Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[C:21](C)[C:22]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=O.[OH-].[Na+]>C(O)CC>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:22]1[CH:21]=[CH:20][N:17]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH:9]=2)[N:16]=1
Reactant: CC(=CN(C)C)C(=O)c1ccco1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1cc(Nc2nccc(-c3ccco3)n2)cc(-n2ccnc2)c1
Yield: 44.5 %

Procedure:
Two and 73 hundredths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 1.6 grams of 3-dimethylamino-1-(2-furyl)-2-methyl-2-propen-1-one, 25 ml of n-propanol and 2 equivalents (2 ml) of 10N NaOH at pH=11 is refluxed for twenty-four (24) hours. The products are isolated by quenching the reaction mixture including any precipitated solids into water followed by filtration. These filtered solids are re-suspended in water to remove inorganic salts, filtered and air dried to give 1.35 g (44.5% yield) of the desired product, mp 175°-178° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]3[CH2:20][CH2:19][N:18](CC=O)[CH2:17][CH2:16]3)=[N:12][C:11]=2[CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:6][CH:5]=1.CO>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:12][C:11]=2[CH2:24][O:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:6][CH:5]=1
Reactant: O=CCN1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc(-c2oc(C3CCNCC3)nc2COCC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 170 g (4.25 mol) sodium hydroxide in 250 mL of water is added to a stirred solution of 84 g (210 mmol) 1-(4-[5-(4-fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidin-1-ethanone, prepared as in Part D, in 1L of methanol. The mixture is stirred at 50° C. for 8 hours, cooled to 20° C., and stirred for an additional 12 hrs. The methanol is removed from the reaction mixture under reduced pressure, and the residue is diluted with 1 L water. The mixture is extracted with methylene chloride (3×300 mL). The layers are separated and 50 g of sodium chloride is added to the aqueous phase. The aqueous phase is extracted with methylene chloride (3×300 mL). The organic phases are combined, dried with anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure. The residue is dissolved in 200 mL of ethyl acetate and 600 mL of saturated sodium bicarbonate solution is added and the mixture is stirred at room temperature for 12 hours. The solid is filtered and washed three times with 200 mL of water, and with ether (3×50 mL). The product is dried under reduced pressure at 40° C. to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-dichlorophenylboronic acid (176 mg, 0.85 mmol) the subtitle compound was obtained (176 mg, 74%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.44(dd, 1H), 7.89(d, 1H), 7.70(d, 1H), 7.65(d, 1H), 7.54(d, 2H), 7.44(dd, 1H), 7.26(d, 1H), 4.08(s, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)(C#CCBr)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(C#CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 62.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (60.8 mg, 0.105 mmol), 6-bromo-3-ethyl-4-hexyn-3-ol (108 mg, 0.525 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (38.4 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1cc(N)n(-c2ccc(Cl)c(Cl)c2)n1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(Cl)c(Cl)c1

Procedure:
5-Amino-3-methyl-1-(3,4-dichlorophenyl)pyrazole (16.6 g.) and 1-acetyl-2-imidazolinone (10.6 g.) were reacted as described in Example I to give 8.5 g. of product, mp 156°-157°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]Br)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCC(N3CCCc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-piperidinyl)-7-methoxy-1,2,3,4-tetrahydroquinoline (250 mg), 2-(4-methoxyphenyl)ethyl bromide (260 mg) and diisopropylethylamine (270 mg) in DMF (5 ml) was heated at 60° C. for 12 hr under stirring. After the completion of the reaction, the reaction solution was cooled to room temperature and water was added thereto followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting obtained residue was purified by silica gel column chromatography (toluene/acetone system) to give 1-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This free compound was dissolved in ethyl acetate and 8.5% HCl/ethyl acetate was added thereto. The resulting hydrochloride was recrystallized from ethanol/ether to give the title compound (225 mg) (yield: 53%).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:6]Cl.[Cl:12][CH2:13][C:14](=[O:16])[CH3:15].Cl>CCOCC.O1CCCC1>[Cl:12][CH2:13][C:14]([CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:10]=[C:9]([CH3:11])[CH:8]=1)([OH:16])[CH3:15]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)cc(CCl)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(CC(C)(O)CCl)c1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
25 g of magnesium turnings and 155 g of 3,5-dimethylbenzyl chloride were reacted in 300 ml of ether. After dilution with 200 ml of tetrahydrofuran, a mixture of 92.5 g of chloroacetone and 100 ml of tetrahydrofuran was added dropwise with ice cooling in the course of one hour. After reacting for 2 hours at 25° C., the mixture was poured onto a mixture of ice and 2.5 mol hydrochloric acid. The upper layer was separated off and the aqueous layer was extracted with ether. The combined organic layers were washed with water until neutral, dried using Na2SO4, filtered and distilled. 110 g of 1-chloro-2-(3,5-dimethylbenzyl)-propan-2-ol were obtained at 110°-112° C./0.2 mbar. 109 g of this compound were stirred at 30° C. for 2 hours with 20 ml of methyl tert.-butyl ether and a solution of 31 g of NaOH in 750 ml of water. The layers were then separated, and the organic phase was washed with water until neutral, dried using Na2SO4 and distilled. 65 g of 2-(3,5-dimethylbenzyl)-propylene oxide were obtained at a boiling point of 68°-70° C./0.3 mbar. 80 g of this compound were dissolved in 100 ml of cyclohexane and put into a 0.5 l shaking autoclave with 0.8 g of 5% Pd on active carbon. After flushing with inert gas, the autoclave was pressuried with hydrogen (130 bar) and heated at 150° C. for 8 hours. The cooled mixture was depressurized, flushed with inert gas, the catalyst was filtered off and the filtrate was distilled through a 30-cm long column containing steel helices. 18 g of 2-methyl-3-(3,5-dimethylphenyl)-propan-1-ol passed over at 80°-81° C./0.07 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3-Cyanobenzenesulfonyl chloride (53 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 40 (68 mg, 76% yield) as a yellow solid. LC-MS (M+H=373, obsd.=373).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: BrCC1CC1
Product: Cc1ccccc1N1C(C)N(CC2CC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=554.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and cyclopropyl methyl bromide.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1Cl)=[O:12])[CH3:9].O>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(C)c1Cl
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C)c1-n1cccn1
Temperature: 40 °C
Yield: 9.1 %

Procedure:
Sodium hydride (60% in oil; 767 mg, 19 mmol) was added to a solution of pyrazole (1.36 g, 20 mmol) in dry DMF (40 mL) under nitrogen at 0° C. in an ice-water bath and the mixture was heated to 40° C. for 1 h. 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.89 g, 10 mmol) was added and the mixture was heated to 100° C. overnight and then cooled. Water and ethyl acetate were added, the organic layer was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were concentrated in vacuo and the residue was purified by flash silica chromatography eluting with a gradient of 0-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid ethyl ester (0.2 g, 9%).
Reaction SMILES: CO[C:3]1[CH:4]([CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:17]
Reactant: [Cl-]
Reactant: COC1=NCCCCC1Cc1cccs1
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C1NCCCCC1Cc1cccs1

Procedure:
The title product of Example 56 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:16][O:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26])=[O:19]>N1C=CC=CC=1>[CH3:16][O:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:27])=[O:26])=[O:19]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)OC)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.30 g) and pyridine (5 mL) was added 2-methoxycarbonyl-3-thiophenesulfonyl chloride (0.42 g) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-ethyl acetate.), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (550 mg, yield 92%) as pale-yellow crystals. melting point 173-174° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:5][N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CC(=O)Cl
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC2CCN(C)CC2)n1
Temperature: 40 °C
Yield: 76.4 %

Procedure:
Add acetyl chloride (118 mg, 0.11 mL, 1.50 mmol) slowly to a solution of 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 72, 260 mg, 1.25 mmol) in triethylamine (190 mg, 0.26 mL, 1.88 mmol) and THF (10 mL), heat at 40° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4.5% 2M NH3-methanol in methylene dichloride provides 238 mg (76%) of the title compound as an oil: mass spectrum (ion spray): m/z=250.0 (M+1); 1H NMR (CDCl3, ppm): 7.70 (m, 2H), 7.56 (t, 1H), 6.44 (d, 1H), 4.91 (m, 1H), 2.68 (m, 2H), 2.34 (m, 5H), 2.20 (s, 3H), 2.00 (m, 2H), 1.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([CH3:67])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:61]1[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][C:60]=1[CH3:67])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)c(C)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(NC(C)=O)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (130 mg) was reacted with 2-acetylamino-5-methyl-thiazole-4-sulfonyl chloride (54 mg) to furnish (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-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′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z:. 965) according to General Procedure E. The title compound (16 mg) was prepared by the hydrolysis of (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-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′-cyano-biphenyl-4-yl)-propionic acid methyl ester (20 mg) using General Procedure B. LCMS (m/z): 952.
Reaction SMILES: N[C@H:2]1CCCN(C(OC(C)(C)C)=O)[C@H:3]1C1C=CC=CC=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]([CH:42]([C:47](F)([F:49])[F:48])C(F)(F)F)[CH:39]=[CH:38][C:37]=2[O:51][CH3:52])[C@@H:29]1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]3[C:39]([CH2:2][CH2:3][C:47]([F:48])([F:49])[CH2:42]3)=[CH:38][C:37]=2[O:51][CH3:52])[C@@H:29]1[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)CC(F)(F)CC2

Procedure:
This compound was prepared from Compound 96 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]4([CH3:24])[CH3:23])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.C(Cl)[Cl:35].[C:37](OC(=O)C)(=[O:39])[CH3:38]>O>[ClH:35].[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:37](=[O:39])[CH3:38])[CH2:19][C:18]4([CH3:23])[CH3:24])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(CN2CCNCC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCN(Cc2nc(C)nc3sc(C4CCC(C)(C)CC4)cc23)C(C)(C)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-4-[(2,2-dimethylpiperazin-1-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (40 mg), pyridine (83 μL), and DCM (1.2 mL) was added acetic anhydride (49 μL), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column. To a solution of the obtained purified product in EtOAc was added dropwise 4 M HCl/dioxane, and the precipitate was collected by filtration and dried to obtain 1-(4-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-3,3-dimethylpiperazin-1-yl)ethanone hydrochloride (35 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:13](=[O:22])[C@H:12]([N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:23][C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][N:14]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:13]1=[O:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Yield: 0.1 %

Procedure:
A solution of di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate (0.481 g, 0.895 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (3 mL). After 1 h the reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2×). The organic washes were combined, dried over magnesium sulfate, and concentrated to afford the title compound (0.30 mg). MS 338.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].Cl>O.ClCCl>[Br:15][CH2:16][C:17]([NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cncc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1cncc(NC(=O)CBr)n1

Procedure:
6-Methyl-pyrazin-2-ylamine (150 mg) and potassium carbonate (571 mg) were added to dichloromethane (25 mL). 2-Bromoacetyl bromide (0.120 mL) was added to the suspension with stirring. The reaction was stirred overnight then water (0.1 mL) was added with further stirring. Further quantities of potassium carbonate (571 mg), 2-bromoacetyl bromide (0.120 mL) and water (0.1 mL) were added over 2 hours until the reaction had proceeded to completion. The reaction was diluted with water (100 mL), carefully acidified with hydrochloric acid and extracted with dichloromethane (2×50 mL) which was dried and evaporated to afford the sub-titled compound which was used crude (365 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9]/[C:10](/[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:26]\[OH:27])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cnccn1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cnccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-(4-bromo-phenyl)-1-pyrazin-2-yl-3-o-tolyl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing about 10% of the corresponding Z isomer as a colorless foam, MS (ESI−): m/z=393.8 [M−H]−.