Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:12][S:11][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([S:9][CH2:10]1)[O:7][CH2:6]2)[CH2:2][CH2:3]C.C(C12CSC(CCCCC#C)(SC1)OC2)(C)(C)C.C(C12CSC(CCCCC#C)(SC1)OC2)C(C)C.C(C12SCC(C3C=CC=CC=3)(CS1)CO2)CCCC#C.C1(CC23CSC(CCCCC#C)(SC2)OC3)CC1.C(C(CO)(CS)CS)CCC.C(C(CO)(CS)CS)(C)(C)C.C(C(CO)(CS)CS)C(C)C.OC(C1C=CC=CC=1)(CS)C(C)S.C1(CC(CO)(CS)CS)CC1>>[CH2:13]([C:8]12[S:9][CH2:10][C:5]([CH2:1][CH2:2][CH3:3])([CH2:12][S:11]1)[CH2:6][O:7]2)[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]
Reactant: C#CCCCCC12OCC(CCCC)(CS1)CS2
Agent: C#CCCCCC12OCC(C(C)(C)C)(CS1)CS2
Agent: C#CCCCCC12OCC(CC(C)C)(CS1)CS2
Agent: C#CCCCCC12OCC(CC3CC3)(CS1)CS2
Product: C#CCCCCC12OCC(CCC)(CS1)CS2

Procedure:
In an analogous manner 4-n-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 4-t-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 4-i-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 1-(hex-5-ynyl)-4-phenyl-2-oxa-6,7-dithiabicyclo[2.2.2]octane and 4-cyclopropylmethyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane were prepared from trimethyl orthohept-6-ynoate and 2-n-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-t-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-i-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-hydroxy-methyl-2-phenylpropan-1,3-dithiol and 2-cyclopropylmethyl-2-hydroxymethylpropan-1,3-dithiol respectively.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:12]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 33.93 g of ethyl glycolate, 62.7 g of t-butyldimethylchlorosilane and 58.5 g of imidazole in 150 ml of dimethylformamide is stirred at room temperature for 15 h. The mixture is diluted with ether and washed with water (2×100 ml), brine, dried (MgSO4) and evaporated. The residue is distilled to give ethyl t-butyldimethylsilyloxyacetate, b.p. 100°-105° C. (14 mm/Hg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24](=[O:34])[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=4[F:33])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:40](N(C)C)[N:41](C)C)(C)(C)C.Cl.NO.C([O-])(=O)C.[Na+]>C1COCC1>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[O:34][N:41]=[CH:40][C:25]=4[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=4[F:33])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CCC(NCc4ccccc4)CC3)cc12
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Product: Fc1cccc(-c2cnoc2-c2c[nH]c3ncc(C4=CCC(NCc5ccccc5)CC4)cc23)c1F
Temperature: 60 °C
Yield: 38.4 %

Procedure:
A mixture of 1-[5-(4-benzylamino-cyclohexyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-(2,3-difluoro-phenyl)-ethanone (150 mg, 0.27 mmol. Preparation: see below) and t-butoxybis(dimethylamino)methane (0.27 ml, 1.0 mmol, Brederck's reagent) in THF (5 ml) was heated at 60° C. for 2 h. The reaction mixture was concentrated and dried under high vacuum for 0.5 h. The residue was dissolved in Ethanol (10 ml), refluxed with hydroxylamine hydrogen chloride (94 mg, 1.35 mmol) and sodium acetate (1.62 mmol) for 2.5 h. The mixture was concentrated and suspended in satd. NaHCO3 and filtered. The solid was further purified by chromatography to give 50 mg of the desired product in 38.4% yield.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16]1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH2:25]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:15]([NH2:14])[CH2:16]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of (1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (481 mg, 1.42 mmol) in dichloromethane (6 mL), stirred for 30 minutes at ambient temperature, and concentrated. A solution of the resulting oil in methanol (10 mL) was treated with potassium carbonate (393 mg, 2.84 mmol), stirred for an hour at room temperature, and concentrated to afford the title compound as yellow residue. MS (DCI/NH3) m/z: 239.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(F)cc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,4-difluoroaniline (50 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.53 (1H, s), 8.99 (2H, s), 8.68 (1H, m), 7.54 (1H, m), 7.40 (1H, m), 7.12 (1H, m). MS m/z: 460.05, 462.03 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(C(F)(F)F)=O)=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2[N+](=O)[O-])CC1
Temperature: 50 °C

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine in methanol (150 mL) and water (150 mL) was added K2CO3 (6.0 g) and the reaction was heated to 50° C. for overnight. The reaction was extracted with ethyl acetate. The extract was dried, concentrated and purified on silica gel column (ethyl acetate/hexane) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitrobenzenamine (11.0 g).
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[C:5]([Br:3])(=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=S(Br)Br
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)Br
Temperature: 50 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 7.75 ml (100 mmol) of thionyl bromide, and a water condenser, is placed 12.82 g (50 mmol) of palmitic acid. Addition of the thionyl bromide is completed with heating to about 50° C. over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, palmitoyl bromide. This acyl bromide, 16.02 g (50 mmol), is put into a dry separatory funnel and combined with 75 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[O:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.31 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.18 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34](OC)=[O:35])[CH:30]=3)[CH2:25]2)=[O:23])([CH3:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:34]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:22]([C:18]1([CH3:21])[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]1)=[O:23])[CH2:33][CH2:32]2)=[O:35]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCc3cc(C(=O)NO)ccc3C2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1.95 mL, 3.31 mmol) was added to a solution of methyl 2-{[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (138 mg, 0.331 mmol) in methanol (0.5 mL) and DMF (0.5 mL). After stirring for 3 h at rt, excess reagent was quenched by the addition of acetic acid (0.188 mL, 3.31 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford tert-butyl 4-{[6-(hydroxycarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-4-methylpiperidine-1-carboxylate (103 mg, 74.5%). LC-MS: (FA) ES+ 418; 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 9.00 (s, 1H), 7.59-7.52 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 4.71 (s, 2H), 3.79 (t, J=5.8 Hz, 2H), 3.53-3.44 (m, 2H), 3.15-3.03 (m, 2H), 2.83 (t, J=5.4 Hz, 2H), 2.06-1.96 (m, 2H), 1.47-1.39 (m, 2H), 1.37 (s, 9H), 1.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:31][C@H:30]([C:29]([O:28][CH3:27])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:10]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Chloro-4′-nitrobiphenyl-4-carboxylic acid (0.31 g, 1.12 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.15 mL, 1.7 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.22 g, 1.3 mmol), methylene chloride (10 mL), and triethylamine (0.62 mL, 4.5 mmol). The resulting solution was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in EtOAc, passed through a plug of silica gel, and concentrated under reduced pressure. This yielded 0.305 g (70%) of the title compound. LC/MS m/z 390.9 (MH+), retention time 3.30 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 3.80 (s, 3H), 4.71-4.78 (m, 1H), 6.33 (d, 1H), 6.76 (d, 2H), 7.58-7.80 (m, 5H), 8.35 (d, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH2:30][OH:31])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=[O:31])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
Dimethyl sulfoxide (2.75 ml) is added to a solution of oxalyl chloride (1.7 ml) in methylene chloride (45 ml) at -78° under nitrogen via cannula over six minutes. After 20 minutes, (±) 1-benzyloxycarbonyl-2-hydroxymethylindoline (IV, EXAMPLE 4, 5.003 g) in methylene chloride (20 ml) is added via cannula over 12 minutes. The mixture is stirred for 30 minutes, then triethyl amine (7.40 ml) is added. The mixture is stirred at -78° for an additional 20 minutes then stirred at 20°-25° for one hour, then poured into water (50 ml) and the layers are separated. The aqueous layer is extracted with methylene chloride (5×20 ml). The combined organic layers are washed sequentially with saline, hydrochloric acid (3N, 100 ml), water (100 ml), aqueous sodium carbonate (5%, 100 ml) and again with water (100 ml). The organic layer is then dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil is passed over a silica column (27.5 cm×4.0 cm, 40-63 mm) and is eluted with ethyl acetate/hexane (1/5.6 300 ml, 1/42 l), collecting 29 ml fractions. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, 300 MHz) 9.62, 7.93, 7.34, 7.20, 7.11, 6.97, 5.23, 4.82, 3.36 and 3.13 δ; CMR (CDCl3, 75.47 MHz) 29.74, 65.76, 67.57, 115.05, 123.34, 124.64, 128.08, 128.20, 128.40, 128.61, 135.57, 141.7, 151.9 and 198.73 δ; IR (CHCl3) 2940, 1700, 1600, 1480, 1400, 1320, 1270-1190 and 1030 cm-1 ; MS (m/e) 281, 252, 208, 117, 91 and 65 , exact mass calcd for C17H15NO3 (281.1052), found 281.1066; TLC (ethyl acetate/hexane, 1/3) Rf =0.28.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:27])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8])C.[OH-].[Na+]>C1COCC1.CO>[Cl:20][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=1)[S:11][C:10](=[O:27])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])=[C:18]2[OH:19]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
[(6-Chloro-4-hydroxy-2-oxo-8-phenyl-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (200 mg, 0.479 mmol) was dissolved in THF-Methanol (1:1; 13 mL total volume.) Sodium hydroxide (1.5 mmol, 1.5 mL; 1M) was added and the solution stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (10 mL.) The crude product was precipitated with 1N HCl (3 mL) and isolated via filtration and triturated with hexanes to provide the title compound (177 mg.) MS ESI(+) m/e: 390.118, 392.226 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)[CH:10]=2)=[O:6].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:21][CH:20]=[CH:19][N:18]=1)[CH:10]=2)=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.17 g. of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester (0.90 g.) in dry N,N-dimethylformamide (50 ml.) and the mixture was stirred at room temperature for 1 hour. Benzyl bromide (0.61 g.) was added and the resulting mixture was stirred for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 1-benzyl-6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester, m.p. 120°-122° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.C1(N)CC1>O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:23]1[CH2:25][CH2:24]1)=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(I)cccc1C(=O)O
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(I)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added and stirred at r.t. for 7 min. Cyclopropylamine (52.69 μL, 0.76 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24].Cl>CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:23]([NH2:24])=[CH:22][C:21]([C:20]([CH3:27])([CH3:26])[CH3:19])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Yield: 21.4 %

Procedure:
A yellow solution of Intermediate 16a (1.80 g, 7.22 mmol), 4,4-dimethyl-3-oxopentanenitrile (1.08 g, 8.66 mmol), and HCl (4M in dioxane, 2.70 mL, 10.8 mmol) in EtOH (25 mL) was stirred at reflux for 4 h. The cooled solution was applied to an SCX-2 cartridge (50 g), washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (100 mL); concentration in vacuo left a yellow oil (772 mg). FCC, using 0-5% MeOH in DCM, gave the title compound as a yellow gum (550 mg, 21%). LCMS (Method 3): Rt 2.88 min, m/z 357 [MH+].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][N:21]([CH3:39])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])=[O:23]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:39][N:21]([CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:35]([F:36])([F:38])[F:37])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])=[O:23]
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C(=O)N(C)C)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (214 mg) and 37% formalin (0.14 mL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.47 mL) and 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16](F)[CH:17]=[C:18]([I:23])[CH:19]=2)[N:14]([N:25]([CH2:27][CH:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:26])[CH:13]=1)=[O:11])[CH3:8]>CS(C)=O.O.C(O)(=O)C>[I:23][C:18]1[CH:17]=[C:16]2[C:15]3=[C:20]([C:21](=[O:22])[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]3[N:25]([CH3:26])[CH2:27][C:28]2([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]=1
Reactant: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)CN2C
Temperature: 85 °C
Yield: 75 %

Procedure:
Cesium carbonate (0.367 g) is added to a solution of di(tert-butyl) 2-(((3-(ethoxycarbonyl)-8-fluoro-6-iodo-4-oxoquinolin-1(4H)-yl)(methyl)amino)methyl)malonate (Preparation 37, 0.517 g) in dimethylsulfoxide (5 mL) and the mixture is heated at 85° C. in an oil bath under a nitrogen atmosphere for 2 h. The mixture is cooled in an ice bath, diluted with 65 mL of water containing 2.5 mL of acetic acid, stirred, and the resultant yellow precipitate collected and dried in a vacuum oven to provide the title compound in 75% yield as a golden oil. Physical characteristics: 1H NMR (CDCl3) δ8.79, 8.54, 8.29, 4.40, 4.16, 2.78, 1.51, 1.41; MS (ESI+) m/z 599 (M+H)+; TLC (silica gel GF): Rf=0.59 acetone/CH2Cl2 (1/4).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CC(CS)C(=O)O
Reactant: C1=COCCC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(CSC1CCCCO1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-mercapto-2-methylpropanoic acid (2.4 g.) and freshly distilled 2,3-dihydro-4H-pyrane (1.9 g.) in benzene (60 ml.), boron trifluoride etherate (2.8 g.) is added. After two hours, potassium carbonate (4 g.) is added, the mixture is stirred and filtered. The filtrate is concentrated to dryness to yield 3-(tetrahydropyran-2-ylthio)-2-methylpropanoic acid.