Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7](CC#N)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7]([CH2:26][C:25]([OH:28])=[O:27])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1nc(Cl)c(CC#N)n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-Butyl-4-chloro-5-(cyanomethyl)-1-(4-nitrobenzyl)imidazole (7.08 g) and a 1:1 mixture of 12N HCl and glacial acetic acid (175 mL) were mixed and refluxed for 6 hours. The solvents were removed by rotary evaporation and water (300 mL) was then added to the residue. After a few minutes, the product precipitated and was collected and dried to give 7.35 g of a solid; m.p. 207.0°-210.0°. NMR (200 MHz, DMSO-d6 /CDCl3) δ 8.20 (d, 2H, J=10 Hz); 7.22 (d, 2H, J=10 Hz); 5.28 (s, 2H); 3.42 (s, 2H); 2.52 (t, 2H, J=7 Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7 Hz). Anal. Calcd. for C16H18ClN3O4 ; C, 54.63; H, 5.16; N, 11.94. Found C, 54.52; H, 5.05; N, 12.21.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1)(=[O:42])=[O:41]
Reactant: Cc1ccc(-c2noc(C3CC(O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CC(OS(C)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a stirring suspension of N-(5-(5-(3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (220 mg, 0.565 mmol) (19) in anhydrous DCM (10 mL) at 0° C. was added DIEA (197 uL, 1.13 mmol) and methanesulfonyl chloride (542 uL, 0.678 mmol). The reaction was stirred to room for 30 minutes. The crude product was purified by silica chromatography to give 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl methanesulfonate (81). MS m/z 468.13 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33]C)=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 57.4 %

Procedure:
To a solution of Methyl (1RS,2RS,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane (2 mL) was added 1 M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 48 h, then concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane containing 5% of acetic acid) to afford the title compound (36 mg, 46%). m.p. 199-200° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]([O:14][C:15]3[N:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].Cl.C(N(CC)CC)C.[N-:39]=[N+:40]=[N-:41].[Na+].C1(C)C=CC=CC=1.[C:50](OCC)(=[O:52])[CH3:51]>>[C:50]([C:7]1([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15]3[C:16]([C:17]4[NH:41][N:40]=[N:39][N:18]=4)=[CH:19][CH:20]=[CH:21][N:22]=3)=[CH:23][CH:24]=2)[CH:25]=[CH:26][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:30])[CH:6]1[CH2:27][CH2:28][CH3:29])(=[O:52])[CH3:51]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(C)=O
Reactant: CCCc1c(OCc2ccc(Oc3ncccc3C#N)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1C(O)=C(C(C)=O)C=CC1(OCc1ccc(Oc2ncccc2-c2nnn[nH]2)cc1)C(C)=O
Temperature: 130 °C
Yield: 40 %

Procedure:
Mix 2-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinonitrile (0.16 g, 0.40 mmol), triethylamine hydrochloride (1.11 g, 8.05 mmol), sodium azide (0.52 g, 8.05 mmol) and toluene (6 mL) in a pressure vessel. Seal and heat to 130° C. for 6 hrs. Concentrate under reduced pressure to give a residue. Dilute with ethyl acetate (25 mL) and wash with 1N hydrochloric acid (3×50 mL). Dry over magnesium sulfate, filter, and concentrate to give a residue. Purification by flash chromatography, using 40:1 Chydrochloric acid3/methanol+1% acetic acid to 20:1 chloroformchloroform/methanol+1% acetic acid as a gradient eluent gives the title compound (0.07 g, 40%): MS (m/z): 444.1 (M−1). 1H NMR (DMSO-d6) 12.88 (s, 1H), 8.57 (d, J=7.4 Hz, 1H), 8.32 (d, J=5.0 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.38 (dd, J=5.0 Hz, 7.4 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 6.79 (d, J=9.2 Hz, 1H), 5.31 (s, 2H), 2.62 (t, J=7.4 Hz, 2H), 2.60 (s, 3H), 1.57-1.47 (m, 2H), 0.90 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36]Br)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][N:9]2[C:8](=[O:12])[CH2:7][C:6]3[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: BrCC1CCCN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccccc3)C1)C=C2
Reaction time: 0.75 h

Procedure:
17.54 g (0.08 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are suspended in 150 ml of dimethylsulphoxide and 8.98 g (0.08 mol) of potassium tert.butoxide are added with stirring. After 45 minutes, 21.45 g (0.08 mol) of N-benzyl-3-(bromomethyl)-piperidine dissolved in 50 ml of dimethylsulphoxide are added dropwize to the resulting solution with stirring. After 2 hours the mixture is poured onto ice water. The aqueous phase is extracted three times, each time with 150 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 800 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 3%). Yield: 14.3 g (44% of theory), Rf value: 0.35 (aluminium oxide neutral, eluant: 1% ethanol in methylene chloride).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12].[C:15]([O:18]C(=O)C)(=O)[CH3:16].[N+:22]([O-])([OH:24])=[O:23].C(=O)([O-])O.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[N+:22]([C:5]1[S:1][C:2]([CH:6]([O:14][C:15](=[O:18])[CH3:16])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:12])[CH3:13])=[CH:3][CH:4]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: CN(C)CCOCC(O)c1cccs1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(COCCN(C)C)c1ccc([N+](=O)[O-])s1
Reaction time: 2 h

Procedure:
A mixture of 9.2 g of 1-(2-thienyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol and 18 ml of acetic anhydride was refluxed for 10 minutes. The reaction mixture was dropwise added to a mixture of 7.8 ml of concentrated nitric acid and 27 ml of acetic anhydride at 0° C. in 30 minutes. The resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen-carbonate solution with the pH of the resulting mixture having been adjusted to 7 with a 40% aqueous sodium hydroxide solution. The resulting mixture was adjusted to pH 10 with a 40% aqueous sodium hydroxide solution and 300 ml of chloroform was added thereto. The organic layer was separated and 300 ml of water was added thereto. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated and 300 ml of chloroform was added thereto. The resulting mixture was adjusted to pH 10 with a 40% aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 10.4 g of oily 1-(5-nitro-2-thienyl)-1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 404).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.C(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:8]=[C:7]([I:10])[C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1c(F)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2 M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[CH3:29][S:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][S:16][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:41](=[O:42])[CH2:40][C:37]3[CH:36]=[CH:35][C:34]([O:33][S:30]([CH3:29])(=[O:31])=[O:32])=[CH:39][CH:38]=3)=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:26])=[CH:24][CH:23]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (33 mg, 0.072 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (15 mg, 0.065 mmol) in the same manner as described for example 1. The crude product was purified by flash chromatography (yield: 2.0 mg, 5.6%). Mass Spectrum: M+H+ 547.10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[CH:30][C:10]3[NH:11][C:12]([C:14]4[C:22]5[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=5)[N:16]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[CH:51]1([C:54](O)=[O:55])[CH2:53][CH2:52]1>CN(C=O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:31]=[CH:30][C:10]3[NH:11][C:12]([C:14]4[C:22]5[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:54]([CH:51]6[CH2:53][CH2:52]6)=[O:55])[CH:21]=5)[N:16]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.1 %

Procedure:
3-(5-Morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (30 mg, 0.072 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.53 mg, 0.108 mmol), EDC (20.61 mg, 0.108 mmol) and sodium bicarbonate (6.02 mg, 0.072 mmol) was added to a solution of cyclopropanecarboxylic acid (6.17 mg, 0.072 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (20 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.47 (d, 1H, J=1.6 Hz), 7.75 (dd, 1H, J=2.0 and 9.2 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.14 (m, 1H), 7.05 (dd, 1H, J=2.0 and 8.4 Hz), 5.86 (dd, 1H, J=2.4 and 9.6 Hz), 3.98 (m, 1H), 3.87 (m 4H), 3.81 (m, 1H), 3.16 (m, 4H), 2.64 (m, 1H), 2.14 (m, 2H), 1.81 (m, 2H), 1.71 (m, 2H), 0.99 (m, 2H), 0.88 (m, 2H); ESI-MS [M+H]+:487.22.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16].S>C(O)C.C(OC(C)C)(C)C>[OH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(C)CCN
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methylbutylamine (8.5 cc) is added to a solution of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (5.86 g) in absolute ethanol (135 cc). The mixture is saturated with hydrogen sulphide and then brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is diluted with ethyl acetate (150 cc), washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. before being purified by chromatography on a column (height: 32 cm; diameter: 4 cm) of silica gel (0.06-0.2 mm), eluting with pure ethyl acetate (1000 cc), collecting 60-cc fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is dissolved in isopropyl ether (80 cc). Crystallization is primed by scratching, and the mixture is stirred for 12 hours at 25° C. The crystals are filtered off to give 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (4.3 g) in the form of yellow crystals, m.p. 140° C.
Reaction SMILES: CC[O-].[Na+].C([O:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](OCC)=O)C.O.[NH2:21][NH2:22].Cl>CCO>[OH:7][C:8]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][NH:22][N:21]=1
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1O
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To a solution of NaOEt in EtOH (60 mL, 21 w %) were added diethyl 2-(ethoxymethylene)malonate (10.4 mL, 52.0 mmol) and hydrazine monohydrate (5.04 mL, 104 mmol) with cooling in an ice-water bath. The resulting mixture was then heated at 80° C. for 4 h. After cooling to rt, HCl (1 N, 180 mL) was added to the reaction mixture and then extracted with EtOAc three time. The combined organic layers were washed with brine and dried over Na2SO4. A solid obtained after evaporation was washed with ether and dried under high vacuum to afford the titled compound as an off-white solid (4.42 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl[S:18]([OH:21])(=[O:20])=[O:19].S(=O)(=O)([O-])[NH2:23].N>N1C=CC=CC=1C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:18](=[O:20])(=[O:19])[O-:21])=[CH:7][CH:6]=1.[NH4+:23]
Reactant: NS(=O)(=O)[O-]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=S(=O)(O)Cl
Agent: N
Solvent: Cc1ccccn1
Product: O=S(=O)([O-])Nc1ccc(-c2nc3ccccc3s2)cc1
Product: [NH4+]
Yield: 69 %

Procedure:
2(4'-Aminophenyl)benzothiazole was treated with chlorsulphonic acid in 2-picoline according to the above-described general procedure for preparation of sulphamate salts. About 35% ammonia solution instead of 10% aqueous Na2CO3 was used. A yellow powder was afforded in 69% yield, m.p. 223.1-226.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]([NH:16][C:17]([C@H:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH:21]([CH3:24])[CH2:22][CH2:23][C@@H:19]1[C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:18])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)NC(=O)[C@H]1CCC(C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CCC(C)N1c1nncc2cc(Br)ccc12
Reaction time: 1.33 h

Procedure:
6-bromo-1-chlorophthalazine (215 mg, 881 μmol), (R)-N-isopropyl-5-methylpyrrolidine-2-carboxamide (150 mg, 881 μmol), and cesium carbonate (1435 mg, 4405 μmol) were added to acetonitrile (4.4 mL) and placed in the microwave for 80 min at 200° C. before being diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the crude product. After purification by chromatography, the title compound was obtained. MS (ES+): 377 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]Cl>CC(C)=O>[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][S:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: FC(F)(Cl)CCCCl
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(Cl)CCCSc1nccs1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Solid anhydrous potassium carbonate (9.33 g) was added in two portions to a stirred mixture of 2-mercaptothiazole (7.90 g), 1,4-dichloro- 1,1-difluorobutane (9.70 g) and acetone (150 ml) under a nitrogen atmosphere, and the resultant mixture heated at the reflux temperature for 4 hours. After cooling to the ambient temperature the solid component was removed by filtration and washed with acetone (2×50 ml) and the combined washings and filtrate concentrated by evaporation of the solvent under reduced pressure. Diethyl ether (150 ml) was added to the residue and the resultant solution washed with aqueous potassium carbonate solution (2×100 ml) and with water (100 ml). After drying over anhydrous magnesium sulfate the solution was concentrated by removal of the solvent by evaporation under reduced pressure to yield 2-(4-chloro-4,4-difluorobutylthio)thiazole (13.98 g, 94%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11](O)=[O:12])[CH3:7].C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])[CH3:7]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CCOC(=O)CC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
tert-butanol (2.8 mL, 37.8 mmol) was added to a stirred solution of malonic acid monoethyl ester (5 g, 37.8 mmol) in acetonitrile (45 mL). DCC (8.58 g, 41.6 mmol) dissolved in acetonitrile (5 mL) was added dropwise with stirring over a period of 2 hours. The reaction mixture was filtered and the filtrate was concentrated to afford 4.72 g (66%) of malonic acid tert-butyl ester ethyl ester. LCMS: 189.11 (M+1)+ 93.4%, 1H NMR: (CDCl3): δ 4.2 (q, 2H), 3.3 (s, 2H), 1.4 (s, 9H), 1.3 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Fc1c(Br)ccc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)c(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-7-fluoro-1H-indole (470 mg, 2.19 mmol) in THF (7 mL) at −10° C. was added sodium hydride (175 mg, 4.39 mmol, 60% dispersion) and the mixture was stirred at 0° C. for 30 min. Methyl iodide was added at 0° C. and the reaction was allowed to warm to at 10° C. and stirred for 2 h. The reaction was quenched with saturated ammonium chloride and extracted with DCM. The DCM extract was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel eluting with EtOAc/hexane to afford 6-bromo-7-fluoro-1-methyl-1H-indole. 1H NMR (400 MHz, CDCl3) δ=3.95 (d, J=2.00 Hz, 1H), 6.42 (t, J=2.78 Hz, 1H), 6.94 (d, J=3.03 Hz, 1H), 7.09-7.15 (m, 1H) and 7.20 (d, J=8.34 Hz, 1H); MS (ES+): m/z 228.04 [MH+].
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:24]([CH:34]([CH2:37]O)[CH2:35][OH:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:24]([C@@H:34]1[CH2:35][O:36][C@@H:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[N:21][CH:20]=2)[O:23][CH2:37]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC(CO)CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cn2)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC[C@H]1CO[C@H](c2ccc(-c3ccc(OCCCCCCCC)cc3)nc2)OC1
Reaction time: 1 h

Procedure:
A solution of 2.2 g of 6-[4-(octyloxy)phenyl]-3-pyridinecarboxaldehyde (prepared in accordance with Example 2) and 1.4 g of 2-decyl-1,3-propanediol in 40 ml of toluene was treated with 5 drops of 10 percent (v/v) sulfuric acid. The mixture was heated to boiling for 1 hour, moist toluene being distilled off and being replaced by fresh toluene. The reaction mixture was then neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on 60 g of silica gel with hexane/ethyl acetate (vol. 9:1) and repeated recrystallization of the trans/cis mixture from ethyl acetate gave 0.56 g of pure 5-(trans-5-decyl-1,3-dioxan-2-yl)-2-[4-(octyloxy)phenyl]pyridine; m.p. (C-S) 69.7° C., transition S-SC 137.5° C., cl.p. (SC -I) 179° C.
Reaction SMILES: CN([Si:4](N(C)C)([CH3:6])[CH3:5])C.[O:10]1CC[CH2:12][CH2:11]1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:5][SiH:4]([CH3:6])[O:10][CH2:11][CH2:12][N:16]([CH3:17])[CH3:15]
Reactant: C1CCOC1
Reactant: CN(C)[Si](C)(C)N(C)C
Reactant: CNC
Solvent: CCO
Product: CN(C)CCO[SiH](C)C

Procedure:
A 2 L 3 neck flask equipped with a magnetic stirrer, Frederich's condensor and an addition funnel was charged with 361 mls of bis(dimethylamino)dimethylsilane and an equal volume of tetrahydrofuran. At ambient temperature, 116 mls of anhydrous ethanol was added over one hour. Dimethylamine evolved. The mixture was transferred to a single neck flask and distilled. 264 g of dimethyl(dimethylamino)ethoxysilane, (b.p. 115°-118° C.), was recovered.