Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[O:22])[CH2:17][CH2:16]3)=[N:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[O:22])[CH2:19][CH2:20]3)=[N:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 37 %

Procedure:
To a solution of 1.50 g (3.11 mmol) of 4-(7-methoxycarbonyl-4-quinazolinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide obtained in Example 323 in 20 ml of methanol was added 20 ml of a 1 N aqueous solution of sodium hydroxide, followed by heating at 50° C. with stirring for 3.5 hours. After the mixture was made acidic with concentrated hydrochloric acid, the precipitated crystals were collected by filtration, washed with ethanol and then with chloroform, and recrystallized from methanol to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]#[N:9])[CH3:2]
Reactant: CCOc1cc(C(N)=O)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOc1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 3-ethoxy-4-methoxybenzamide (3.30 g) in pyridine (33 mL) was added phosphorus oxychloride (1.73 mL) under ice-water cooling, and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water under ice-water cooling. The separated organic layer was washed with 1N-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to 4:1) to give 3-ethoxy-4-methoxybenzonitrile as colorless powders (2.83 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:28])([O:6][C:7]([CH2:9][C:10]1([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:8])[CH3:5].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][C:7]([O:6][C:4]([CH3:28])([CH3:3])[CH3:5])=[O:8])([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a suspension of 0.05 g of sodium hydride (60%) in 5 ml of N,N-dimethylformamide was added dropwise a solution of 0.36 g of 3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one in 5 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After stirring the mixture at that temperature for 30 minutes, 0.12 ml of benzyl bromide was added thereto. The whole mixture was stirred for 1 hour and then concentrated. Chloroform was added to the concentrate, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 1-benzyl-3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])O.[Na+].C(O)C>O>[OH:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CNc1cc(O)ccc1[N+](=O)[O-]
Yield: 98 %

Procedure:
3-fluoro-4-nitrophenol 50 g (0.138 mole), glycine 48 g (0.637 mole) and sodium hydrogen carbonate 107 g (1.27 mole) were added to a mixture of ethanol 600 ml and water 100 ml and refluxed for 5 days. The solvent was distilled off in vacuo. The reaction mixture was acidified by adding dilute HCl and filtered. The filtrate was washed with dilute HCl and water, then dried in vacuo to obtain N-(5-hydroxy-2-nitrophenyl)-amino acetic acid as a yellow solid. Yield: 66.4 g (yield: 98%)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[NH:14][C:15](=[O:28])[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=4)[C:7]=3[C:6]=2[CH:5]=1.[C:29](Br)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([N:14]1[C:8]2[CH:9]=[N:10][C:11]3[CH:12]=[CH:13][C:4]([Cl:3])=[CH:5][C:6]=3[C:7]=2[N:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:27])[C:24]#[N:25])=[CH:19][CH:18]=2)[C:15]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Br)c1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)c3ccccc3)c3cnc4ccc(Cl)cc4c32)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (22 mg, 0.557 mmol) was added to dry DMF (5 mL) in a nitrogen atmosphere. The reaction flask was cooled in an ice-bath to 0° C., and 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 100 mg, 0.27 mmol) was added. After 15 minutes benzoyl bromide (61 mg, 0.33 mmol) was added, and the reaction mixture was heated at 50° C. for 24 hours. The reaction mixture was concentrated in vacuum. The crude product was purified by column chromatography (silica gel, 2.5% acetone in chloroform) to obtain the title compound. Yield: 30 mg (23%); 1H NMR (DMSO-d6, 300 MHz): δ 9.372 (s, 1H), 8.048-8.078 (d, 1H, J=9 Hz), 7.905-7.929 (d, 2H, J=7.2 Hz), 7.810-7.839 (d, 2H, J=8.7 Hz), 7.730-7.759 (d, 2H, J=8.7 Hz), 7.611-7.666 (m, 2H), 7.449-7.523 (m, 2H), 6.698-6.705 (d, 1H, J=2.1 Hz), 1.752 (s, 6H); MS: m/z 467 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[C:15]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:19][O:20][C:21]=3[CH3:22])[N:16]=[C:10]2[CH:9]=1)(C)(C)C>Cl>[CH3:22][C:21]1[O:20][N:19]=[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]=1[C:15]1[N:16]=[C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]2[CH:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)OC(C)(C)C)cc2n1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
A mixture of [2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-yl]-carbamic acid tert-butyl ester (1.0 g, 2.56 mmol) in hydrochloric acid (4 M in dioxane, 29 mL) was stirred at room temperature for 6 h. The precipitate was then filtered off and dissolved in a dilute solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was then washed with brine and then dried over sodium sulphate and evaporated to leave a brown foam. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 25:75) afforded the title compound (477 mg, 64%) which was obtained as a light brown foam. MS: m/e=291.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(O)[CH:9]2[S:14][CH2:13][S:12][CH2:11][S:10]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1CCCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:8](=[C:9]2[S:10][CH2:11][S:12][CH2:13][S:14]2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1SCSCS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: Fc1ccc(C(=C2SCSCS2)c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
A mixture of 2.0 g of 2-{bis(4-fluorophenyl)hydroxymetyl}-1,3,5-trithiane, 0.2 g of p-toluenesulfonic acid and 50 ml of benzene was refluxed with heating for 15 minutes by means of a Dean-Stark reflux condenser. After being cooled, the mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium hydrogencarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to obtain a material, which was recrysallized from cyclohexane to give 1.7 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]\[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: C#Cc1cccnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2cccnc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (113 mg, 0.50 mmol; Example 2B) and 3-ethynylpyridine (0.206 g, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as one of two isomers: 1H NMR (300 MHz, methanol-d4) δ ppm 1.62-1.76 (m, 2H), 1.81-1.96 (m, 2H), 2.38 (s, 3H), 2.92-3.08 (m, 3H), 3.09-3.22 (m, 2H), 4.21 (s, 2H), 6.75 (d, J=8 Hz, 1H), 6.84-7.03 (m, 3H), 7.14-7.30 (m, 3H), 8.02 (d, J=2 Hz, 1H), 8.26 (dd, J=5, 2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]([C:10]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCCCCCBr
Reactant: O=C(Cc1ccccc1)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CCCCCCCOc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 20 °C

Procedure:
A mixture of 40.1 parts of 2,5-dihydroxyphenyl benzyl ketone, 42.7 parts of isodecylbromide, 48.5 parts of potassium carbonate and 400 parts of dry acetone was stirred under reflux for 120 hours. On cooling to 20° C the inorganic salts were filtered off and the acetone filtrates evaporated to give a brown oil. This residue was dissolved in 200 parts of petroleum ether, filtered to remove insoluble matter, and then washed with 4 × 50 parts of N sodium hydroxide solution and finally with water. The petrol solution was dried and evaporated to yield 42.4 parts of 2-hydroxy-5-isodecyloxyphenyl benzyl ketone as a brown oil.
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[F:6][C:7]([F:13])([F:12])[S:8]([OH:11])(=[O:10])=[O:9].Cl>>[F:6][C:7]([F:13])([F:12])[S:8]([O:11][Si:2]([O:11][S:8]([C:7]([F:13])([F:12])[F:6])(=[O:10])=[O:9])([CH3:4])[CH3:3])(=[O:10])=[O:9]
Reactant: C[Si](C)(Cl)Cl
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cl
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Yield: 60.1 %

Procedure:
An oven-dried 100 mL-RB flask is charged with dichlorodimethylsilane (6.45 g, 0.05 mol). Then trifluoromethanesulfonic acid (15 g, 0.10 mol) is added dropwise. The mixture is heated at 60° C. until no HCl evolves. The residue is distilled to yield 10.7 g (60%) of the product as a clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 0.88 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Na+].[Cl-]>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:21]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:26][CH2:27][CH2:28]1)=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.9 ml triethylamine was added to the mixture of 2.79 g of 1-((S)—N-(1-(ethoxycarbonyl)-3-phenylpropyl)-L-alanine and 1.15 g of L-proline in 100 ml of acetonitrile and 5 ml DMF and during stirring 3.8 g O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate was added. The reaction mixture was stirred for further 30 minutes at room temperature. 300 ml of saturated NaCl solution was added and the mixture was extracted twice with 100 ml of ethyl acetate. Combined extracts were washed with 70 ml of water/1 ml of conc. HCl mixture and then with 130 ml of water, dried with Na2SO4 and evaporated at 40° C. in vacuum. 3.55 g of enalapril was obtained.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12].C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH:46]1[CH2:56][CH2:55][CH2:54][CH:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:52]([O:51][C:49]([C@@H:48]1[CH2:54][CH2:55][CH2:56][N:46]([CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[CH3:12])[C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])[CH2:47]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccsc1C(=COCCO)c1sccc1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2sccc2C)c2sccc2C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
The above alcohol (0.53 g, 0.0019 mol) was dissolved in dry toluene (20 ml) and the solution was cooled to 0° C. A solution of n-butyllithium (2.5 M in hexane) (0.9 ml, 0.0023 mol) was introduced, and the reaction mixture was allowed to stand at 0° C. for 1 h after which time a solution of p-toluenesulphonyl chloride (0.47 g, 0.0025 mol) in toluene (10 ml) was added. The mixture was left at room temperature for 20 h and to the resulting tosylate solution was added the (R)-enantiomer of ethyl nipecotate (0.59 g, 0.0038 mol) and powdered, dried potassium carbonate (1.04 g, 0.0075 mol). The temperature was increased to 80° C. and maintained for 50 h. The reaction mixture was cooled and water (50 ml) was added. The toluene phase was separated and the water phase was extracted with ethyl acetate (50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give an oil, which was purified by flash chromatography on silica gel. Elution with cyclohexane/ethyl acetate (19/1-5/1) provided the title compound (0.25 g, 31%) as a gum. TLC: rf 0.26 (Si02; heptane/THF 7/3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Cl[C:20](OCC)=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:20](=[O:21])[O:14][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]23)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Product: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1

Procedure:
A suspension of 40 g of 2-(4-methoxyphenylamino)benzoic acid in 200 ml of ethyl chloroformate was heated at reflux for 24 hours. The reaction mixture was cooled in an ice-bath and the solid which separated was collected by filtration to give 31 g of N-(4-methoxyphenyl)isatoic anhydride after 6 hours of drying in a vacuum oven. An additional 9 g of product was obtained by concentration of the filtrate in vacuo.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]([C:10]1[N:11]2[CH:17]=[N:16][CH:15]=[C:12]2[S:13][CH:14]=1)=O.[NH2:18][CH2:19][CH2:20][OH:21].C#N.[B].[Na]>CO>[OH:21][CH2:20][CH2:19][NH:18][CH2:8][C:10]1[N:11]2[CH:17]=[N:16][CH:15]=[C:12]2[S:13][CH:14]=1
Reactant: O=Cc1csc2cncn12
Reactant: NCCO
Agent: C#N
Agent: Cl
Agent: [B]
Solvent: CO
Solvent: C1COCCO1
Product: OCCNCc1csc2cncn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.25 ml potion of a 4N hydrochloric acid/dioxane solution and 76 mg of 3-formylimidazo[5,1-b]thiazole were added to 2 ml of a methanol solution containing 0.181 ml of 2-aminoethanol, and the mixture was stirred at room temperature for 30 minutes. Then, 42 mg of sodium boron cyanohydride was added thereto, and the mixture was then stirred at room temperature for 3 hours. Afterward, 0.25 ml of a 4N hydrochloric acid/dioxane solution was added thereto, followed by stirring at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and to the resulting residue, an aqueous anhydrous potassium carbonate solution was then added so as to adjust the solution to pH 10.8. Afterward, the mixture was extracted three times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by Cephadex LH-20 to obtain 61 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Na+]>C1COCC1>[OH:19][CH2:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:20])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Mix 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (1.0 g, 3.6 mmol), 1 N NaOH (25 mL) in THF (5 mL). Stir at room temperature overnight. Wash with diethyl ether (2×20 mL). Acidify the aqueous layer with 5 N HCl to about pH=2. Extract with ethyl acetate (2×20 mL), concentrate and purify (silica gel chromatography eluting with 1% acetic acid in ethyl acetate and hexanes) to give the title compound (0.80 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=O)[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>ClCCl.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:38][CH:37]=3)=[O:15])[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a suspension of 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylic acid (7.7 g, 27 mmol) in dichloromethane (60 ml) was added oxalyl chloride (5.1 ml, 59 mmol). The mixture was stirred at room temperature for 2.0 h, after which time the solvent was removed on a rotary evaporator. To this brown residue was added 4-(methanesulfonyl)aniline hydrochloride (5.8 g, 28 mmol), tetrahydrofuran (THF) (80 ml) and diisopropylethylamine (DIEA) (14 ml, 80 mmol). The solution was stirred at room temperature for 2.0 h. The reaction mixture was concentrated and to the residue was added 2N HCl (80 ml) and water (80 ml) and resulting suspension was stirred for 30 min. The solid was filtered and washed with water and diisopropyl ether (IPE) to give the title compound as a white solid (11 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15](C(OC(C)(C)C)=O)[N:14]=1)(C)C>CCO>[C:12]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1)#[CH:11]
Reactant: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Potassium carbonate (880 mg, 6.4 mmol, 0.1 eq.) was added into a solution of tert-butyl 3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate (20 g; 63.6 mmol; 1.0 eq.) in EtOH (400 mL) and the reaction mixture was stirred overnight at RT. Solvent was removed under vacuum while maintaining bath temperature below 25° C. The residue was dissolved in Et2O, washed with water (twice) and brine (four times). Organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound as a brown solid (7.1 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ: 13.44 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.59 (d; J=8.5 Hz, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.50 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH:9]2[CH2:13][C:12]3[C:14]([O:35][CH3:36])=[C:15]([C:23](=[O:34])[CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:16]([O:20][CH2:21][CH3:22])=[C:17]([O:18][CH3:19])[C:11]=3[O:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>N1C=CC=CC=1>[N:3]1([CH:9]2[CH2:13][C:12]3[C:14]([O:35][CH3:36])=[C:15]([CH:23]([OH:34])[CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:16]([O:20][CH2:21][CH3:22])=[C:17]([O:18][CH3:19])[C:11]=3[O:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOc1c(OC)c2c(c(OC)c1C(=O)C=Cc1ccc(OC)cc1)CC(N1CCCCC1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOc1c(OC)c2c(c(OC)c1C(O)CCc1ccc(OC)cc1)CC(N1CCCCC1)O2
Yield: 75 %

Procedure:
65.2g of pyridine, 2ml of concentrated soda and then 31.3g of powdered sodium borohydride is added to a solution in 500ml of 96° alcohol of 77g of piperidino-6-ethoxy-5-p-methoxycinnamoyl-4,7-dimethoxy-2,3-dihydrobenzofuran obtained in the preceding stage, over a period of 10 to 15 minutes. The mixture is refluxed for 7 hours, the solvents removed, the residue is dissolved in water extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated to dryness. The crude product obtained is recrystallised from 96° alcohol.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:33][C:31]([F:32])([F:34])[O:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(OCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.3 %

Procedure:
Trifluoroacetic acid (40 ml) was added to a dichloromethane solution (40 ml) of 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (18.6 g), and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and ice water was added to the resulting residue. The result was treated with 6 N sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was concentrated to dryness under reduced pressure to afford the title compound as a white powder (14 g).