Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: C[C@H]1CO1
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)Cn1ccc2cc(F)c(F)cc21
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of 0.12 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.46 mlof (S)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with water. The mixture was diluted with ether, washed twice with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.5 g (74%) of (S)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol as yellowish crystals with m.p. 116°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[C:9]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(OC([NH:24][CH2:25][CH2:26]O)=O)(C)(C)C>>[ClH:1].[NH2:24][CH2:25][CH2:26][O:13][C:10]1[C:9]([CH:14]([CH3:16])[CH3:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1ccc(Cl)cc1
Product: CC(C)c1c(OCCN)noc1-c1ccc(Cl)cc1
Product: Cl
Yield: 189.8 %

Procedure:
5-(4-Chlorophenyl)-3-hydroxy-4-isopropylisoxazole (0.15 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.11 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.19 g, 79%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (48%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (S)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 320 mg 6-(2,4-difluoro-phenoxy)-2-((S)-(+)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido [2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=175.1-179.1° C.).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:37][CH2:38]5)=[CH:29][CH:28]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
2-[4-(4-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide was prepared from 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide in an analogous manner to Example 1052a. Product isolated as an orange solid (104 mg, 54%). m.p.=170-173° C.; LCMS (m/e) 571 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.52-7.44 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 7.19 (d, 2H, J=8.3 Hz), 7.19-7.08 (m, 1H), 7.00 (d, 1H, J=4.7 Hz), 6.87-6.80 (m, 2H), 5.45 (bs, 1H), 4.88 (s, 2H), 3.05 (s, 2H), 3.06-2.97 (m, 2H), 2.58-2.43 (m, 1H), 2.38-2.25 (m, 2H), 1.94-1.85 (m, 2H), 1.85-1.70 (m, 2H), 0.97 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[C:13](OC)=[O:14])=[CH:4][CH:3]=1.[NH3:24]>CO>[N+:20]([C:19]1[CH:18]=[CH:17][C:12]([C:13]([NH2:24])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23])([O-:22])=[O:21]
Reactant: N
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Solvent: CO
Product: NC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 80 °C
Yield: 22.8 %

Procedure:
Methyl N-(4-chlorophenyl)-4-nitroisophthalamate (220 mg) obtained in step A was dissolved in 10 mL of a methanol solution of 7 mols of ammonia. After the reactor was sealed, the solution was heated for 36 hours at 80° C. with stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The resulting solid was dried under reduced pressure to obtain 48 mg (23%) of 4-nitro-3-N-(4-chlorophenyl)-isophthalamide.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[NH2:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10]C=1.[CH2:13](O)C>>[Cl:1][C:2]1[CH:3]=[CH:10][C:9]2[N:5]([CH:6]=[CH:7][N:8]=2)[CH:13]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)nc1
Reactant: CCO
Product: Clc1ccc2nccn2c1

Procedure:
To a solution of 50% aq. chloroacetaldehyde (1.1 eq, 291 mmol, 37 ml) in ethanol (700 ml) is added 3-amino-6-chloro-pyridine (1 eq, 264 mmol, 34 g) at room temperature. The reaction mixture is refluxed for 3 hours. The solvent is removed in vacuo and the crude product is dissolved in water (400 ml). The aqueous solution is treated with sodium bicarbonate to pH=8 and extracted with dcm (3×250 ml), the organic layer is dried (MgSO4) and evaporated to give a brown solid (39.2 g) 6-chloro-imidazo[1,2-a]pyridine; [M+H]+153(155)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=C([CH:14]=[CH:15][CH:16]=1)OC1CCC(=O)CC1.[C:19]([NH:21][C:22]([NH2:24])=[NH:23])#[N:20].C(O[CH2:28][CH2:29][O:30][CH2:31][CH2:32]O)C>>[NH2:23][C:22]1[N:21]=[C:19]([NH2:20])[C:2]2[CH2:32][CH:31]([O:30][CH2:29][C:28]3[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=3)[CH2:15][CH2:16][C:3]=2[N:24]=1
Reactant: CCOCCOCCO
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Product: Nc1nc(N)c2c(n1)CCC(OCc1cccc(C(F)(F)F)c1)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.5 grams (0.013 mole) of 4-(3-trifluoromethylphenoxy)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(3-trifluoromethylphenylmethoxy)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1=c2cnc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of Example 69e (0.02 g, 0.053 mmol), triethylamine (53.6 mg, 0.53 mmol), and acetyl chloride (0.019 mL, 0.265 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 2 hours. Additional acetyl chloride (0.057 mL, 0.795 mmol) and triethylamine (161 mg, 1.59 mmol) were added, and the reaction mixture was stirred for additional 3 hours. The solvent was evaporated, and the residue was treated with dioxane (3 mL) and 2.0 NaOH (1 mL). The reaction mixture was heated at 80° C. for three hours. The solvents were partially removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC(C18, CH3CN/water (0.1% TFA), 0-100%) to afford 0.018 g (67.3%) of the title compound as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J=5.8, 1H), 10.31 (s, 1H), 8.53 (d, J=2.75 Hz, 1H), 8.42 (d, J=2.44 Hz, 1H), 7.74 (s, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.03-7.07 (m, 2H), 6.57-6.60 (m, 2H), 4.65 (br s, 2H), 4.07 (s, 3H), 2.13 (s, 3H). MS (DCI+) m/z 420.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[C:3]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[C:3]([C:6]([Br:1])([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
Bromine (16.7 g., 0.104 mole) dissolved in carbon tetrachloride (100 ml.) is added dropwise to a stirred solution of ethyl 8-acetyl-12-acetoxyheptadecanoate (Example 1, Step C) (37.4 g., 0.094 mole) in carbon tetrachloride (200 ml.) during one hour. The solvent is distilled in vacuo. The residual oil is dissolved in ether and washed with dilute sodium bicarbonate, water and brine and dried over sodium sulfate. Evaporation of the ether leaves the crude bromo ester as a yellow oil weighing 43 g. It is purified by column chromatography on silica gel with benzene as the eluant. This procedure serves to separate the desired bromo ester from a small amount of a by-product, ethyl 8-bromoacetyl-8-bromo-12-acetoxyheptadecanoate. Ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate is thus obtained as a pale yellow oil weighing 12.7 g. (28%).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:12]([N:14]1[C:3](=[O:11])[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:10][C:15]1=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: COC(=O)c1cccnc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCn1c(=O)[nH]c2ncccc2c1=O
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A mixture of 20.00 g (0.132 mol) of 2-aminonicotinic acid methyl ester, 17.67 g (0.248 mol) ethyl isocyanate and 2 g (0.016 mol) 4-dimethylaminopyridine in dry pyridine was refluxed for 23 hours. The pyridine was removed under reduced pressure and the residue was treated with 370 ml methanol. The mixture was refluxed for 10 minutes and allowed to cool down first to room temperature. The mixture is further cooled to 0° C. and the crude 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was allowed to crystallize over night. The crude 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was further purified by preparative column chromatography on straight phase silica (eluent:chloroform:methanol 9:1). The isolated 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was recrystallized from dimethyl formamide, isolated by filtration and washed twice with ethanol and twice with tert butyl methyl ether. The isolated compound was further recrystallized from methanol. A first crop of 2.5 g was isolated. Upon concentration of the filtrate a second crop of 0.5 g was isolated. Both fractions were pooled and finally 3.00 g (12%) of 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 240-1° C.)
Reaction SMILES: C([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:5][C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])([CH3:13])([CH3:9])[CH3:7]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g), benzoyl formic acid (1 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (35 ml) and saturated sodium bicarbonate (15 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture, and slowly warmed to room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (20 ml) and the organic layer was washed several times with water. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white gum. The crude product was chromatographed on silica gel (G:230-400 mesh) using a methylene chloride ether solvent system as eluant to afford a 65% yield of a white solid.
Reaction SMILES: [C:1]1([N:7]=[CH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:15]([CH:16]1[CH:8]([N:7]([C:31]([O:33][CH3:34])=[O:32])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:17]1)=[O:18]
Reactant: COC(=O)Cl
Reactant: C=CC(=O)OC
Reactant: Cc1ccsc1C=Nc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCc2ccsc2C1N(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
3-methylthiophene-2-aldehyde phenylimine (50 g, 0.248 mol), methyl acrylate (224 ml, 2.48 mol) and diisopropyl ethylamine (173 ml, 0.993 mol) were mixed in xylene (1000 ml) and stirred under ice cooling. Methyl chloroformate (76.8 ml, 0.993 mol) was added to the mixture. After completing the addition, the reaction mixture was heated under reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride and dried over sodium sulfate. After distilling off the solvent, 83 g of crude N-methoxycarbonyl-N-phenyl-7-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid methyl ester was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH:38]=[N:37][N:36]=[N:35]3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH:38]=[N:37][N:36]=[N:35]3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-n3cnnn3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-n3cnnn3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(tetrazol-1-yl)phenyl]piperidin-3-ol (0.6 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 0.48 ml of triethylamine (3.4 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.54 g, 3.4 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 0.4 g of the titled compound.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][O:23][C:24]1[CH:53]=[CH:52][C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)[O:30][C:26]=2[CH:25]=1>CO>[ClH:1].[CH3:22][O:23][C:24]1[CH:53]=[CH:52][C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)[O:30][C:26]=2[CH:25]=1
Reactant: COc1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)oc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2nc(N3CCNCC3COc3cccnc3)oc2c1
Reaction time: 2 h
Yield: 44 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-methoxybenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (150.6 mg, 0.225 mmol) in MeOH (1 mL). After 2 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH, and brine (20 mL) was added. This was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.031 mL) was added. The mixture was concentrated under reduced pressure to give 37.4 mg (44%) of the desired product as the hydrochloride salt. LC-MS: RT=4.00 min, [M+H]+=341.1.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCOCC>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[O:29][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=Cc2ccc(Oc3cc(C)ccc3C)cc2OC1C(F)(F)F
Temperature: 110 °C

Procedure:
To 0.200 g (0.689 mmole) of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 2.5 mL of DMF was added 0.118 g (0.946 mmol) of 2,5-dimethyl phenol to the vessel followed by 0.131 g (0.946 mmole) of potassium carbonate. The suspension was prepared in a capped vial and placed in a J-KEM heating block equipped with shaker, condenser and nitrogen atmosphere. The block was heated to 110° C. for 20hrs. For work up, 10 mL of H2O and 5 mL of ether was added to the mixture. The organic layer was separated and then the aqueous was extracted 3 times with ether. The product was then run through a pre-packed silica gel plug (20 mL, 5 g capacity) and the silica column washed with 4×5 mL aliquots of ether. Concentration of the solution afforded the product with was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[NH4+].[O-:13][C:14]#[N:15].[K+]>O>[NH:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:15][C:14]1=[O:13]
Reactant: N#C[O-]
Reactant: Nc1ncccc1C(=O)O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: O=c1[nH]c(=O)c2cccnc2[nH]1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A slurry of 2-aminonicotinic acid (10 g, 72.5 mmol), ammonium chloride (39 g, 725 mmol) and potassium cyanate (30 g, 362 mmol) in water (80 ml) was heated to 80° C. and maintained at this temperature with stirring for 30 minutes before being heated to 200° C. The mixture was stirred for 2 hours at this elevated temperature and then left to cool. Water (200 ml) was then added and the resultant mixture filtered. The solid was washed with hot water (100 ml) and then with cold water (2×100 ml) to give a yellow solid which corresponded to the title compound (11.79 g, 99%) in suitably clean form to be used without any further purification. m/z (LC-MSW, ESP):164 [M+H]+, R/T=2.11 mins.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19]CC(Br)Br)(=[O:18])[CH2:16][CH3:17]>CC(C)=O>[O:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH2:16][CH2:15]1.[CH3:17][CH2:16][C:15]([O-:19])=[O:18]
Reactant: Oc1ccccc1O
Reactant: CCC(=O)OCC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)[O-]
Product: c1ccc2c(c1)OCCO2
Reaction time: 4 h
Yield: 699.4 %

Procedure:
Ortho-dihydroxybenzene (11 g, 100 mmol) and anhydrous acetone (70 mL) were refluxed under nitrogen. Potassium carbonate (5 g, 36 mmol), dibromoethyl propionate (6.56 g, 25.3 mmol) were added portion-wise in sequence over a period of 1.5 hours. After 4 hours, the reaction was completed, which was confirmed by thin film chromatography. The crude product was cooled to room temperature, concentrated under reduced pressure to remove acetone, added with NaHCO3 solution, and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and condensed to afford 18.51 g the product (89% yield).