Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Cl[C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C@H:5]1[CH2:4][C@@H:3]([NH:2][C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Reactant: Clc1cnccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2cnccn2)C[C@@H]1C
Temperature: 120 °C
Yield: 37 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (100 mg, 0.232 mmol), 2-chloropyrazine (0.041 mL, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol) and sodium tert-butoxide (44.6 mg, 0.464 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. A further portion of 2-chloropyrazine (0.041 mL, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol), sodium tert-butoxide (44.6 mg, 0.464 mmol) and 1,4-dioxane (1 mL) were added and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-4-(pyrazin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (40 mg, 0.085 mmol, 37% yield). LCMS: (Formate, 2 min), Rt=0.68 mins, MH+473
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14]Cl)[CH:8]=1)[C:4]([OH:6])=[O:5].[C:16]([S-:21])(=[S:20])[O:17][CH2:18][CH3:19].[K]>O>[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][S:21][C:16]([O:17][CH2:18][CH3:19])=[S:20])[CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=S)[S-]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: Cl
Agent: [K]
Solvent: O
Product: CCOC(=S)SCc1cc(C(N)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid hydrochloride (1 g, 0.004 mole) in 20 ml of water is added carbonodithioic acid, O-ethyl ester, potassium salt (1.26 g, 0.08 mole). Within a few minutes a precipitate begins to form. The mixture is stirred at room temperature for 3 hours. The solid precipitate is filtered, washed with water and dried to give 58.3% of the title compound.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2CCO)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O.[CH2:24]([OH:26])[CH3:25]>[Fe]>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:25][CH2:24][OH:26])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ammonium chloride (1.5 g) and iron powder (13.8 g) were added to a mixed solvent of water (51 ml) and ethanol (170 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(2-hydroxyethylpiperazin-1-yl)benzonitrile (17 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (13 g), melting point: 137–138° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[F:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([F:1])[CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=1)=[O:10]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1cc(F)cc(F)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cc(F)cc(F)c2)cc1
Yield: 69.2 %

Procedure:
A solution of 2-(3,5-difluoro-phenoxy)-nicotinic acid (0.300 grams, 1.19 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.197 grams, 1.19 mmole) and 1-hydroxybenzotriazole hydrate (0.177 grams, 1.31 mmole) in dry dimethylformamide was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.273 grams, 1.43 mmole) and stirred over night. The mixture was poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 40% ethyl acetate/hexane to give an oil. Recrystalization from ethyl acetate/hexane gave a white solid (0.328 g). M.P. 68-70° C.; Anal. calcd. for C22H20N2O3F2: C, 66.32; H, 5.06; N, 7,03; N, 703. Found: C, 67.30; H, 5.39; N, 6.56.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>ClCCl>[OH:27][CH2:26][C:25]([NH:24][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3])([CH3:29])[CH3:28]
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)NC(C)(C)CO)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A mixture of 10 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 3 parts of 2-amino-2-methyl-1-propanol and 260 parts of dichloromethane was stirred overnight at room temperature. The precipitated product was filtered off, washed with dichloromethane and 2-propanone and dried, yielding 11.7 parts (91.9%) of N-(2-hydroxy-1,1-dimethylethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 221.6° C. (int. 7).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:9]2[CH2:13][O:12][CH2:11][C@H:10]2[OH:14])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]>C(OC=C)(=O)C>[Br:1][C:2]1[C:3]([C@H:9]2[CH2:13][O:12][CH2:11][C@@H:10]2[OH:14])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C)c([C@@H]2COC[C@H]2O)c1Br
Solvent: C=COC(C)=O
Product: Cc1sc(C)c([C@H]2COC[C@@H]2O)c1Br
Reaction time: 24 h
Yield: 49 %

Procedure:
Solid Novozym 435 is added to a solution of trans-4-(4-bromo-2,5-dimethyl-3-thienyl)tetrahydro-3-furanol (0.153 mol) in 425 ml of vinyl acetate and the mixture is subsequently stirred for 24 hours. The enzyme is removed by filtration and the residue is washed with tert-butyl methyl ether. After removal of the solvent, the two products are separated by means of chromatography. (3R,4S)-4-(Bromo-2,5-dimethyl-3-thienyl)tetrahydro-3-furanol is obtained in a yield of 49% (>99% ee) and (3S,4R)-4-(bromo-2,5-dimethyl-3-thienyl)tetrahydro-3-furanol acetate is obtained in a yield of 50% (>97% ee).
Reaction SMILES: [C:1]([N:5]1[CH2:14][C:13]2[C:8](=[N:9][C:10](S(C)(=O)=O)=[N:11][CH:12]=2)[N:7]([CH3:19])[C:6]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:22]>>[C:1]([N:5]1[CH2:14][C:13]2[C:8](=[N:9][C:10]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:23]([CH2:34][CH3:35])[CH2:21][CH3:22])=[CH:33][CH:32]=3)=[N:11][CH:12]=2)[N:7]([CH3:19])[C:6]1=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)N(C(C)(C)C)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C(C)(C)C)C3)cc1
Temperature: 180 °C
Yield: 19.8 %

Procedure:
A mixture of 250 ml (0.83 mmol) of 3-tert.butyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 600 mg (2.9 mmol) of 4-(2-(diethylamino)ethoxy)aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 30 ml of dichloromethane. The solution was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 70 mg (21%) of 3-tert.butyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].Cl.[CH3:26][NH:27][OH:28].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][N:27]([CH3:26])[OH:28])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(O)CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 6.9 %

Procedure:
A mixture of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.30 g, 7.7 mmol), N-methylhydroxylamine hydrochloride (0.64 g, 7.7 mmol) and potassium carbonate (0.97 g, 7.7 mmol) in ethanol (10 ml) was heated at reflux for 30 minutes. Water was added and the mixture extracted with dichloromethane. The organic phase was separated and the solvent evaporated under reduced pressure. The residue was washed with diethyl ether, affording 0.19 g of 6-nitro-2,2-dimethyl-3-(N-methyl-N-hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)S(O[C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([C@H:24]3[C:29]4=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]4[CH2:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccc(F)c(Cl)c4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16 mg) was added to a mixture of (3-chloro-4-fluorophenyl)boronic acid (85 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 16 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), dissolved in MeCN/DMSO (2500/300 μM) and purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat. NaHCO3 aq., extracted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (20 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3F)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (1.28 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.08 g of desired compound (melting point: 70.0°-73.0° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOCC1
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1Cl
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOCC3)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[1-(3-chloro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 458.5 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[CH2:15]([OH:17])[CH3:16]>O1CCOCC1>[ClH:14].[CH2:15]([O:17][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)=[NH:2])[CH3:16]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5.16 g (29 mmol) of ethyl 4-cyanobenzoate was stirred in 50 ml of 4N solution of hydrogen chloride in dioxane. 5 ml of ethanol was added to the resultant mixture, and they were stirred at room temperature for 4 days. The solvent was evaporated, and the residue was washed with ethyl acetate and dried to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:6]=2[N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:4][CH2:3]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1([CH3:26])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CCC(C)(C)S2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)O)ccc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylate (450 mg, 1.149 mmol) in THF (10 mL), MeOH (10.00 mL) and water (10.00 mL) was added lithium hydroxide (55.1 mg, 2.299 mmol). The reaction was allowed to stir at room temperature for 8 h. The solvent was removed under reduced pressure. The aqueous solution was acidified with 1 N HCl (10 mL), which resulted in the formation of a white solid. The mixture was washed with EtOAc (3×30 mL) and the combined organics were dried over Na2SO4 and concentrated in vacuo. 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxylic acid (434 mg, 1.149 mmol, 100% yield) was isolated as an off white solid and used without further purification. LCMS (+ESI) m/z=377.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[S:17][C:16]2[C:15](=[O:18])[N:14]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:13](=[O:32])[N:12]([CH2:33][C:34]3[N:35]=[N:36][N:37]([CH2:39][CH3:40])[N:38]=3)[C:11]=2[CH:10]=1.[ClH:41]>O1CCOCC1>[ClH:41].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[S:17][C:16]2[C:15](=[O:18])[N:14]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:13](=[O:32])[N:12]([CH2:33][C:34]3[N:35]=[N:36][N:37]([CH2:39][CH3:40])[N:38]=3)[C:11]=2[CH:10]=1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cccc(F)c4F)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cccc(F)c4F)cc32)n1

Procedure:
Tert-butyl 4-[6-(2,3-difluorophenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (44 mg, compound B61) and a solution of hydrogen chloride in 1,4-dioxane (0.2 ml+0.9 ml, 4.0 M) in 1,4 dioxane (2 ml) are reacted according to the procedure described in example B79 to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:29][CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CN)c1csc(N)n1)C(=O)O
Yield: 62.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (143 mg, 0.181 mmol), DCM (1.81 mL) and TFA (837 μl, 10.9 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (60 mg, 62%) as a white powder. LCMS: Rt=0.28 min, m/z=532.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J=9.1 Hz, 1H), 8.40 (br s, 3H), 8.06 (s, 1H), 7.59-7.27 (m, 2H), 6.84 (s, 1H), 5.37 (dd, J=9.0, 5.5 Hz, 1H), 4.61-4.51 (m, 1H), 4.49-4.34 (m, 3H), 4.25 (dd, J=15.3, 5.8 Hz, 1H), 1.37 (s, 6H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:13])[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:27]([CH2:28][CH:29]([OH:31])[CH3:30])[C:5]=12
Reactant: CC(O)CN
Reactant: Cc1cccc2c1CC(CC=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reaction time: 0.75 h
Yield: 27.5 %

Procedure:
A solution of 1.9 g of (RS)-2-(2-oxoethyl)-4-methyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator, A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 0.63 g (28%) of (RS)-1-(5-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a white solid which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([OH:7])=O.[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[Br:20][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:33][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:32])=[O:31])=[O:7]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Product: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 54.4 %

Procedure:
3,5-dibromo-4-(3-bromobenzyloxy)benzoic acid (0.17 mmol) was coupled with 3-nitrobenzenesulphonamide (0.89 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 60 mg (54%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-3-nitrobenzenesulphonamide.