Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([O:26]CC)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].OS([O-])(=O)=O.[K+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Temperature: 0 °C
Yield: 90.1 %

Procedure:
A solution of (R)-ethyl 1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylate (3.99 g) in a mixture of methanol (10 ml), tetrahydrofuran (10 ml) and water (10 ml) was added lithium hydroxide (1.27 g) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was acidified with 5% KHSO4 aqueous solution and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo to give (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (3.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(COCC[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nn(COCC[Si](C)(C)C)cc1N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5.97 g, 15.6 mmol) in 25 mL ethanol was added 50 mL water, ammonium chloride (3.37 g, 62.9 mmol), and iron powder (4.367 g, 78.2 mmol). The reaction mixture was stirred at 75° C. for 1.5 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 5.50 g (100%) of 3-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=354.3; 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, 1H), 7.34 (d of d, 1H), 7.28 (s, 1H), 6.92 (d, 1H), 5.24 (s, 2H), 3.52 (t, 2H), 0.85 (t, 2H), −0.04 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]#[C:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[CH2:19]([O:18][C:13]([C:14]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:15]=1[CH3:16])=[O:17])[CH3:20]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1ccc(F)cc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Yield: 58.3 %

Procedure:
In a fashion similar to that for preparation 15, 2,4-difluorobenzoyl chloride oxime (2.00 g, 10.4 mmol), ethyl 2-butynoate (1.76 g, 15.7 mmol), triethyl amine (2.9 ml, 21 mmol) in diethyl ether (10 ml), and diethyl ether 30 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2,4-difluorophenyl)isoxazole (1.62 g, 58%) after column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14]CC2C=CC=CC=2)[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A stirred solution of trans-4-benzylamino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.170 g, 0.551 mmol) in methanol (2 ml) and was treated with ammonium formate (0.139 g, 2.20 mmol) and 10% palladium on activated carbon (0.059 g, 0.055 mmol) and stirred at 50° C. for one hour. The mixture was then filtered through Celite, washed with copious methanol and concentrated under vacuum to give 118 mg (100%) of trans-4-amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester that was used without further purification. LCMS (Method F): RT=0.14 min, m+H=219.0; 1H NMR (400 MHz, DMSO) δ 4.22-4.01 (m, 1H), 3.96-3.68 (m, 2H), 3.62-3.52 (m, 1H), 3.22-2.94 (m, 2H), 2.89-2.77 (m, 1H), 1.81-1.63 (m, 2H), 1.39 (s, 10H), 1.28-1.16 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[C:30]2[C:31]([N+:41]([O-])=O)=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:34]=2)=[CH:4][C:5]([F:21])=[C:6]([S:8]([N:11]([CH2:18][O:19][CH3:20])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C(O)C.[Cl-].[NH4+]>[Fe]>[NH2:41][C:31]1[C:30]([C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[O:22][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([N:11]([CH2:18][O:19][CH3:20])[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[C:5]([F:21])[CH:4]=2)=[CH:34][N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:32]=1
Reactant: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2N)cc1F
Temperature: 80 °C
Yield: 97.8 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-2-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenoxy)-2-fluoro-N-(methoxymethyl)-N-(pyrimidin-4-yl)benzenesulfonamide (80 mg, 0.1 mmol) in ethanol (4 mL, 70 mmol) was added saturated aqueous ammonium chloride solution (0.4 mL, 6 mmol) and iron (328 mg, 5.87 mmol). The reaction solution was heated at 80° C. for 20 minutes then filtered. Saturated aqueous sodium bicarbonate was added until the pH was 9. The mixture was concentrated in vacuo to remove the ethanol. Water was added and the mixture was extracted three times with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel (hexane to 100% ethyl acetate gradient) to give 61 mg of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[C:16]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][C:20]([O:22][CH3:34])=[O:21])[C:16]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of [1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acetic acid (4.16 g), methyl iodide (0.95 ml), potassium carbonate (2.76 g), and N,N-dimethylformamide (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl [1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acetate (4.21 g, yield 98%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 58–59° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN1C(=O)CCC1.O>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1
Reactant: Cc1nnc2c(Cl)nc(Br)cn12
Reactant: CC(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc2c(NC(C)C)nc(Br)cn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1 (30.00 g; 121.2 mmol), isopropylamine (14.30 g; 242.44 mmol) and hünigbase (17.20 g; 133.33 mmol) are dissolved in 150 ml NMP and are stirred for 2 hours at 80° C. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over MgSO4 and evaporated to dryness.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:9])(=[O:8])[CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32](O)[CH:33]4[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]4)=[CH:28][CH:27]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C(OCC)(=O)C>[C:6]([O:9][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:31][CH:30]=1)[CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (0.0562 ml) was added to an acetic acid solution (3.5 ml) of tert-butyl 3-[[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]phenyl](hydroxy)methyl]-1-piperidinecarboxylate (366 mg, 0.702 mmol) obtained in Example 128, which was stirred under room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, which was washed with potassium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate: methanol=3:1), and powdered with diisopropyl ether, to give the titled compound (210 mg).
Reaction SMILES: [C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH:28]C(=O)C(N)CC2C=CC=CC=2)[C:10]1=[O:40])[C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH2:28])[C:10]1=[O:40])[C:6](=[O:8])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N(N1C(=O)C(NC(=O)C(N)Cc2ccccc2)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(N1C(=O)C(N)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Yield: 92 %

Procedure:
Prepared as above from 1-(N-t-butylacetamido)-3-(2-amino-3-phenylpropionamido)-5,7-diphenylhexahydroazepin-2-one (less polar isomer) as an oil in 92% yield, αD =+3.21° (C=0.8, ethyl acetate). The 1H-NMR spectrum matches that of the racemate.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:37][C@@H:38]([CH2:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)[C:39](O)=[O:40])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[CH2:16][CH2:15][N:14]([C:39](=[O:40])[C@@H:38]([NH2:37])[CH2:42][C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)[CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: O=C(NCC1CCCCC1)C1(Cc2ccc(-c3ccccc3)cc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide (3.98 mmol; 1.7 g) in DMF (20 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (4.63 mmol; 1.26 g), N,N-diisopropyl-N-ethylamine (13.9 mmol; 2.46 mL) and HBTU (6.02 mmol; 2.28 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:13]2[O:17][C:16](=[O:18])[NH:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[NH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.CCOCC>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[O:17][C:16](=[O:18])[NH:15][CH2:14]4)[C:3]([CH3:19])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:22]=[C:21]([CH3:20])[C:29]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CNC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 140 °C

Procedure:
A mixture of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one (17 mg, 0.056 mmol) (racemic mixture of two diastereomers from step 3) 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.067 mmol), cesium carbonate (27 mg, 0.084 mmol) and potassium iodide (0.93 mg, 0.0056 mmol) in N,N-dimethylformamide (0.18 mL) was heated at 140° C. for 1 hour. The mixture was diluted with ether, washed with water, concentrated and purified by preparative LCMS (pH 10) to give the desired compound as a racemic mixture of two diastereomers, 2.2 mg, 9%; LCMS calculated for C19H22ClN6O3 (M+H)+: m/z=417.1; found: 417.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[C:12](O)([CH3:19])[CH2:13][CH2:14][C:15]=3[C:16]([Br:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2=[CH:17][C:16]([Br:18])=[C:15]3[C:11]([C:12]([CH3:19])=[CH:13][CH2:14]3)=[C:10]2[CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(Br)c3c(c2CC1)C(C)(O)CC3
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2cc(Br)c3c(c2CC1)C(C)=CC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
Into a glass vial, the product from step (a) (0.45 mmol) dissolved in 4N HO/dioxane (2 ml) was placed. The reaction mixture was stirred at 60° C. for 1 h. The mixture was cooled to room temperature and the solvent was evaporated in vacuo to give the crude product as a brown solid. The residue was purified by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexane) to give the sub-titled compound as a white solid (80 mg). MS: ESI (positive): 350, 352 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:2]1=2.[S:15]1[C:19]([NH2:20])=[N:18][CH:17]=[N:16]1.C1COCC1.[OH-].[Na+]>Cl>[S:15]1[C:19]([NH:20][S:11]([C:9]2[CH:8]=[CH:7][C:3]3[NH:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)(=[O:13])=[O:12])=[N:18][CH:17]=[N:16]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2
Reactant: Nc1ncns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A vial was charged with 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (from HangZhou Trylead Chemical, Hangzhou, China) (74.42 mg, 0.318 mmol), 1,2,4-thiadiazol-5-amine (70.9 mg, 0.701 mmol), and THF (1991 μL) to give a cloudy solution. The vial was cooled in an ice-bath for 5 min, then sodium hydroxide (6N aq.) (117 μL, 0.701 mmol) was added dropwise. After 45 min, the mixture was allowed to warm to room temperature with the bath. The mixture was diluted with 1N aq. HCl and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (4% MeOH/DCM). Several mixed fractions at the tail end of the elution were discarded, and the remainder that contained product were combined and concentrated to give N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (33.19 mg, 0.111 mmol) as a white foam. m/z (ESI) 299.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[C:4]1([C:3]2[CH2:13][CH:12]([C:11]([O:15][CH3:16])=[O:14])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccccc2)=NO1
Reaction time: 22 h
Yield: 73.2 %

Procedure:
A solution of N-hydroxybenzimidoyl chloride (0.500 g; 3.21 mmol) in ethyl acetate (4 mL) was added dropwise to the mixture of methyl acrylate (0.58 mL; 6.43 mmol), sodium bicarbonate (0.818 g; 9.64 mmol), water 0.1 mL and ethyl acetate (16 mL) at room temperature and the resulting mixture was stirred for 22 hours. The solid was eliminated by filtration and washed with ethyl acetate. The filtrate was evaporated and the residue purified by flash chromatography on silica gel (eluent: 15 to 100% dichloromethane in heptane) to afford 0.482 g (73%) of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH:4]([OH:17])[C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[CH:7][C:6]=1[O:15][CH3:16].[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:2]([NH:1][CH2:23][C:24]([CH3:28])([CH3:27])[CH3:25])=[C:3]([CH:18]=1)[CH:4]([OH:17])[C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([O:13][CH3:14])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(OC)c(C(O)c2cc(Cl)ccc2N)c(OC)c1
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(OC)c(C(O)c2cc(Cl)ccc2NCC(C)(C)C)c(OC)c1
Reaction time: 8 h

Procedure:
After a solution of 2.5 g of 2-amino-5-chloro-α-(2,4,6-trimethoxyphenyl)benzyl alcohol, 1.01 ml of trimethylacetaldehyde and 0.56 g of acetic acid in 30 ml of ethanol was stirred at room temperature for 1.5 hours, 0.81 g of sodium cyanoborohydride was added, followed by stirring overnight. After concentration and subsequent dilution with water, the solution was extracted with ethyl acetate. After solvent removal, the residue was subjected to silica gel column chromatography to yield 2.2 g of a crystal.
Reaction SMILES: [Mg].BrCCBr.C(Cl)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.[CH3:21][C:22]([CH3:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([C:22]([OH:23])([CH3:24])[CH3:21])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: CC(C)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(O)C(C(=O)O)c1ccc(F)cc1
Yield: 109.6 %

Procedure:
24.3 g (1.00 mol) of magnesium shavings were suspended in 50 ml of tetrahydrofuran under argon and while stirring in a 1.5 l four-necked sulphonation flask fitted with a reflux condenser, mechanical stirrer, 500 ml dropping funnel, thermometer and a device for inert gasification. After the dropwise addition of 0.5 ml of 1,2-dibromoethane, a solution of 86.4 g (1.10 mol) of isopropyl chloride in 225 ml of tetrahydrofuran was added dropwise within 90 minutes, with the reaction temperature being held at about 30°. The resulting dark grey suspension was stirred at RT for a further 18 hours. Then, a solution of 73.0 g (0.473 mol) of p-fluorophenylacetic acid in 150 ml of tetrahydrofuran was added dropwise to the mixture within 90 minutes while maintaining the temperature at about 25° and thereafter the suspension was heated to 35-40° and stirred at this temperature for a further 1 hour. After cooling 30.0 g (0.516 mol) of acetone were added dropwise at about 25° within 30 minutes and subsequently the mixture was stirred at 35-40° for a further 1 hour. The reaction mixture was treated with 350 ml of 14.2% sulphuric acid while cooling with an ice bath at <30°. The aqueous phase was separated, extracted with 200 ml of tetrahydrofuran and the organic phases were combined and evaporated at 50° on a rotary evaporator. 110 g of crude 2-(p-fluorophenyl)-3-hydroxy-3-methylbutyric acid were obtained as a dark viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH2:22]4)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH:12]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:16][CH2:15]2)[CH2:22]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Clc1ccc2c(C3=CCN(CCCCC4CNc5ccccc54)CC3)c[nH]c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(CCCCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Temperature: 5 °C
Yield: 49.9 %

Procedure:
A mixture of 6-chloro-3-[1-[4-(2,3-dihydro-1H-indol-3-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 30b (4.9 g), triethylamine (3.7 g), and THF (200 ml) was cooled (5° C.), and the mixture was added a solution of acetyl chloride (1.0 g) in THF (50 ml). The reaction mixture was allowed to warm to room temperature, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-ethanol-triethylamine (90:10:5) to give the crude product, which was recrystallized (methanol-ethyl acetate) to give the title compound (2.7 g).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:15]([S:17]C)=S)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1.C>C(O)C>[CH3:1][NH:2][C:15]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1)=[S:17]
Reactant: CN
Reactant: CSC(=S)C1(c2ccccn2)CCCCS1
Solvent: CCO
Product: CNC(=S)C1(c2ccccn2)CCCCS1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (7.5 cc) is added dropwise and in the course of 15 minutes to a solution of methyl 2-(pyrid-2-yl)-tetrahydrothiopyran-2-carbodithioate (9 g) in ethanol (60 cc), kept at a temperature of about 20° C. The solution is then stirred for 16 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (7.8 g) is thus obtained, which is redissolved in boiling ethanol (96 cc); decolourising charcoal (0.4 g) is added to the solution thus obtained, which is filtered hot, and the filtrate is then cooled for 30 minutes at 0° C. The resulting crystals are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N-Methyl-2-(pyrid-2-yl)-tetrahydrothiopyran-2-carbothioamide (6.3 g), melting at 153° C., is thus obtained.