Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][C:16]([C:13]1[CH:12]=[C:11]([CH2:20][CH2:21][C:22]2[O:23][C:1](=[S:2])[NH:25][N:24]=2)[CH:10]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:14]=1[OH:15])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
Thiophosgene (0.55 mL, 6.80 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (2.0 g, 6.8 mmol) in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane. The product is chromatographed on a column of silica with ethyl acetate/dichloromethane (5/95) and recrystallized from dichloromethane/hexane to afford 0.36 g (16%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 164.5°-165.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:14]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (2.29 g, 10 mmol) in methylene chloride (30 mL) was added 25% ammonium hydroxide (10 mL) at room temperature and the mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was redissolved in ethyl acetate (50 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The resulting solid was recrystallized from ether-hexane to give the title compound (1.429 g, 68.2% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[C@@H:24]([OH:38])[C@H:23]3[OH:39])=[C:15]([NH:40][CH2:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:27][C@H:25]1[CH2:26][C@@H:22]([N:19]2[CH:18]=[N:17][C:16]3[C:20]2=[N:21][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][C:15]=3[NH:40][CH2:41][CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:23]([OH:39])[C@@H:24]1[OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-4-benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate L5) (1.24 g, 1.7 mmol) in MeOH (3 ml) is treated with 4M HCl in dioxane (5 ml) and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% HCl). The fractions are collected and the MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracted are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES+) m/e 649 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[CH:49]=[N:48][NH:47][C:44]3=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:42]=[C:43]4[CH:49]=[N:48][NH:47][C:44]4=[N:45][CH:46]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC1(C)OB(c2cnc3[nH]ncc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cnc4[nH]ncc4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (51 mg, 0.095 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (28 mg, 0.123 mmol) in degassed 1,4-dioxane (250 μL) and water (25 μL) was added aqueous K2CO3 (95 μL of a 2.0 M solution) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The reaction mixture was heated at 100° C. for 6 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was used without any further purification. LCMS-ESI+: calc'd for C31H34ClN4O3S: 577.2 (M+H+); Found: 577.3 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:33]4[CH:32]=[C:31]5[C:36](=[CH:35][CH:34]=4)[N:28]([CH3:27])[N:29]=[CH:30]5)[CH:42]=3)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cn1ncc2cc(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)ccc21
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (300 mg, 0.65 mmol), 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole (260 mg, 0.78 mmol), Pd(PPh3)4 (75 mg, 0.065 mmol), 2N K2CO3 (1.6 mL) in dioxane (5 mL) was heated at 95° C. for hours. After the reaction finished, the reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C33H36BrN3O3S: 634.2 (M+H+); Found: 634.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11]C)(OC)[CH2:7][CH2:6][N:5]([C:13]([O-:15])=[O:14])[CH2:4]1.CO.Cl.O1CCO[CH2:21][CH2:20]1>>[CH3:1][O:2][CH:3]1[C:8](=[O:11])[CH2:7][CH2:6][N:5]([C:13]([O:15][CH2:20][CH3:21])=[O:14])[CH2:4]1
Reactant: COC1CN(C(=O)[O-])CCC1(OC)OC
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(=O)C(OC)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared by taking 3,4,4-trimethoxypiperidine-1-carboxylate (210 mg, 0.00085 mol) in Methanol (5 mL, 0.1 mol) and adding 4 M of Hydrogen chloride in 1,4-dioxane (5 mL). The reaction was allowed to stir for 4 h at ambient temperature. The residue obtained by removing the solvent in vacuo was used in the next step as-is (170 mg, 99%). MS calculated for C9H15NO4: (M+H) 202; found 202.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CO
Product: COc1cc(C=Nc2ccccc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and aniline (560 mg, 6.01 mmol, 0.35 ml, neat liquid) was added to the solution by syringe. The resultant reaction mixture was stirred overnight at room temperature under nitrogen then taken to dryness in vacuo. The yellow crystals thus obtained were triturated with hot ether, allowed to cool, filtered and the collected solid was washed with ether to yield the title product: 1H NMR (300 MHZ, CDCl3) δ , 8.33 (S, 1H), 7.42-7.39 (m, 2H), 7.21-7.18 (m, 5H), 5.84 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: ClC(Cl)C(O)=[O:4].[CH3:7][C:8]1[C@@H:13]2[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12]2)[CH2:10][CH:9]=1>O>[CH3:7][C:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:4])([CH3:16])[CH3:15])[CH2:10][CH:9]=1
Reactant: CC1=CC[C@@H]2C[C@H]1C2(C)C
Reactant: O=C(O)C(Cl)Cl
Solvent: O
Product: CC1=CC[C@H](C(C)(C)O)CC1
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Followiwng a procedure described in Matsubara, et al., Chem. Abstr., 84:165069b (1976), 64.5 g of dichloroacetic acid was added dropwise over 20 minutes at 5°-6° C. to a magnetically stirred mixture of 68.0 g of (+)-alpha-pinene ([alpha]D +47.1°) and 9.0 g of water. after stirring overnight at 5°-30° C. (ice allowed to melt slowly), the mixture was extracted with 400 ml of methylene chloride. The extract was washed successively with water, aqueous potassium carbonate solution and water, dried and Claisen distilled at 4 mm to give 11.2 g of forecut, b.p. 40°-71° C. and 47.5 g of the desired (+)-alpha-terpineol, b.p. 71°-83° C. Redistillation through a micro Vigreaux column gave 40.5 g of (+)-alpha-terpineol with [alpha]D +79.3° (CHCl3), b.p. 58°-60° C. (1 mm).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[C:28](F)[C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].CCCCCCC>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)c(F)c(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)cc(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Temperature: 0 °C
Yield: 80.2 %

Procedure:
The compound (50 mg) prepared in Example 14 (3) was dissolved in ethyl acetate (1.4 mL) at 70° C. To the solution, n-heptane (0.68 mL) was added at room temperature, which was then cooled to 0° C. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (39 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[H-].[Na+].Br[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[N+:23]([O-:25])=[O:24]>O>[N:1]1([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1oc2ccccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1oc2ccccc2c1-n1ccnc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 0.1 g. (12 mmole) of imidazole in 20 ml. of N,N-dimethylformamide is added 0.5 g. (12 mmole) of 57.6 percent suspension of sodium hydride in mineral oil. After cooling to 20° C., 2.4 g. (10 mmole) of 3-bromo-2-nitrobenzofuran in 20 ml. of N,N-dimethylformamide is added. After stirring 45 minutes, the mixture is heated on a steam bath for 15 minutes, then 50 ml. of water are added. Cooling and filtration provide yellow needles of 3-(N-imidazolyl)-2-nitrobenzofuran, m.p. 147°-149° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH2:28][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:30]=[CH:31][CH:32]=1)(=[O:23])=[O:24]
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Product: CS(=O)(=O)c1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][Cl:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]2[C:29]=1[CH:28]=[CH:27][C:26]([Cl:30])=[CH:25]2)=[O:20])[CH3:17]>CS(C)=O>[ClH:7].[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:3][CH2:2][N:4]([CH2:8][CH3:9])[CH2:5][CH3:6])[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]2[C:29]=1[CH:28]=[CH:27][C:26]([Cl:30])=[CH:25]2)=[O:20])[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.2 g. of 2-diethylaminoethyl chloride hydrochloride in 35 ml. of dimethylsulfoxide is treated with 8.3 g. of finely ground dry potassium carbonate and stirred at room temperature for 15 minutes. Then, there are added thereto 3.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester; the mixture is stirred intensively for 18 hours under an atmosphere of nitrogen at room temperature and subsequently poured onto 80 ml. of ice-water. After the addition of 5 g. of sodium chloride, the separated oil is immediately extracted with ether, and the extract concentrated to about 30 ml. and treated with 30 ml. of 0.5-N hydrochloric acid. The mixture is thoroughly shaken and cooled in an ice-bath. The crystallized hydrochloride is isolated and purified in an analogous manner to that given in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 248°-250° C. (decomposition).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:27]=[CH:28][C:29]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:30][N:31]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCNCC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCN(C)CC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 1-methylpiperazine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=65:35 to 15:85) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.[CH3:29][O:30][C:31](=[O:49])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:48])(=[N:41][C:42](=[O:47])C(F)(F)F)=[O:40])[CH:34]=1>>[CH3:29][O:30][C:31](=[O:49])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:48])(=[N:41][C:42]([C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[C:10]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=4)=[O:21])[CH:14]=3)[CH:9]=2)=[O:47])=[O:40])[CH:34]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)C(F)(F)F)c1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 496 (step 5), 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid and methyl{3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate were reacted to give the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]=[C:10]([CH3:12])[CH3:11].C(OOC(C)(C)C)(C)(C)C>>[CH2:1]([O:3][P:4]([CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=C(C)C
Reactant: CCOP([O-])OCC
Agent: CC(C)(C)OOC(C)(C)C
Product: CCOP(=O)(CC(C)C)OCC
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In a 10-liter flask with stirrer, internal thermometer, reflux condenser (-80° C.) and a cooled dropping funnel, 2070 g of diethylphosphite is heated to 150° C. Then over a period of about 90 minutes a mixture of 2070 g of diethylphosphite, 1680 g of isobutene and 44 g of ditertiarybutyl peroxide is added drop by drop. The reaction heat that develops is removed by external cooling. Then heating at 150° C. continues for about 30 minutes. Vacuum distillation through a 12-tray column delivers an 81% yield of pure product.
Reaction SMILES: [Li]CCCC.[C:6]([NH:10][C:11](=[O:13])[OH:12])([CH3:9])([CH3:8])[CH3:7].Cl[CH2:15][CH2:16][CH2:17][S:18]([NH2:21])(=[O:20])=[O:19]>C1COCC1>[C:6]([NH:10][C:11](=[O:12])[OH:13])([CH3:9])([CH3:8])[CH3:7].[CH:17]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:15][CH2:16]1
Reactant: NS(=O)(=O)CCCCl
Agent: CC(C)(C)NC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)C1CC1
Temperature: -78 °C

Procedure:
Step IIc) A solution of n-BuLi (74.7 mL, 119.5 mmol, 1.6 M in hexane) was dissolved in dry THF (105 mL) and cooled to −78° C. under a Argon atmosphere. To this solution was added a solution of 3-chloropropylsulfonylamine tert-butylcarbamate (14 g, 54.3 mmol) in dry THF (105 mL) slowly dropwise over 20-30 min. The dry ice bath was removed and the reaction mixture was allowed to warm to rt over a period of 2 h. The reaction mixture was quenched with glacial AcOH (3.4 mL), concentrated in vacuo, and partitioned between CH2Cl2 (100 mL) and water (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to afford the cyclopropylsulfonylamine tert-butyl carbamate as a waxy offwhite solid (12.08 g, 100%): 1H NMR (CDCl3) δ 1.10 (m, 2H), 1.34 (m, 2H), 1.50 (s, 9H), 2.88 (m, 1H), 7.43 (s, 1H). 13C NMR (CDCl3) δ 6.21, 28.00, 31.13, 84.07, 149.82.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][O:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([N:14]([O:13][CH3:12])[CH3:24])=[O:23])=[CH:22][CH:21]=1)=[O:10]
Reactant: CON(C)C(=O)Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C

Procedure:
Cool a slurry of aluminum chloride (87 g, 650 mmol) in methylene chloride (100 mL) with an ice bath. Add 4-chlorobutyryl chloride (51 g, 360 mL) dropwise over 0.5 hours. Add N-methoxy-N-methyl-benzeneacetamide (53 g, 300 mmol) over 0.5 hours. Allow the resultant solution to warm to room temperature. Then heat at reflux for 6 hours. Cool the solution to room temperature. Pour the solution into ice (1 L) and add methylene chloride (1 L). Separate the organic phase. Extract the aqueous phase with methylene chloride (2×500 mL). Dry the combined organics over anhydrous magnesium sulfate and concentrate to provide a solid which contains a ca. 1:1 mixture of the title compound and the meta isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21]([C:20]1[C:19]([CH3:26])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile (Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). 1H NMR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H), 1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8](Br)=[CH:7]2.[CH3:13][S-:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:14][CH3:13])=[CH:7]2
Reactant: Nc1cccc2cc(Br)cnc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cnc2c(N)cccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of 8-amino-3-bromoquinoline (200 mg) and sodium thiomethoxide (109 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 days. After diluted with ethyl acetate, the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate) to give 8-amino-3-methylthioquinoline (113 mg) as an oil.