Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=S)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CCCCCC.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][O:28][C:29]([CH2:30][C:9]1[S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:32]
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
The starting material can be produced, for example, in the following manner: 6 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, 3.57 g of bromoacetic acid methyl ester are slowly added dropwise, the mixture is then stirred for 1 hour at room temperature, poured into 500 ml of ice-water, extracted by shaking twice with 300 ml of ethyl acetate each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. The remaining oil is dissolved in toluene and purified by chromatography over 50 g of silica gel. The eluate with toluene/ethyl acetate (95:5) is concentrated by evaporation under reduced pressure. 2-Methoxycarbonylmethyl-4,5-bis-phenylthiazole having a melting point of 65°-67° is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11]([NH2:13])=[N:10][N:9]=1.[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(#N)C>[NH2:13][C:11]1[O:12][C:8]([C:4]2[S:5][CH:6]=[CH:7][C:3]=2[NH:2][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:15]=2[Cl:14])=[O:21])=[N:9][N:10]=1
Reactant: Nc1nnc(-c2sccc2N)o1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CC#N
Product: Nc1nnc(-c2sccc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(3-Aminothiophen-2-yl)[1,3,4]oxadiazol-2-ylamine hydrochloride (30 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[CH:18][N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[CH:18]=[CH:19][S:20][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), 6-bromo-9H-purine (0.031 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H15FN7OS (M+H)+: m/z=408.1. Found: 408.0.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:4]=1[CH3:19].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(O)(=O)C>[Cl-:1].[CH3:17][N:16]([CH3:18])[C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[N:8][N+:5]2[CH:6]=[CH:7][N:3]([N:2]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)[C:4]=2[CH3:19])=[CH:11][CH:12]=1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc([N+](=O)[O-])cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
56 mg (0.2 mmol) of 1-amino-3-[[p-(dimethylamino)-benzylidene]amino]-2-methylimidazolium chloride and 30 mg (0.2 mmol) of p-nitrobenzaldehyde are dissolved in 5 ml of glacial acetic acid. After 2 days the solution is evaporated, and the residue is chromatographed on 5 g of silica gel (particle size 0.063-0.200 mm) while eluting chloroform/methanol (87:13) and recrystallized from methylene chloride/petroleum ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-methyl-3-[[p-nitrobenzylidene]amino]-imidazolium chloride of melting point 252° (decomposition).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]1=[O:23].[CH2:24]([O:26][C:27](=[O:50])[C@H:28](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:25].CN1CCOCC1>>[CH2:24]([O:26][C:27]([C@@H:28]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]1=[O:23])[CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:50])[CH3:25]
Reactant: NC1CCc2ccccc2N(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
The reaction of 15 g of 3-amino-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 22.1 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 6.45 ml N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-nitrobenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one. Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.78, polar component 0.69.
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].[CH3:7][C:8]([CH3:13])([CH2:11]O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH2:3][CH2:4][CH3:5])[O:10][CH2:9][C:8]([CH3:13])([CH3:11])[CH2:7][O:6]1
Reactant: CC(C)(CO)CO
Reactant: CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1(C)OCC(C)(C)CO1

Procedure:
2-Pentanone, 2,2-dimethyl-propane-1,3-diol, and a catalytic amount of p-toluenesulfonic acid (PTSA) were refluxed in toluene to provide a crude product. Distillation provided the product 2,5,5-trimethyl-2-propyl-[1,3]dioxane.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][C:12]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:2]>[Pd].O1CCOCC1>[CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][C:12]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc(-c2cc(C=Cc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1

Procedure:
Palladium on charcoal catalyst (10%; 50 mg) was added to a degassed solution of 5-(2,4-Bis-benzyloxy-5-styrylphenyl)-isoxazole-3-carboxylic acid ethylamide (690 mg, 1.30 mmol) in 1,4-dioxane (50 mL) under a nitrogen atmosphere. The reaction mixture was hydrogenated for a total of 4.75 hrs with further Pd on charcoal catalyst (50 mg) added at 0.75 and 2.5 hrs. The reaction mixture was filtered through a pad of celite, which was washed with 1,4-dioxane (20 mL) and dichloromethane (20 mL). The combined filtrate solvents were removed in vacuo to afford a cream-coloured solid, which was purified by flash chromatography on silica gel (20 g, IST) eluting with 10 to 50% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-isoxazole-3-carboxylic acid ethylamide as a pale yellow solid (609 mg, 88%). LCMS: [M+H]+ 533. 1H NMR (400 MHz, CDCl3) δ1.26 (t, 3H), 2.86-2.96 (m, 4H), 3.49 (m, 2H), 5.03 (s, 2H), 5.18 (s, 2H), 6.56 (s, 1H), 6.81 (t, 1H), 7.07 (s, 1H), 7.15-7.20 (m, 3H), 7.23-7.28 (m, 2H), 7.31-7.42 (m, 10H), 7.73 (s, 1H).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:1][C:14]1[S:13][C:12]([N:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[N:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)cs1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)c(Br)s1
Yield: 98.9 %

Procedure:
A solution of 2.34 g (0.015 mol) of bromine in 5 ml of glacial acetic acid is added dropwise with stirring in the course of 45 minutes at room temperature to a mixture of 4.5 g (0.013 mol) of methyl N-[4-(4-bromophenyl)-thiazol-2-yl]-N-methylaminoacetate and 2.5 g (0.03 mol) of sodium acetate in 30 ml of glacial acetic acid, the mixture is subsequently stirred with an excess of aqueous saturated sodium hydrogen carbonate solution, and the precipitate which has separated out is filtered off with suction. After drying, 5.4 g (97% of theory) of methyl N-[5-bromo-4-(4-bromophenyl)-thiazol-2-yl]-N-methylaminoacetate are obtained as an oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:14])[C:5]1[N:28]([CH2:29][C@H:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: C[C@@H](O)CN
Reactant: O=CCC1Cc2cc(F)c(F)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)c(F)cc1C2
Reaction time: 0.75 h
Yield: 45.4 %

Procedure:
A solution of 2.1 g of (RS)-2-(2-oxoethyl)-5,6-difluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.13 g (45%) of (R)-1-(6,7-difluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown solid which was used without further recrystallization in the next reaction.
Reaction SMILES: C([O:8][C:9]1[C:29]([O:30][CH3:31])=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:32])C1C=CC=CC=1>[Pd].C(O)C.C1COCC1>[Cl:32][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([O:30][CH3:31])[C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:27]=[N:26][N:25]=[CH:24]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1O
Reaction time: 24 h

Procedure:
Palladium on charcoal (100 mg, 5% Pd) was added to a solution of 4-[(4-benzyloxy-3-chloro-5-methoxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02177, 1.34 g, 3.0 mmol) in ethanol (60 mL) and THF (40 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 24 h (TLC monitored), then filtered through celite and concentrated under reduced pressure. The residue was dried under high vacuum. Yield: 1.06 g (99%), white powder. 1H-NMR (400 MHz, d6-DMSO) δ=3.77 (s, 3H, —OCH3), 4.92 (s, 2H), 6.79 (d, J=9.0 Hz, 2H), 6.81 (d, J=1.8 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.79 (s, 2H), 9.49 (s, 1H, —OH). LRMS (FAB+): 356.0 (100, [M+H]+). HRMS (FAB+): 356.09234 C17H15N15O2Cl requires 356.091428.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][NH:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][N:15]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:9][CH:10]=1)([F:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(C(C)(F)F)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(C(C)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.30 g (3.78 mmol, purity 82%) of the compound from Example 50A in dichloromethane (44 ml) was admixed with 1.84 ml (1.34 g, 13.2 mmol) of triethylamine and then admixed at 0° C. with 762 mg (3.78 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 1.93 g (92% of theory, purity 81%, 2:1 mixture of methyl and ethyl ester)
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([OH:24])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)O.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:22](=[O:24])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 2-(trityloxy)acetic acid (7.2 g, 22.62 mmol) in DCM (250 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (7.92 g, 18.85 mmol), EDC (4.34 g, 22.62 mmol), and DMAP (4.60 g, 37.7 mmol) were added at RT. The solution was stirred at the same temperature overnight. A sat. sol. of K2CO3 was added, and the organic phase was separated, washed with HCl 2N and brine, dried over Na2SO4 and evaporated under vacuum. The resulting brown crude was purified by flash chromatography on silica gel (DCM 100% as eluent). (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(trityloxy)acetoxy)ethyl)pyridine 1-oxide was obtained (8.53 g, 11.84 mmol, 62.8% yield, MS/ESI+ 720.1 [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][N:26]=1)CCC>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>[NH2:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ncco2)c(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
A solution of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (500 mg, 1.672 mmol), 2-(tributylstannyl)oxazole (0.704 ml, 3.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.167 mmol) in dioxane (10 ml) was heated at reflux for 13 hours. After cooling to room temperature over 8 hours, the solvent was evaporated and the resulting residue triturated with hot methanol to remove a yellow solid impurity. The remaining crude material was used without further purification. LC-MS: Rt 0.95 min; MS m/z 288 [M+H]+; Method 2minLC_v003.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1.O.CCOC(C)=O.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(Cl)c(CN2CCNCC2)c1
Reaction time: 40 h
Yield: 44.4 %

Procedure:
A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylpiperazine in 35 mL of 37% HCl was stirred for 40 h at reflux. Subsequently, 30 mL of water and 30 mL of EtOAc were added at room temperature, adjusting the pH to 11 via addition of 35% NaOH. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The crude was purified via flash chromatography (CHCl3-MeOH 7:3) giving 4.46 g (50%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH2:18]([NH:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1c2c(nc3sccc13)CCCC2=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCc2nc3sccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h

Procedure:
4-Amino-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one (6.21 g) was dissolved in 60 ml of dimethylsulfoxide (DMSO). Potassium hydroxide (2.3 g, calculated as 85%), which had been pulverized under pentane, was added to the reaction mixture. After 30 minutes 5.0 g of benzyl bromide was added, and after an additional 30 minutes, 1.0 g of potassium hydroxide and 2.0 g of benzyl bromide were added. After a total reaction time of 90 minutes, 200 ml of water was added to the reaction mixture, causing a gummy precipitate to separate. The crude product was collected by filtration and purified by flash chromatography (10% ethyl acetate/dichloromethane) followed by recrystallization from ethyl acetate. Obtained in this manner was 2.35 g of analytically pure product, mp 159°-160°.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([OH:30])[CH3:29].Cl>C(Cl)(Cl)Cl>[CH2:28]([O:30][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1)=[NH:2])[CH3:29]
Reactant: CCO
Reactant: N#Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 96 h

Procedure:
1-[1-(4-Cyanobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) is dissolved in chloroform (10 ml) and thereto is added ethanol (0.18 ml). Under ice cooling, hydrochloric acid gas is passed through the mixture to saturate and further the mixture is stirred at 5°-7° C. for 4 days. After the reaction, the solvent is concentrated to give 1-{1-[4-(1-ethoxy-1-iminomethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g). This product is used for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37](=O)[CH2:38]Br>CCO>[Cl:33][C:34]1[CH:35]=[C:36]([C:37]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=3)[CH2:5][CH2:6][C:7]3[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=3)[S:3][CH:38]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(-c3cccc(Cl)c3)cs2)cc1
Yield: 60.6 %

Procedure:
A solution of ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (162 mg; 0.35 mmol) and 3-chlorophenacyl bromide (82 mg; 0.35 mmol) in EtOH (4 ml) was heated to reflux for 12 hr. Upon cooling the mixture was concentrated and the residue purified by flash chromatography using ethyl acetate-hexane mixtures (5–50% gradient) to afford ethyl 2-[4-(2-{[4-(3-chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (128 mg; 61% yield).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:9]1[CH2:10][CH2:11][S:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1
Reactant: c1ccc(C2CNCCS2)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCSC(c4ccccc4)C3)c2cc1OC
Temperature: 180 °C

Procedure:
2-Phenyl-thiomorpholine (1 mole equivalent), 4-Chloro-6,7-dimethoxy-quinazoline (1 mole equivalent) and potassium carbonate (1 mole equivalent) were added to a 1:1 mixture of toluene and 2-propanol, corresponding to a final concentration of about 0.5 molar. The reaction mixture was heated in a microwave oven at 180° C. for 15 minutes, and filtrated. The solvent was removed under vacuum and the resultant solid was subjected to preparative LC-MS-purification. Fractions containing the product were collected, pooled and evaporated in vacuo to give the product.