Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH3:6])[CH2:4][Cl:5].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[Cl:5][CH2:4][CH:3]([CH3:6])[CH2:2][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CC(CCl)CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(C)CCl)OCC
Yield: 57.2 %

Procedure:
A mixture of 1-bromo-3-chloro-2-methylpropane (95 g.) and triethyl phosphite (61.4 g.) was heated to reflux for 5.5 hours with stirring and then excess 1-bromo-3-chloro-2-methylpropane was distilled off under reduced pressure to give oily diethyl 3-chloro-2-methylpropylphosphonate (48.3 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[CH:26][NH:27]3)=[CH:23][CH:22]=2)=[O:20])[CH2:9][O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[CH:26][NH:27]3)=[CH:23][CH:22]=2)=[O:20])[CH2:9][O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2cc[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccc(F)cc2)CC1

Procedure:
Using alkylation method A, N-[1-(4-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (900 mg, 2.3 mmol) and acetone (25 mL, 340 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 45 mg (5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:24][NH:23][C:10](=[O:11])[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2ccccn2)=C1c1ccc(Cl)cc1
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
A mixture of 0.67 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-pyridyl)-2(5H)-furanone, 0.25 g of hydrazine monohydrate and 8 ml of 1-butanol was stirred for 5 hours on an oil bath of 110° C. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The resultant solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 0.32 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1>FC(F)(F)C(O)=O.O.O=[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Reaction time: 96 h
Yield: 74.6 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtO2 (0.5 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL of H2O and extracted with 50 mL of CHCl3. The organic portion was removed and discarded. The aqueous portion was then made basic (pH˜12) by addition of 10% NaOH solution. This was then extracted with CHCl3 (6×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal. The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with Et2O to give 3.19 g of 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>O1CCOCC1>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(I)cc1
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL) was cooled to 10° C. Bromine (1.1 equiv, 61.6 mmol) was added dropwise to the reaction mixture. After 10 min, the cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo, poured into water (100 mL), and extracted with (3×100 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to a tan solid (18.2 g) which was used directly in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1[N:12]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=[N:14][CH:15]=1
Reactant: c1nnn[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 31.1 %

Procedure:
4-Fluoronitrobenzene (2 g, 0.014 mol), tetrazole (1 g, 0.014 mol), potassium carbonate (1.96 g, 0.014 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), the resulting yellow solid filtered of and dried in vacuo to afford the title compound (831 mg, 31%).
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: Nc1ccccn1
Product: COc1ccc(-c2cc(=O)n3ccccc3n2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 150.8 %

Procedure:
Ethyl veratroylacetate (4.5 g) was added dropwise under stirring at 60°-70° C. to a suspension of 2-aminopyridine (0.84 g) in polyphosphoric acid (13.7 g). The reaction mixture was stirred at 100° C. for 3 hrs and poured into ice-water (50 ml). The aqueous solution was extracted with chloroform, washed with water, dried and evaporated to give dark oily residue which was chromatographed on silica gel using n-hexaneethyl acetate. The fractions were evaporated and the resulting residue was triturated with ethanol-isopropyl ether to give 2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine (3.8 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([C:9]1[C:13]2[N:14]=[C:15]([C:19]3[C:20]([O:26][CH2:27][CH2:28][CH3:29])=[N:21][CH:22]=[C:23](I)[CH:24]=3)[NH:16][C:17](=[O:18])[C:12]=2[N:11]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:10]=1)[CH3:8].C(#N)C>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:7]([C:9]1[C:13]2[N:14]=[C:15]([C:19]3[C:20]([O:26][CH2:27][CH2:28][CH3:29])=[N:21][CH:22]=[C:23]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:24]=3)[NH:16][C:17](=[O:18])[C:12]=2[N:11]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:10]=1)[CH3:8]
Reactant: CCCOc1ncc(I)cc1-c1nc2c(CC)nn(CCN3CCOCC3)c2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)nn(CCN3CCOCC3)c2c(=O)[nH]1
Reaction time: 10 h
Yield: 16.1 %

Procedure:
Trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added to a solution of the title compound of example 5 (1.0 g, 1.86 mmol) in triethylamine (20 mL). Acetonitrile (1 mL), bis(triphenylphosphine)palladium (II) chloride (33 mg, 2.5 mol %), and copper (I) iodide (9 mg, 2.5 mol %) were added and the resultant mixture stirred at room temperature for 1 h after which further trimethylsilylacetylene (0.39 mL, 2.79 mmol) was added and the mixture stirred for 10 h. After removal of the solvent in vacuo, the residue was partitioned between ethyl acetate (25 mL) and water (20 mL), the aqueous phase separated and extracted with further ethyl acetate (3×25 mL). Combined organics were washed with brine (25 mL), dried over MgSO4, and concentrated to an oil which was crystallised from diisopropyl ether to afford the title compound as a white solid (156 mg, 0.30 mmol). The addition of pentane to the concentrated mother liquors afforded a second crop (509 mg, 1.0 mmol).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21].CCN(C(C)C)C(C)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21])=[O:8]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C(Cl)CCCCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CCCCCBr)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification.
Reaction SMILES: C(OC(=O)CC[C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[CH2:22]([O:25]C1C=CC(C#N)=CC=1)[CH2:23][CH3:24]>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:11]=[CH:10][C:9]([O:25][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=1
Reactant: CCCOc1ccc(C#N)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Product: CCCOc1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-propoxy-benzonitrile; LC-MS: tR=0.71*min, [M+1]+=195.28.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH2:25])[CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)[CH:24]=1)=[O:19]
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: COC(=O)c1cc(N)nn1Cc1cc(F)c(F)c(F)c1
Product: COC(=O)c1cc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nn1Cc1cc(F)c(F)c(F)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 5-amino-2-(3,4,5-trifluoro-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester from example 39b). The title compound was obtained as a yellowish solid (Yield=34%). MS ISP (m/e): 472.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=O)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].Cl.[NH2:24][OH:25].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[N:24][OH:25])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CC=NO)ccc1OCCNc1ncnc(C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
6.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine were dissolved in 50 ml of ethanol, and a solution of 1.4 g of hydroxylamine hydrochloride in 5 ml of water was added thereto. Subsequently, a solution of 0.8 g of sodium hydroxide in 5 ml of water was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. It was then poured into water. Crystals precipitated, and these were collected by filtration, washed with water and dried to obtain 5.2 g of 5-chloro-4-{2-[4-(2-hydroxyiminoethyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine as an intermediate.
Reaction SMILES: [C:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C:2]=1[C:6]([OH:8])=[O:7].[H][H]>[Ni].C(O)C>[C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)C1=C(C(=O)O)CCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C(O)[C@H]1CCC[C@H]1C(=O)O

Procedure:
1-Cyclopentene-1,2-dicarboxylic acid (10.0 g., 0.064 mole) in 200 ml. of absolute ethanol is hydrogenated (Paar shaker) in the presence of Raney nickel at 40-50 psi/60°. After uptake of one equivalent of hydrogen (~24 hours), the mixture is cooled, filtered through a Celite (diatomaceous earth) pad, and the filtrate concentrated in vacuo to a solid. Direct recrystallization from water (~30 ml.) followed by drying in vacuo over phosphorus pentoxide yields 6 g. (60%) of cis-1,2-cyclopentanecarboxylic acid, m.p. 132°-135°. The mother liquor from the recrystallization can be lyophilized to a solid, which is sufficiently pure for use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:20]([O:22]CC)=O)=[N:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[CH3:17].C([O:27][CH2:28][CH2:29][O:30][NH2:31])=C>>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:20]([NH:31][O:30][CH2:29][CH2:28][OH:27])=[O:22])=[N:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[CH3:17]
Reactant: C=COCCON
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(SC)cc1F
Product: CSc1ccc(Nc2c(C(=O)NOCCO)nn(C)c(=O)c2C)c(F)c1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield (2 steps) by the procedures described in Example 166 (steps I and J) using ethyl 4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (50 mg, 0.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (44 mg, 0.43 mmol). MS APCI (−) m/z 381 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H), 7.03 (dd, 1H), 6.87 (t, 1H), 3.99 (t, 2H), 3.79 (s, 3H), 3.74 (t, 2H), 2.47 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[OH:20])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](OC(=N)C(Cl)(Cl)Cl)([CH3:30])[CH3:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][C@@H:6]1[O:20][C:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)([CH3:30])[CH3:29])=[O:4]
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1OC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-benzenesulfonyl)-2-hydroxy-cyclopentanecarboxylic acid methyl ester (100 mg, 0.314 mmol, example 48, step 5) and 2,2,2-trichloro-acetimidic acid 1-(4-chloro-phenyl)-1-methyl-ethyl ester (270 mg, 0.514 mmol) were dissolved in a mixture of DCM (1 ml) and cyclohexane (2 ml). Then a solution of trifluoromethanesulfonic acid (0.836 μl, 0.00941 mmol) in DCM (0.1 ml) was added and the reaction mixture was stirred at room temperature for 6 h. Then saturated NaHCO3 solution was added and the mixture was extracted 3 times with ether. The combined organic layers were dried (Na2SO4) and evaporated. The remaining light yellow oil was purified by silica gel chromatography (heptane/EtOAc 4:1-3:1) to obtain the title compound (47 mg, 32%) as white solid. MS (EI): 488.1 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[CH3:13][O:14][CH:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)[CH:3]=2)=[CH:19][CH:18]=[CH:17][NH:16]1
Reactant: Brc1cccc(-c2cnco2)c1
Reactant: COc1ncccc1B(O)O
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: C1CCOC1
Solvent: O
Product: COC1NC=CC=C1c1cccc(-c2cnco2)c1

Procedure:
A mixture of 5-(3-bromo-phenyl)-oxazole VI-a (1.33 g, 5.94 mmol), 2-methoxy-3-pyridinylboronic acid (1.00 g, 6.53 mmol), Pd(PPh3)4 and K2CO3 (1.81 g, 13.1 mmol) in THF (20 mL) and water (10 mL) was heated to reflux for 4 h. The mixture was cooled, then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and the residue purified by column chromatography (SiO2; eluting with 30% EtOAc in cyclohexane) to afford the desired product VI-b as brown oil which crystallized on standing (1.37 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J=1.8, 5.0 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.64 (d, J=6.9 Hz, 2H), 7.53-7.44 (m, 2H), 7.37 (s, 1H), 6.99 (dd, J=5.0, 7.2 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (6.36 g, 32.9 mmol) and 2,6-dichlorobenzothiazole (5 g, 24.5 mmol) in isopropanol (150 mL) was added 4 N HCl solution in 1,4-dioxane (1.5 mL, 6 mmol). The mixture was refluxed at 100° C. for 7 h, and then allowed to cool to room temperature. The resulting precipitate was isolated by filtration to yield the first crop of the title compound as a white solid (3.13 g). The mother liquor was concentrated in vacuo and then stirred in a mixed solvent of TFA (20 mL) and dichloromethane (20 mL) overnight. The solvent was removed in vacuo, the obtained residue triturated with isopropanol/ethyl acetate. The isolated white solid was further stirred in a mixed solvent of isopropanol (12 mL) and ethyl acetate (8 mL) for 0.5 h, then isolated by filtration to yield a second crop of the title compound (3.5 g) (total 6.63 g, 85%). HPLC/MS (Method C): retention time=2.51 min, [M+H]+=305.3.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccccc2[C@H](Nc2ccccc2)C[C@@H]1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2[C@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 90 °C
Yield: 40 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.163 g, 0.58 mmol, 1.0 equiv) and 2-furoyl chloride (0.285 mL, 2.9 mmol, 5.0 equ), pyridine (1.0 equiv.) and dry toluene (3 mL). The solution was heated to 90° C. for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (50% hexane/50% ethyl acetate) to yield the cis isomer 40% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[N:11][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[OH:21].Cl>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[N:11][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[OH:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetyl chloride (0.6 ml.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.). The solution was stirred at room temperature for 16 hours and then was poured onto a mixture of ice (100 g.) and 5N-hydrochloric acid (50 ml.). The mixture was kept at 4° C. for 4 hours, and the solid precipitate was then filtered off, washed with water (10 ml.), dried as much as possible on the filter, and recrystallised from ethanol to give ethyl 6-acetylamino-4-hydroxycinnolin-3-yl carboxylate, m.p. 280°-281° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12])[CH3:2].C1(=O)O[CH2:16][CH2:15][O:14]1>[Br-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH2:16][CH2:15][OH:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cccc(C=O)c1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCOc1cccc(C=O)c1OCCO
Temperature: 140 °C

Procedure:
A mixture of 40 g of 3-ethoxysalicylaldehyde, 22 g of ethylene carbonate and 40 g of tetraethylammonium bromide was heated at 140° C. for 4 hours. After cooling to room temperature ethyl acetate was added to the reaction mixture, the solid material was filtered off, the filtrate was washed with water and the organic phase was dried over magnesium sulfate and evaporated. The residue was distilled under reduced pressure.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC[C@H]1CCCN1
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (R)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.11 (d, J=13 Hz, 1H), 3.90 (d, J=6 Hz, 2H), 3.41 (m, 2H), 3.34 (m, 3H), 2.89 (m, 1H), 2.71 (m, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 1.93 (m, 2H), 1.54 (m, 3H).