene chloride (30 mL) under nitrogen was stirred at room temperature for 30 minutes. To the solution was added 0-methyl hydroxylamine hydrochloride (175 mg, 2.09 mmol) followed by the addition of 1-methyl piperidine (0.26 mL, 2.14 mmol). The mixture was stirred at room temperature for 2 hours and then was heated to reflux for 14 hours. The cooled reaction mixture was washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL), and then dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave a solid which was stirred with ether (10 mL) for 30 minutes. This suspension was filtered and the solid was washed with ether (2×10 mL) to give 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamide as a white solid (360 mg, 67% yield): mp, 138.0–139.5° C.; 1H NMR (CDCl3) δ 1.41 (t, J=6.9 Hz, 3H, CH3), 2.95 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.53 (dd, J=11.2, 14.5 Hz, 1H, CHH), 3.62 (s, 3H, CH3), 3.84 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 4.23 (d, J=17.1 Hz, 1H, NCHH), 4.46 (d, J=17 Hz, 1H, NCHH), 5.49 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.78–6.99 (m, 3H, Ar,), 7.27–7.51 (m, 3H, Ar), 7.78 (dd, J=7.4 Hz, 1H, Ar), 10.08 (br s, 1H, NH); 13C NMR (CDCl3) δ 14.66, 37.52, 49.48, 54.94, 5.91, 64.01, 64.41, 111.37, 112.12, 119.26, 122.75, 123.54, 128.04, 131.38, 131.68, 132.58, 141.44, 148.56, 149.15, 167.81, 169.47. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C, 65.23; H, 6.52; N, 6.88.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.C(Cl)C[Cl:67].C(OC([N:76]1[CH2:81][CH2:80][CH2:79][CH2:78][CH:77]1[C:82](O)=[O:83])=O)(C)(C)C>C(Cl)Cl>[ClH:53].[ClH:67].[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([C:82]([CH:77]5[CH2:78][CH2:79][CH2:80][CH2:81][NH:76]5)=[O:83])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:40][CH:41]=1
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)C3CCCCN3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was suspended in DCM, 0.1 mL DIEA added and mixture concentrated to provide a solid. In a separate vial, EDC (35 mg) and piperidine-1,2-dicarboxylic acid mono-tert-butyl ester (83 mg) were dissolved in DCM and stirred 15 min. This solution was added to the solid and mixture stirred for 4 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed (2 mg removed before deprotection) and deprotected according to General Procedures B and C to provide the title compound (10 mg). LCMS (m/z): 850.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[CH:20]=3)=[N:15]2)=[O:10])[N:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[N:8]=[C:4]([CH:1]([OH:3])[CH3:2])[S:5][CH:6]=3)=[O:10])[CH3:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Into a flask containing (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (1 g, 2.416 mmol) dissolved in ethanol (10 ml), sodium borohydride (0.137 g, 3.62 mmol) was added in small parts under nitrogen atmosphere. The following mixture was stirred overnight in RT. Next morning water (1 ml) was added dropwise and the pH of the mixture was adjusted to under 7 with 1 M HCl and the mixture was evaporated. 30 ml of ethyl acetate was added and stirred for 30 min, filtered and the filtrate was evaporated and dried in vacuum at 40° C. The product was purified by recrystallizing it twice from diethyl ether/ethanol to yield 41.6% of the title compound. 1H-NMR (400 MHz; DMSO-d6): δ 1.10-1.16 (m, 3H), 1.44-1.48 (m, 3H), 4.29-4.52 (m, 3H), 4.94-4.02 (m, 3H), 6.22-6.26 (m, 1H), 6.95-6.99 (m, 1H), 7.83-7.88 (m, 1H), 7.93-8.00 (m, 2H), 8.07-8.10 (m, 1H), 8.11 (d, 1H), 8.33-4.39 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
2,3-Dichloropyrazine (2.67 mL, 25.6 mmol), 4-aminophenol (2.29 g, 21 mmol), and cesium carbonate (8.21 g, 25.2 mmol) in dimethyl sulfoxide (70 mL) under argon was stirred at 100° C. for 18 h. The cooled reaction mixture was poured into water (100 mL), resulting in the precipitation of a brick-colored solid. After stirring for 10 min, the brown slurry was filtered to give a relatively pure crop of 4-(3-chloropyrazin-2-yloxy)aniline (3.67 g, 79% yield) as a brick-colored solid. [M+1]=222.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][C:14]1([CH2:17]O)[CH2:16][CH2:15]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:13][C:14]2([CH2:16][CH2:15]2)[CH2:17][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1(CO)CC1
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COCC2OCC3(CC3)CO2)cc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 1,1-bis(hydroxymethyl)cyclopropane (4.08 g, 40 mmol), p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol) and toluene (70 ml) was refluxed for 2 hours while removing water by the Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, triethylamine (4 ml) was added to the reaction mixture and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: ethyl acetate/heptane=5/95 to 1/9) to obtain the title compound (6.1 g, yield: 78.2%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH:14][C:15]([NH:17][CH3:18])=[S:16])=O.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[N:17]([CH3:18])[C:15]([SH:16])=[N:14][N:13]=1
Reactant: CNC(=S)NNC(=O)CNc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1NCc1nnc(S)n1C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred hot solution of 52.8 g (0.198 mol) 1-[alpha-(2,6-dimethylphenylamino)acetyl]-4-methylthiosemicarbazide in 560 ml ethanol was added quickly 8 g (0.198 mol) sodium hydroxide. The reaction mixture was heated under reflux for 2 hours and allowed to stand overnight. The ethanol was then evaporated under reduced pressure to give a solid residue. Water (500 ml) was added to the solid residue and the resulting aqueous mixture was filtered to remove a small amount of a solid. The filtrate was neutralized with concentrated hydrochloric acid, the colorless solid was filtered, washed with water and partially dried in vacuuo over potassium hydroxide pellets at 50° C. The nearly dried product was dissolved in dichloromethane and the aqueous layer separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 43.5 g of the product as a colorless solid, m.p. 172°-173° C. The product is tabulated in Table I as Compound No. 3.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C>[Cl:40][C:36]1[CH:37]=[C:38]([CH3:39])[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step D) (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture was then stirred for 30 minutes at 0° C. Then, 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, Step A) (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10° C. The reaction mixture was stirred 60 minutes at 0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g).