Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[NH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=1[C:14]#[N:15].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:12]1[C:13]([C:14]#[N:15])=[C:9]([C:5]2[S:4][CH:8]=[CH:7][CH:6]=2)[NH:10][C:11]=1[C:16]([F:19])([F:17])[F:18]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1cccs1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2cccs2)[nH]c(C(F)(F)F)c1Cl
Reaction time: 0.25 h
Yield: 15 %

Procedure:
Sodium hypochlorite (12 mL of a 5.25% solution, 17 mmol) is added dropwise to a solution of 2-(2-thienyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.00 g, 8.26 mmol) in tetrahydrofuran. The reaction mixture is stirred for 2 hours and 15 minutes, quenched with a 1% sodium bisulfite solution and diluted with ether. The layers are separated and the organic layer is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a yellow solid. Flash chromatography of the solid using silica gel and a 15% ethyl acetate in hexane solution gives a solid which is recrystallized from ethyl acetate and hexane to obtain the title product as a yellow solid (0.35 g, 15%, mp 221°-223° C.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][NH:25]C(=O)OC(C)(C)C)[O:21][N:20]=1)(=[O:12])=[O:11]>O1CCOCC1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][NH2:25])[O:21][N:20]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)NCc1nc(C2CCCCN2S(=O)(=O)c2nc3ccccc3[nH]2)no1
Solvent: C1COCCO1
Product: NCc1nc(C2CCCCN2S(=O)(=O)c2nc3ccccc3[nH]2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
tert-Butyl N-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethyl)carbamate (0.88 g) [see Preparation 85] was dissolved in dioxan (20 ml) and cooled to 0° C. Hydrogen chloride gas was then bubbled through for 10 mins. The reaction mixture was then stirred at room temperature for 1 hr. the solvent was then removed under reduced pressure to afford 3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethylamine (0.67 g) as the hydrochloride salt as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35].N1C=CN=C1.C1(C)C=CC=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:38]([CH3:40])([CH3:39])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the diol of Step 3 (36.56 g, 79.8 mmol) in 400 mL of CH2Cl2 was added tert-butyl-chlorodimethylsilane (18.21 g, 121 mmol), imidazole (10.97 g, 161 mmol) and 4-(dimethylamino)pyridine (0.988 g, 8.1 mmol) and the mixture was stirred at r.t. for 3 days. Toluene (400 mL) was then added and the product was filtered through silica with EtOAc:toluene 0:100 to 5:95. The title product was concentrated and stripped with toluene to remove any remaining silyl chloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)(=O)=O)=CC=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][N:30]([CH2:12][CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH3:29])=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN2c3ccccc3COc3ccccc32)cc1
Reactant: CNCCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN(C)CCN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(4-methylphenylsulfonyl)oxyethyl]dibenzo [b,e][1,4]oxazepine (650 mg, 1.65 mmol), N-methyl-4-methoxyphenethylamine (290 mg, 1.76 mmol), sodium carbonate (195 mg, 1.84 mmol) and sodium iodide (25 mg, 0.17 mmol) were added to acetonitrile (20 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with ethyl acetate and hexane (6:1) and then with the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-(4-methoxyphenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (423 mg, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=1)[O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(O)c2occc(=O)c2OCc2ccccc2)cc1
Reactant: C1=COCCC1
Product: CSc1ccc(C(OC2CCCCO2)c2occc(=O)c2OCc2ccccc2)cc1

Procedure:
3-Benzyoxy-2-[(4-methylthiophenyl)-(tetrahydropyran-2-yoxy)-methyl]-pyran4-one: Reaction of 16.7 g of 3-benzyloxy-2-[hydroxy-(4-methylthio-phenyl)-methyl]-pyran-4-one with 3,4-dihydro-2H-pyran analogously to Example 1b yields crude 3-benzyloxy-2-[(4-methylthio-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-pyran-4-one in the form of a diastereoisomeric mixture. Rf value 0.65 (silica gel 60, hexane/dichloromethanelethyl acetate 1/1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-chlorophenoxy)benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.17 (1H, d, J=2.8 Hz), 7.93 (2H, m), 7.65 (1H, d, J=7.4 Hz), 7.42–7.19 (5H, m), 6.97–6.81 (3H, m), 5.32 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 1.49 (3H, d, J=6.9 Hz).
Reaction SMILES: CC[O-].[Na+].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:18]([O:17][C:15]([C:14](=[CH:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)[CH2:13][C:12]([OH:21])=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)CC(=O)O
Yield: 49 %

Procedure:
Sodium ethylate (41.4 g, 0.61 mol) was added under vigorous stirring to a solution of thiophene-2-carbaldehyde (57 g, 0.51 mol) and diethyl succinate (176 g, 1.01 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 300 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 60 g (0.25 mol, 49%) of 3-(ethoxycarbonyl)-4-thien-2-ylbut-3-enoic acid as a light-brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1
Reactant: c1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2ccnc2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example A.51) (0.5 g, 0.8 mmol) and commercially available imidazole (0.112 g, 1.6 mmol) according to the general procedure IVa. Obtained as a white solid (0.060 g, 24%). MS (ISP) 304.0 [(M+H)+], 306 [(M+2+H)+] and 308 [(M+4+H)+]; mp 227° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Br)[CH:3]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)[CH:3]=1
Reactant: Clc1ccc(Br)cc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cc(Br)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g. 16.7 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.83 g, 12.9 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (200 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The solid residue was treated with water (500 mL). The solid product was recovered by filtration, washed with water (2×50 mL), diethyl ether (3×50 mL), and hexanes (3×50 mL), and then dried in vacuo, affording the title compound (3.23 g, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.00 (s (br), 1H), 7.41 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=2.3 Hz, 8.4 Hz), 7.86 (d, 1H, J=2.0 Hz); M+ 347.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)(Cl)Cl.[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[NH:23][C@@H:22]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[F:18].N1C=CC=CC=1>O>[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[N:23]3[C@@H:22]([C:24]([CH3:25])([CH3:26])[O:27][C:1](=[O:5])[C:2]3=[O:3])[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: CC(C)(O)[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)C(=O)N2[C@H](c3ccc(F)c(F)c3)CC[C@@H]21

Procedure:
Under ice-cooling, oxalyl chloride (713 μL) was added dropwise into a chloroform (70 mL) solution containing 2-[(2R,5S)-5-(3,4-difluorophenyl)pyrrolidine-2-yl]propane-2-ol (1.66 g) and pyridine (10 mL). After stirring for 30 minutes at the same temperature, water was added to the reaction solution, and the organic layer was partitioned. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the resulting solid was washed with a mixture solvent of ether/heptane (1/1), and the title compound (1.3 g) was obtained. The physical property values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([NH:14][S:15]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)(=[O:17])=[O:16])[C:11]([OH:13])=O.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([NH:14][S:15]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)(=[O:16])=[O:17])[C:11]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[O:13]
Reactant: COC(=O)C1CCNCC1
Reactant: O=C(O)C(CCc1ccccc1Cl)NS(=O)(=O)c1cccc2[nH]ccc12
Product: COC(=O)C1CCN(C(=O)C(CCc2ccccc2Cl)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
methyl 1-{4-(2-chlorophenyl)-2-[(1H-indol-4-ylsulfonyl)amino]butanoyl}piperidine-4-carboxylate is prepared from 4-(2-chlorophenyl)-2-[(1H-indol-4-ylsulfonyl)amino]butanoic acid and methyl piperidine-4-carboxylate in same manner Example 106 is synthesized. ESI MS Calc. 517.1; Found: 518.5 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: Oc1ccccn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1COc1ccccn1
Temperature: 80 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
In 4 ml of benzene were suspended 0.095 g (1.0 mmol) of 2-hydroxypyridine and 0.14 g (0.5 mmol) of silver carbonate, N-bromomethylphthalimide [0.29 g (1.2 mmol)] was added at room temperature, and the mixture was stirred at 80° C. for 14 hours under heating. After cooling, the residue was filtered and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/hexane=10:1) to obtain powder. The powder was recrystallized from ethyl acetate to obtain 0.10 g of the desired compound (yield: 39.0%, colorless columns).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][CH:4]([OH:6])[CH3:5].C(C(=CC1C=CC=CC=1)C=O)CCCC.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)=CCCC(C)=CC(C)O
Agent: CC(C)[O-]
Agent: CCCCCC(C=O)=Cc1ccccc1
Agent: [Al+3]
Product: CC(=O)C=C(C)CCC=C(C)C

Procedure:
150 g of 4,8-dimethyl-3,7-nonadien-2-ol, 252.5 g alpha-amylcinnamaldehyde and 16.9 g of aluminum isopropoxide are refluxed for 30 min at 1 mbar. A product/reactant mixture is then distilled over a 15 cm packed column (reflux ratio 1:1). This gives 130 g of the mixture of E- and Z-4,8-dimethyl-3,7-nonadien-2-ol and E- and Z-4,8-dimethyl-3,7-nonadien-2-one . The sum of the two isomers of 4,8-dimethyl-3,7-nonadien-2-ol is 23%, and the sum of the two isomers of 4,8-dimethyl-3,7-nonadien-2-one is 70%.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:28]([O:30]CC)=[O:29].Cl.O1CCCC1>C(O)C>[CH3:22][N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[C:9]([O:23][C:24]([F:26])([F:27])[F:25])[CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:28]([OH:30])=[O:29])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A mixed solution of ethyl 1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (0.75 g), 6N hydrochloric acid (15 mL), tetrahydrofuran (4 mL) and ethanol (16 mL) was stirred at 80° C. for 18 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless solid was dissolved in a mixed solution of tetrahydrofuran (10 mL) and methanol (10 mL). aqueous solution (5 mL) of 85% potassium hydroxide (0.35 g) was added, and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.65 g, yield 100%) as pale-pink crystals. The obtained crystals were washed with ethyl acetate-hexane to give colorless prism crystals. MS:421 (MH+). melting point 245-246° C.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.CC1(C)OB([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[CH:33]=2)OC1(C)C.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH:19]1([O:18][C:3]2[C:2]([C:29]3[CH:30]=[N:31][N:32]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]4)[CH:33]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:17])[N:8]3[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: C[C@H]1CCc2c(ccc(Br)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A 250-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with (2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline (2.0 g, 5.5 mmol), tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (2.5 g, 6.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.45 g, 0.55 mmol), potassium carbonate (2.3 g, 16.64 mmol), 1,4-dioxane (50 mL) and water (5 mL). The resulting mixture stirred overnight at 100° C. The reaction mixture was cooled to room temperature and then filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified via column chromatography on silica gel (gradient elution with 0-30% ethyl acetate-petroleum ether) to afford (S)-tert-butyl 4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.2 g, 75%) as a light yellow solid. MS (ES, m/z): 535 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH:6](Br)[CH3:7].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCCC1>[CH3:7][CH:6]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCCC(C)CCCC(C)Br
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)n1ccnc1
Temperature: 160 °C
Yield: 83 %

Procedure:
52.6 parts by weight of 6,10-dimethylundec-2-yl bromide and 27.2 parts by weight of imidazole are dissolved in 80 parts by weight of tetrahydrofuran and the solution is placed in a 250 ml autoclave and heated for 15 hours at 160° C. The reaction product is then filtered and the solvent is removed from the filtrate at atmospheric pressure. Distillation in vacuo of the residue obtained gives 41.5 parts by weight (83% of theory) of 1-(1,5,9-trimethyldecyl)-imidazole; b.p.: 185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[F:39])=[O:30])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[F:39])=[O:30])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate (100 mg, 0.19 mmol) in 10 ml of MeOH was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for one hour and poured into 100 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid as white solid. Yield: 95 mg, 98%.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[CH3:7][C:8]([CH3:10])=O>Cl.C1CCCCC1>[CH3:7][C:8]1([CH3:10])[S:1][CH:2]([CH2:3][OH:4])[CH2:5][S:6]1
Reactant: CC(C)=O
Reactant: OCC(S)CS
Agent: Cl
Solvent: C1CCCCC1
Product: CC1(C)SCC(CO)S1
Yield: 29.4 %

Procedure:
To a mixture of 10.18 g (0.082 mole) of 2,3-dimercapto-1-propanol, 20 mL of cyclohexane, and 5.0 g (0.086 mole) of acetone was added 4 drops of concentrated hydrochloric acid, and the mixture was stirred at reflux temperature for 3.5 hours to give, after fractional distillation of the reaction mixture, 5.85 g of a colorless oil, bp 96°-106° C./1.2-1.5 mm Hg, which solidified on standing. Recrystallization from toluene-hexane gave 3.96 g of product, mp 45°-50° C.
Reaction SMILES: C[C:2]([CH3:36])([CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[C:3](N)=O.CC#[N:39].O>>[NH2:39][C:2]([CH3:36])([CH3:3])[CH2:6][C@@:7]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])[CH2:9][CH2:8]1
Reactant: CC#N
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)OC1=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)N)(c2ccccc2)OC1=O
Reaction time: 24 h

Procedure:
A foil covered flask charged with 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (20 mg, 0.04 mmol) in 1:1 CH3CN/H2O (1 mL) was treated with PhI(O2CCF3)2 (31 mg, 0.07 mmol). The reaction was complete after 24 h. The solvent was removed and the crude material purified by prep HPLC to afford (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (16 mg). LC/MS ES+=460 (M+1). LC-MS Method 1 tR=1.06 min, m/z=460 (M+1); 1H NMR (CDCl3) 7.60 (dd, 1H, J=9 Hz, 2 Hz), 7.46 (d, 1H, J=3 Hz), 7.39-7.27 (m, 5H), 7.20 (d, 2H, J=7 Hz), 7.1 (d, 2H, J=8 Hz), 6.78 (d, 1H, J=9 Hz, 5.61 (q, 1H, J=7 Hz), 3.65 (s, 3H), 2.87 (m, 1H), 2.80 (d, 1H, J=16 Hz), 2.23 (d, 1H, J=16 Hz), 2.19-2.08 (m, 3H), 1.54 (d, 3H, J=7 Hz), 1.41 (s, 3H), 0.96 (s, 3H).