Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-ethyl-piperazine following General Procedure C.
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl:44])[NH:40][CH:39]=[C:38]2[CH:45]=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([CH:45]=[O:46])=[CH:39][NH:40]2)=[CH:36][C:35]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: OC1(c2ccc(Br)cc2)COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)cc3)cc12
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (149.0 mg, 0.44 mmol), oven dried potassium acetate (173.0 mg, 1.75 mmol) and 3-(4-bromo-phenyl)-oxetan-3-ol (100.0 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.0 mg, 0.044 mmol) and subjected to microwave irradiation at 110° C. for 1 hour. The cooled reaction mixture was filtered through celite and concentrated in vacuo to give a black oil. To the dark oil was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (112.0 mg, 0.43 mmol), 2 N aqueous potassium carbonate (0.4 mL, 0.80 mmol), toluene (1.5 mL) and EtOH (0.5 mL). The reaction mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 0.034 mmol), and heated in a pressure tube to 110° C. for 2 hours. The cooled reaction mixture was purified by flash chromatography (33-100% EtOAc/heptanes) to give a solid. The solid was triturated in MeOH and filtered to afford the title compound (50 mg, 35%) as a yellow solid. MS (ES+) 328.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1 H), 9.92 (s, 1 H), 8.35 (s, 1 H), 8.02 (s, 1 H), 7.66 (d, J=9.4 Hz, 2 H), 7.44 (d, J=8.2 Hz, 2 H), 6.36 (s, 1 H), 4.80-4.76 (m, 2 H), 4.75-4.71 (m, 2 H).
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ncc(C(=O)O)cc1OC1CCCC1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A solution of potassium hydroxide (168 mg) in water (1 mL) is added to a solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (250 mg) in methanol (3 mL) and the mixture stirred for 4 hours then allowed to stand at room temperature overnight. The mixture is concentrated, the residue dissolved in water and the mixture adjusted to pH 6 by the addition of concentrated hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts dried (MgSO4) and concentrated to give a cream solid. The solid is dried at 100° C. to give 5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p. 191-2° C. [Elemental analysis: C, 60.7; H, 6.43; N, 5.78%. calculated: C, 60.75; H, 6.37; N, 5.90%.].
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]([OH:20])=O)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[NH2:32][C:33]1[C:41]([CH3:42])=[CH:40][C:39]([I:43])=[CH:38][C:34]=1[C:35](O)=[O:36]>C(#N)C>[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]3[O:20][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([I:43])[CH:40]=[C:41]([CH3:42])[C:33]=4[N:32]=3)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) in acetonitrile (50 mL) was added dropwise a mixture of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step C) (10.0 g, 34.31 mmol) and triethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at −5° C. The reaction temperature was then maintained at 0° C. throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Step A) (9.51 g, 34.31 mmol) was added and stirring was continued for an additional 10 minutes. A solution of triethylamine (9.56 mL, 68.62 mmol) in acetonitrile (15 mL) was then added dropwise, and the reaction mixture was stirred 30 minutes, followed by the addition of methanesulfonyl chloride (2.91 mL, 37.74 mmol). The reaction mixture was then warmed to room temperature and stirred 2 hours. The solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 8.53 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][CH2:18][O:19][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (ESI) m/z 434 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1>C(N(CC)CC)C.ClCCl>[CH2:5]([O:4][C:2]([N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:13]2[NH:12][CH:16]=[CH:15][CH:14]=2)=[N:18]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1c[nH]c(-c2n[nH]c3ncccc23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1nc(-c2ccc[nH]2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (150 mg) (Aldrich, Milwaukee, Wis.) was added to a mixture of 3-(1H-pyrrol-2-yl)-1H-pyrazolo[3,4-b]pyridine (120 mg) (from Example 2) and triethylamine (3 drops) in dichloromethane (DCM). After stirring at room temperature for one hour, the reaction was concentrated and purified on a silica gel column to give 3-(1H-pyrrol-2-yl)-pyrazolo[3,4-b]pyridine-1-carboxylic acid benzyl ester. It was then combined with di-morpholine methane (300 mg) (Aldrich, Milwaukee, Wis.), THF (2 mL), water (0.2 mL) and acetic acid (2 drops). The mixture was heated at 90° C. for 20 hours. The reaction was concentrated and purified on a silica gel column to give 30 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([O-:6])=[O:5].[NH2:10][C@H](C(O)=O)CC.C(N)(C)C.P([O-])([O-])([O-])=O>>[NH2:10][C@H:3]([C:4]([OH:6])=[O:5])[C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Reactant: CC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)N
Product: CC(C)(C)[C@H](N)C(=O)O

Procedure:
L-tert-Leucine was produced with a conversion of 97% by conducting reactions using 50 mL of a mixture of 0.3 M trimethylpyruvate, 20 mM L-homoalanine, 0.45 M isopropylamine, 0.5 mM PLP, 50 mM phosphate pH 8, 35 U/mL BCTA and 30 U/mL OATA. 1.365 g of pure L-tert-leucine was obtained through purification based on solubility.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.[NH:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]1>CN(C)C=O.O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Temperature: 120 °C
Yield: 80 %

Procedure:
Cesium carbonate (4.68 g, 14.4 mmol), 2-chloroquinoline (0.782 g, 4.8 mmol) and tert-butyl azetidin-3-yl-carbamate hydrochloride (1.0 g, 4.8 mmol) were dissolved in dry dimethylformamide (15 mL) and the resulting mixture was heated at 120° C. overnight. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate. The organic was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% ethyl acetate in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)-carbamate (1.14 g, 3.84 mmol, 80% yield) as white solid.
Reaction SMILES: C(N)CCC.[S:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3[C:18](=CC=CC=3)[C:17]2=[O:26])[S:7]1.C1(C)C=CC=CC=1>CO>[S:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[CH3:18])[S:7]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: CO
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: CC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
1 ml of butylamine was added to a mixture of 1.3 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione, 9 ml of toluene and 2 ml of methanol. The resulting mixture was stirred at room temperature for 3 hours, after which the reaction mixture was allowed to stand at room temperature for 2 days. 1 ml of butylamine was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 3 hours. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of anhydrous tetrahydrofuran were then added to the residue. 0.28 ml of triethylamine and 0.14 ml of acetyl chloride were then added to dropwise to the resulting mixture, whilst ice-cooling, and then the mixture was stirred at room temperature for 1 hour and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromotagraphy, using 1:0 and 10:1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 161 mg of the title compound as yellow crystals, melting at 28 to 33° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2>ClCCl.CO>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Yield: 84.1 %

Procedure:
2-Chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid is prepared as in Example 44, from 0.9 g of methyl 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate. 0.72 g of 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a white powder (Rf=0.43; thin layer chromatography on silica gel; eluent: 9/1 dichloromethane/methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)=O.CC(C)=O.[CH2:17]([Mg]Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCC[Mg]Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 3-bromobenzaldehyde (5.00 g, 27.02 mmol) in dry THF (100 mL), under nitrogen at −78° C. (dry ice/acetone bath) was added nBuMgCl (16.2 mL of a 2.0M solution in THF, 0.032 mol) and the reaction stirred for 1 hour at −78° C. and then allowed to warm to rt overnight. The reaction was then quenched with water, extracted with EtOAc and the layers separated. The organic layer was washed with water then brine, dried (Na2SO4) and reduced under vacuum to give a colourless oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane:EtOAc 9:1 afforded the title compound as a colourless oil (4.07 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]([CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>>[CH:9]1([C:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]([CH2:18][CH2:19][CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Product: CCCN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCC2)c2ccccc21
Yield: 7.8 %

Procedure:
The title compound was prepared from 3(R,S)-amino-5-cyclopentyl-1,3-dihydro-1-propyl-2H-1,4-benzodiazepin-2-one (321 mg, 11.2 mmol) and 4-nitrophenyl chloroformate (229 mg, 11.4 mmol) using the procedure described in Example 20, Step 1. The crude product was triturated with ether (10 ml) to give the title compound (396 mg, 78%) as a white solid. 1H NMR (360 MHz, CDCl3) 0.83 (3H, t, J=7.4 Hz), 1.33-1.82 (8H, m), 1.97 (1H, m), 2.15 (1H, m), 3.34 (1H, m), 3.60 (1H, m), 4.32 (1H, m), 5.16 (1H, d, J=8.3 Hz), 6.89 (1H, d, J=8.4 Hz), 7.30-7.37 (4H, m), 7.52 (1H, t of d, J=7.8 and 1.6 Hz), 7.59 (1H, dd, J=7.8 and 1.5 Hz), 8.22 (2H, d, J=9.2 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.IC1C=C2C(=CC=1)N=CN=C2NC1SC2C(N=1)=CC=CN=2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1cnccn1
Reactant: COc1ccc2ncnc(Cl)c2c1
Agent: Ic1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Product: COc1ccc2ncnc(Nc3cnccn3)c2c1

Procedure:
The compound of Example 37 was manufactured using 4-chloro-6-methoxy-quinazoline and 2-aminopyrazine by the same method as in Example 1 for the manufacture of (6-iodoquinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, by a similar method thereto or by a combination of such a method with a conventional method.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:10]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[CH2:11]>>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH:10]([C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:11]
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=CN1CCCC1=O
Product: CC(c1cccc2[nH]nnc12)N1CCCC1=O
Yield: 64 %

Procedure:
This product is synthesised, in 64% yield, from benzotriazole and 1-vinyl-2-pyrrolidinone by the same method described in Example 1. The product distils at 180°/0.05 mbar and solidifies, on standing, to yield a white solid mp 77°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]2[C:5]([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13](=[O:15])[C:3]=12)=[O:7]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2c(Cl)cc(Cl)c(Cl)c2C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
3,4,6-Trichlorophthalic acid (500 g, 1.86 moles), glacial acetic acid (4 L), and aniline (175 mL, 1.92 moles) were charged to a 12 L 3-neck flask equipped with a condenser, a stirrer and a thermometer. The mixture was heated with stirring and maintained at 100°-101° C. for 2 hours, then cooled to room temperature and filtered. The filter cake was washed with cold water and vacuum dried (70° C., 0.2 mmHg) for 24 hours to yield 590.7 g of 97.5% pure 3,4,6-trichloro-N-phenylphthalimide (m.p. 199°-200° C.).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[S:7]1[CH:11]=[CH:10][C:9](C=O)=[CH:8]1.C1(C)C=CC=CC=1.N1C=CC=CC=1>CCOC(C)=O.CCCCCC.C([O-])(=O)C.[NH4+]>[S:7]1[CH:11]=[CH:10][C:9]([CH:4]=[CH:3][C:1]#[N:2])=[CH:8]1
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccsc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#CC=Cc1ccsc1
Yield: 53.1 %

Procedure:
A mixture of cyanoacetic acid (7.56 g, 88.9 mmol), thiophene-3-carbaldehyde 79 (Aldrich, Wis.) (10.97 g, 97.8 mmol), ammonium acetate (0.36 g, 4.7 mmol), toluene (89 mL), and pyridine (47 mL) was heated at reflux for 20 h in a flask fitted with a Dean-Stark trap and condenser. After evaporation of solvents, a solution of the residue in CH2Cl2 (300 mL) was washed with water, dried over Na2SO4, filtered, and evaporated. The crude product was isolated by flash chromatography on a silica gel column using 10% to 20% gradient of EtOAc in hexane as eluent to afford 3-thiophen-3-yl acrylonitrile (6.38 g) in a 1.8 to 1 ratio of trans to cis isomer as a dark brown oil. The product was then dissolved in pyridine (100 mL) and EtOH (20 mL). To the resulting solution was added NaBH4 (3.57 g, 94.4 mmol). The solution was then heated at 100° C. until completion of the reaction approx. (4 h) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 11% EtOAc in hexane). The major fractions were combined and concentrated to give 80 (4.03 g) as a yellow liquid. 1H NMR (400 MHz, d6-DMSO) δ: 7.50 (dd, J=3.0 and 5.0 Hz, 1H), 7.31 (m, 1H), 7.07 (dd, J=1.0 and 5.0 Hz, 1H), 2.89 (m, 2H), 2.81 (m, 2H). MS (EI) m/z (M+H+) 138.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][CH3:28]>CN(C=O)C>[CH2:27]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1)[CH3:28]
Reactant: CCc1cnccc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnccc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.56 g, 8.0 mmol) was dissolved in anhydrous DMF (50 mL), and then potassium carbonate (3.3 g, 23.9 mmol) and 4-(bromomethyl)-3-ethylpyridine (10.3 mmol) in DMF (10 mL) were added. The reaction mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(3-ethylpyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (357 mg, 14% yield for 3 steps); 1H NMR (500 MHz, DMSO-d6): δ 1.21 (t, J=7.5 Hz, 3H), 2.75 (q, J=7.5 Hz, 2H), 4.46 (s, 2H), 6.65 (s, 1H), 7.41 (d, J=5.1 Hz, 1H), 8.34 (d, J=5.0 Hz, 1H), 8.42 (s, 1H); LRMS (ES+) m/z 316 (100%, M+1).
Reaction SMILES: [Br-:1].[Na+].[CH3:3][C:4]1[C:5](=[O:21])[O:6][C:7]([CH2:15]OS(C)(=O)=O)=[C:8]([CH3:14])[C:9]=1[O:10][CH2:11][O:12][CH3:13]>CN(C=O)C>[Br:1][CH2:15][C:7]1[O:6][C:5](=[O:21])[C:4]([CH3:3])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:8]=1[CH3:14]
Reactant: COCOc1c(C)c(COS(C)(=O)=O)oc(=O)c1C
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)c(CBr)oc(=O)c1C
Reaction time: 1 h

Procedure:
Sodium bromide (500 mg) was added to a solution of 3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy)methyl-2H-pyran-2-one (1.35 g) in DMF (20 ml), and after the stirring the mixture at room temperature for one hour, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(C)c2oc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-benzoxazolinone (200 mg, 1.23 mmol, described in Intermediate 24) in DMF (2 mL) was added sodium hydride (59 mg of a 60% dispersion in mineral oil, 1.47 mmol). The mixture was stirred at ambient temperature for 10 min, then tert-butyl bromoacetate (287 mg, 1.47 mmol) was added and stirring was continued for 2 h. The reaction mixture was quenched with H2O and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=222 (M−C4H7).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C1(C)C=CC=CC=1.[S:16]1[CH2:18][CH2:17]1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:18][CH2:17][SH:16]
Reactant: C1CS1
Reactant: CC1CCCC(C)N1
Solvent: Cc1ccccc1
Product: CC1CCCC(C)N1CCS

Procedure:
In a 500 ml three-necked flask 113.2 g(1 mol) of 2,6-dimethylpiperidine in 250 mol toluene was heated at 90° C. Then 60.12 g (1 mol) thiirane is added to the resulting reaction mixture dropwise and the reaction mixture is heated for 5 hours under reflux. The reaction mixture is concentrated in vacuum with a rotary evaporator and is fractionally distilled using a Vigreux column. The yield amounts to 60.55 g of the named compound(35%).