Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@H:8]([NH:11][S:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccnc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-bromo-pyridin-4-yl)-prop-(E)-ylidene]-amide (6.0 g, 19 mmol) in THF (280 mL) was added a 1 M solution of L-Selectride in THF (37.8 ml, 37.8 mmol) dropwise. After 2.5 hours, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes to afford an oily solid, which after further drying provided 2-methyl-propane-2-sulfinic acid [(R)-1-(2-bromo-pyridin-4-yl)-propyl]-amide as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[OH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.CN(C=O)C.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:13])[CH:19]=2)=[CH:6][N:7]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CNC(=O)c1nc(Br)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Temperature: 95 °C
Yield: 71.3 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (1.34 g, 5.8 mmol) and 3-hydroxyphenylboronic acid (1.2 g, 8.7 mmol) were taken into DMF (10 mL) followed by addition of [1,1′-bis(diphenylphosphinoferrocene]dichloropalladium (II) dichloromethane complex (440 mg, 0.54 mmol) and triethylamine (4.8 mL, 35 mmol). The mixture was heated to 95° C. for 12 hours then cooled to room temperature and diluted with an excess of ethyl acetate. The organic solution was washed with 0.5 M aqueous hydrochloric acid (1×), water (3×) then brine and dried over anhydrous magnesium sulfate. The mixture was then filtered and the organic solution concentrated and the residue purified by silica gel flash chromatography using ethyl acetate:hexanes (3:1) eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (1.01 g, 71% yield) as a yellow solid: MS (EI) for C12H13N4O2: 245 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=O.C(O)(=O)C.[CH:19](N)=[NH:20]>C(OCCO)C>[C:11]([C:7]1[S:6][C:5]2[C:3]([OH:2])=[N:20][CH:19]=[N:10][C:9]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: N=CN
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Solvent: CC(=O)O
Solvent: CCOCCO
Product: CC(C)(C)c1cc2ncnc(O)c2s1
Yield: 99.3 %

Procedure:
3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.00 g, 4.69 mmol, 1 eq.), formamidine acetate (1.46 g, 4.69 mmol, 3 eq.) and 2-ethoxyethanol (10 mL) were refluxed under nitrogen for 4 hours. Purified over silica gel in 3:1 to 1:1 Hexanes/ethyl acetate to 100% ethyl acetate to obtain 970 mg of yellow solids as product. LCMS detects (M+H)+=209.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19].O=O.[K+].O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:19][C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-Bromophenyl isothiocyanate (3.639 g, 17.00 mmol) was added to a solution of 2-amino-4-chlorophenol (2.441 g, 17.00 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. The resulting brown solution was then added dropwise, via a dropping funnel, to a suspension of potassium superoxide (6.04 g, 85.0 mmol) in acetonitrile (20 mL) pre-cooled to 0° C. in an ice bath. After 20 minutes the initial exotherm had subsided and the reaction was allowed to warm to room temperature for 40 minutes. Water (120 mL) was added dropwise and the resulting off-white solid was collected by filtration, washed with additional water (60 mL) and dried overnight on a lyophilizer to afford N2-(4-bromophenyl)-5-chloro-1,3-benzoxazol-2-amine as an off-white solid (4.06 g, 74%);
Reaction SMILES: N1CCCCC1.O[CH:8]=[C:9]([CH3:13])[C:10](=O)[CH3:11].[Na].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16]>C(O)(=O)C.O>[OH:19][C:18]1[N:20]=[C:10]([CH3:11])[C:9]([CH3:13])=[CH:8][C:17]=1[C:15]#[N:16]
Reactant: CC(=O)C(C)=CO
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C#N)c(O)nc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (7.93 mL) was treated sequentially with piperidine (13.6 mL), water (208 mL), 4-hydroxy-3-methylbut-3-en-2-one, sodium salt (31.7 g, 0.257 mol) then 2-cyanoacetamide (23.8 g, 0.283 mol) then heated to reflux for 6 hours. The reaction mixture was then cooled to <20° C., treated with acetic acid (28.3 mL), stirred for 10 minutes at 0° C., then filtered and washed with water (200 mL) to yield 2-hydroxy-5,6-dimethylnicotinonitrile. To the wet solid was added 6N hydrochloric acid (200 mL) and the mixture was heated to reflux for 3 days. The cooled reaction mixture was poured into ice-water and basified with concentrated ammonium hydroxide (200 mL) and stirred for 10 minutes. The mixture was filtered, washed with water and dried under vacuum at 60° C. to yield 5,6-dimethylpyridin-2-ol (9.57 g, 22%). 400 M Hz 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 7.19 (d, 1H), 6.04 (d, 1H), 2.09 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N1CCCN2CCCCCC=12.Cl>CN(C)C=O.O>[OH:39][C@H:32]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:31][N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:24])=[C:19]([O:26][CH2:27][CH:28]([CH3:29])[CH3:30])[CH:18]=2)=[CH:13][CH:12]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylic acid (170 mg) in N,N-dimethylformamide (1.70 ml) was added 1,1′-carbonylbis(1H-imidazole) (61.7 mg) and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. To the reaction mixture were added methanesulfonamide (36.3 mg) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.057 ml) and the mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, to the reaction mixture was added water (10 ml) and the pH was adjusted to 5.98 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice), washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude produce which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1.5) and further purification by column chromatography on silica gel (eluent: chloroform/methanol=100/0 to 99/1) gave tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3′-isobutoxy-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate (63 mg) as a white foam.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]>O>[F:12][C:13]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 5 h
Yield: 71.6 %

Procedure:
0.3 g of p-toluenesulphonic acid is added to an emulsion of 284.8 g of crude diethyl 2,3,4,5-tetrafluorobenzoylmalonate in 300 ml of water. The emulsion is heated to boiling for 5 hours, stirring vigorously, then it is cooled and extracted several times with methylene chloride, and the combined methylene chloride solutions are washed once with saturated NaCl solution, dried with Na2SO4, and the solvent is removed by distillation in vacuo. Fractionation of the residue under fine vacuum provides 160.2 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate of boiling point 100°-110° C./0.09-0.1 mbar. Melting point 47°-49° C.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[CH2:24][N:25]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:26]([C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:36]1([O:35][C:33](=[O:34])[C@@H:26]([N:25]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:24][CH:12]2[C:13]3[NH:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]=3[CH2:22][CH2:23][NH:11]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(CC1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC1NCCc2c1[nH]c1ccccc21)[C@H](C(=O)OC1CCCC1)c1ccccc1
Yield: 90 %

Procedure:
A solution of stage 5 dicarbamate (0.5 g, 0.78 mmol) in ethanol (40 ml) was stirred under the atmosphere of hydrogen in the presence of 10% Pd/C (0.4 g) for 2 h under balloon pressure. The reaction mixture was filtered through a pad of celite and evaporated to dryness yielding the required product (0.35 g, 90%), 91% purity by LCMS, m/z 504 [M++H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].[C:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)#[C:19]C.[CH2:28](NCC)C>[Cu](I)I>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:23]=[CH:22][C:21]([C:26]#[C:25][CH3:24])=[CH:18][CH:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:2][CH3:28]
Reactant: CCNCC
Reactant: C#Cc1ccc(-c2ccc(CCC)cc2)cc1
Reactant: CC#Cc1ccc(I)cc1
Agent: I[Cu]I
Product: CC#Cc1ccc(C#Cc2ccc(-c3ccc(CCC)cc3)cc2)cc1

Procedure:
4-Ethynyl-4'-propylbiphenyl (prepared according to the method disclosed in Japanese patent application laid-open No. Sho 58-110527/1983) (2.2 g, 0.01 mol) and 4-(1-propynyl)iodobenzene (2.4 g, 0.01 mol) were dissolved in diethylamine (20 ml), and then copper iodide (0.11 g, 0.15 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g, 0.3 mmol) were added. The resulting mixture was subjected to reaction and purification operation in the same manner as in Example 1, to obtain the objective 4-(4-propylphenyl)-4'-(1-propynyl)tolan (compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:50][C:51]1[CH:59]=[CH:58][C:54]([CH2:55][CH2:56][NH2:57])=[CH:53][CH:52]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:57][CH2:56][CH2:55][C:54]3[CH:58]=[CH:59][C:51]([CH3:50])=[CH:52][CH:53]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Cc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and 1-hydroxybenzotriazole hydrate (34 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47 mg, 0.24 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, and 4-methylphenethylamine (30 mg, 0.23 mmol) was added. After stirring was at ambient temperature for a further 30 minutes, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (2 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless oil (96 mg, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]4[NH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][C:21]=5[C:27](O)=[O:28])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.C1N=C[N:32](C(N2C=NC=C2)=O)C=1.CN(C)C=O.N>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]4[NH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][C:21]=5[C:27]([NH2:32])=[O:28])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccc(Nc2cc(-c3cc4cccc(C(=O)O)c4[nH]3)c3[nH]ncc3c2)n1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2cc(-c3cc(Nc4ccnc(N)n4)cc4cn[nH]c34)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
A solution of 2-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indole-7-carboxylic acid (Example #F.5.11, 0.100 g, 0.000259 mol) and N,N-carbonyldiimidazole (0.0842 g, 0.000519 mol) in N,N-dimethylformamide (2.5 mL, 0.032 mol) was heated at about 55° C. for about 45 min. The mixture was cooled with an ice bath and treated with ammonia gas for about 15 min at about 0° C. The mixture was sealed and allowed to warm to ambient temperature. After about 1 hour the mixture was opened to atmosphere, and a 1.2 mL portion of the mixture was purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) then filtered to remove the remaining acid. The filtrate was then lyophilized to yield 2-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indole-7-carboxylic acid amide (2 mg, 2% yield): LC/MS Rt (Method e) 0.7 min; m/z (M+H)+ 385.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:35]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)NC1=O
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (R)-1-((5)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.6 g, 1.45 mmol) in CH2Cl2 (15 mL) was added to m-CPBA (0.59 g, 2.9 mmol). The resulting solution was stirred overnight. The mixture was diluted with methyl tert-butyl ether (100 mL) and washed with 30 wt % aq sodium thiosulfate (3×50 mL) and saturated aqueous sodium bicarbonate (3×50 mL). The organic layer was dried over Na2SO4, filtered and then concentrated to afford (4S)-1-((S)-1-(4-bromophenyl)ethyl)-4-((2-methyloxiran-2-yl)methyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.61 g, Yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Yield: 80 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.510 g; 1.3 mmol), LHMDS 1N in THF (1.44 mL; 1.44 mmol), 1-iodopropane (0.215 mL; 1.95 mmol) in DMF (4 mL) for 5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.434 g (79%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:16]=[C:11]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: C1=Cc2ccccc2C1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(C2=Cc3ccccc3C2)cc(C(F)(F)F)c1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 6.8 g (20 mmole) of 1-iodo-3,5-bis(trifluoromethyl)-benzene and 0.134 g (0.6 mmole) and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under relux for 12 h. After it all triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of water and 50 ml of diethyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cccc(F)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg) and commercially available 3-fluorophenol (0.20 ml) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform to obtain 125 mg of the title compound (yield: 94%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: C[C@H](O)C(=O)O
Agent: O=C(O)CO
Product: CC(O)C(=O)O
Yield: 228.9 %

Procedure:
A 90 wt % aqueous solution of L-lactic acid (90 g) and 10 g of glycolic acid were put into a reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the mixture was concentrated at 150° C. for 5 hours with stirring in a stream of nitrogen to give 50 g of lactic acid-glycolic acid oligomer. To the obtained oligomer was added 1.1 g of Baylith 5A with which sodium elution (381 ppm) had been observed. Then, the temperature was raised to 200° C., and the pressure was reduced gradually to 20 mmHg over 30 minutes. The mixture was stirred at 195±5° C. for one hour. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 195±5° C. for 7 hours to give lactic acid-glycolic acid copolymer in the molten state. The product was cooled to room temperature to give 29.24 g of lactic acid-glycolic acid copolymer as a white solid. The weight-average molecular weight of this copolymer was 93,000.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH2:18][O:19][CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][CH2:18][C:8]1[O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:7]=1[CH:2]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COCc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-(methoxymethyl)-5-phenylfuran (439 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (63 mg, 9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCc1ccccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-pyridineethanol (5 g), 1,6-dibromohexane (20 ml), 50% (w/v) sodium hydroxide (20 ml) and TAB (500 mg) was stirred at room temperature for 6 h. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether (1:1) to give the title compound as a colourless oil (6.6 g), t.l.c. (hexane-ether 1:1) Rf 0.19.