Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:40]1[N:45]=[CH:44][C:43]([C:46]([NH:48][CH3:49])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:49][NH:48][C:46](=[O:47])[C:43]1[CH:42]=[CH:41][C:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:45][CH:44]=1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47) in N,N-dimethylformamide (˜0.06 M) under a dry nitrogen atmosphere is placed in a microwave vial and stirred. Sodium hydride or a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equivalents) is added to the reaction mixture and stirring is continued for 45 minutes. 6-Chloro-N-methyl-3-pyridinecarboxamide (CAS #54189-82-1, 1.2 equivalents) is added to the reaction mixture and stirring is continued for 2-3 hours at 100° C. under microwave irradiation with the cooling air remaining on for the duration of the heating cycle. The reaction mixture is cooled to ambient temperature, dried (MgSO4), and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with 98:2 dichloromethane/2 M NH3 in methanol. Fractions containing product are combined and concentrated under reduced pressure to give (R)—N-methyl-6-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yloxy)nicotinamide.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)=[CH:2]1.[Br:19][C:20]1C=C(CC=O)C=C[CH:25]=1>C(Cl)Cl.CO>[Br:19][C:20]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[CH:4]=[CH:5][CH:25]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-bromophenyl)-acetaldehyde. The title compound: ES-MS: 348.9 [M+2]+; single peak at tR=3.92 min (System 2); Rf=0.47 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([F:14])=[CH:9][C:8]=2[C:7]2[C:15]([C:26](OC)=[O:27])=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18](=[O:19])[C:6]1=2)[CH3:4]>O1CCCC1.CO>[CH2:3]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([F:14])=[CH:9][C:8]=2[C:7]2[C:15]([CH2:26][OH:27])=[N:16][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:18](=[O:19])[C:6]1=2)[CH3:4]
Reactant: CCn1c2ccc(F)cc2c2c(C(=O)OC)nn(-c3ccccc3)c(=O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c2ccc(F)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
5.1 g (135 mmol) of sodium borohydride are added, in several portions and at room temperature, to a solution of 10 g (27.3 mmol) of methyl 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 200 ml of tetrahydrofuran and 5.8 ml of methanol and the mixture is stirred for 4 h at reflux. The mixture is poured onto an ice-cold 0.1N hydrochloric acid solution, an insoluble material is separated by filtration, the insoluble material being washed with water and with diethyl ether, on sintered glass, and then it is dried. 7.2 g (21.4 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]3([N:25]4[CH:29]=[N:28][C:27]([Cl:30])=[N:26]4)[CH2:24][CH2:23]3)[CH2:21][O:20]2)=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2([N:25]3[CH:29]=[N:28][C:27]([Cl:30])=[N:26]3)[CH2:24][CH2:23]2)([OH:20])[CH2:21][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1

Procedure:
13 g (191 mmol) of imidazole and 1 g (9 mmol) of potassium tert. butoxide are initially introduced under a nitrogen atmosphere into 100 ml of acetonitrile under reflux and 18 g (61 mmol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane dissolved in 30 ml of acetonitrile are added dropwise. The mixture is allowed to react under reflux conditions for 10 hours and the solvent is then evaporated in vacuo. The residue is taken up in ethyl acetate and washed with water. The solution is dried over sodium sulphate and the solvent is removed in vacuo. Chromatographic purification on silica gel (solvent: dichloromethane/ethanol=90/10) gives 7.1 g (32% of theory) of the title compound of m.p. 231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Cl
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 50 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 500 ml of methanol is added HCl gas until all the material dissolves. Stirring is continued overnight, the solvent removed, ether added, filtered, dried over magnesium sulfate and evaporated to dryness to obtain methyl 2-methoxy-4-amino-5-chlorobenzoate which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Temperature: 40 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:25])[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH:18]([CH3:25])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1CNC(C)c2ccccc21
Product: CC1CN(C(=O)c2cc3ncc(Br)cn3n2)C(C)c2ccccc21

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][O:25]C(=O)C)=[O:23])=[CH:17][CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[NH:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:23])[CH2:24][OH:25])=[CH:19][CH:20]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NC(=O)COC(C)=O)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NC(=O)CO)cc3)nc2c1
Yield: 26.2 %

Procedure:
The yellow solid was triturated with ether and methanol to provide acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (112 mg, 37%). To a solution of acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methyl ester (0.23 g, 0.59 mmol) in THF/methanol mixture (3.5 mL/3.5 mL) was added potassium carbonate (0.41 g, 2.95 mmol). The reaction mixture was heated at reflux overnight and the solvent was concentrated under vacuum and diluted with water (60 mL) to obtain a precipitate. The yellow solid was filtered, washed with water (20 mL), methanol and dried under vacuum to provide crude compound. The yellow solid was triturated with ether and methanol to provide the desired compound N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide (55 mg, 55%). Selected data: MS (ES) m/z: 356.1; mp 318-319° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:8]=[CH:7][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COCCN
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(Nc2cccc(Cl)c2)ncn1
Temperature: 200 °C
Yield: 70 %

Procedure:
75 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 30 mg of 2-methoxyethanamine and 88 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-(3-Chlorophenyl)-N6-(2-methoxyethyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.C1C[N:44]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O1CCOCC1.N>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([NH2:44])=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:29])[CH3:30])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(N)=O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 243.8 %

Procedure:
4-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid (107 mg, 0.192 mmol) was treated with PyBOP (169 mg, 0.326 mmol) and 1,4-dioxane (5 mL) and DMF (1.0 mL) and stirred at RT for 10 min. The reaction was then cooled in an ice bath and treated with NH3, 0.5 M solution in 1,4-dioxane (1.9 mL, 0.96 mmol) and stirred at 0° C. for 1.5 h. The reaction was quenched with water, extracted with EtOAc (25 mL), washed with brine (2×25 mL), dried over MgSO4, filtered and concentrated affording 261 mg of the crude amide. MS (ESI, pos. ion) m/z: 558.2 (M+H)+. The crude material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([N:28]([CH3:27])[NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CNN
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: O
Solvent: C1CCOC1
Product: CN(N)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1.0 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 0.28 ml of methylhydrazine and 16 ml of tetrahydrofuran was stirred at room temperature for 19 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.97 g of 3-bromo-N-[4,6-dibromo-2-(N-methylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[CH:3]1[CH2:6][O:5][CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:13][N:12]1[C:8]([CH2:7][N:2]([CH3:1])[CH:3]2[CH2:4][O:5][CH2:6]2)=[CH:9][C:10]([NH2:14])=[N:11]1
Reactant: CN(Cc1cc([N+](=O)[O-])nn1C)C1COC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(Cc1cc(N)nn1C)C1COC1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
To a solution of 302b (1.8 g, 7.96 mmol) in ethanol (20 mL) and water (20 mL), NH4Cl (3.3 g, 63.6 mmol) and iron powder (1.80 g, 31.8 mmol) were added. The reaction mixture was heated at 70° C. for 2 h. After that, the mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was extracted with methylene chloride (3×30 mL), dried Na2SO4, and concentrated to afford the crude product, which was purified on flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to afford 302c as a yellow oil (1.3 g, 83%). LCMS: (M+H)+ 197
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[CH:1]1([CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: OCCNCC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(CCO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 2-(cyclohexylmethylamino)-ethanol (600 mg, 3.8 mmol) in DCM (6 mL) at 0° C. was added DIPEA (588 mg, 4.6 mmol) and then acetoxyacetyl chloride (467 mg, 3.44 mmol) over 5 min. The resulting mixture was warmed to room temperature, stirred overnight under an atmosphere of nitrogen, diluted with DCM and washed successively with 1 N aqueous HCl, saturated NaHCO3, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield the title compound (914 mg). (m/z): [M+H]+ calcd for C13H23NO4, 258.16. found, 258.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[S:18]1(=[O:30])(=[O:29])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=[C:2]([N:21]2[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:18](=[O:30])(=[O:29])[CH2:19][CH2:20]2)[CH:11]=1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: FC(F)(F)Oc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: CCCCO
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A mixture of 2,4-dichloro-6-(trifluoromethoxy)quinoline (250 mg, 0.89 mmol), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (210 mg, 1.06 mmol) and n-butanol (2 mL) was heated with stirring in a 5 mL of microwave process vial for 3 hours at 150° C. under microwave irradiation. The mixture was filtered. The formed solid was collected by filtration and washed with 10 mL of mixture solution of petroleum ether and ethyl acetate (V/V=10/1) to afford 0.3 g of the product (yield was 77%).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[CH2:12][CH3:13])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: CC[C@@H]1C(=O)N[C@@H]1C=COC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N[C@@H]1CCOC(C)=O
Reaction time: 6 h
Yield: 99.1 %

Procedure:
Cis-(±)-4-[2-(acetoxy)ethenyl]-3-ethyl-2-azetidinone (20 g, 0.109 mole) is dissolved in ethyl acetate (150 ml) warming the mixture until complete solution. Then, 10% Palladium on carbon catalyst (1 g) is added and the starting compound is hydrogenated at room temperature and with a pressure of 3 atmosphere of hydrogen gas, in a Parr autoclave. After six hours the autoclave is discharged and the catalyst is filtered. The solvent is evaporated and the crude cis-(±)-4-[2-(acetoxy)ethyl]-3-ethyl-2-azetidinone (20 g) thus obtained is placed in a 250-ml flask equipped with a calcium chloride drying tube and a dry nitrogen inlet tube, charged with potassium carbonate (5 g, 3.6×10-2 mole) and anhydrous methanol (130 ml). The reaction mixture is stirred at room temperature for about one hour, then it is neutralized by the addition of citric acid (5.5 g, 2.9×10-2 mole), and filtered through a Buchner funnel. The solid on filter is washed with methanol (2×10 ml) and the filtrate plus the methanol washings are concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water (100 ml) and extracted with methylene chloride (3×20 ml). The combined methylene chloride extracts are washed with water (2×15 ml) and then discarded. The aqueous solutions are combined, saturated with ammonium sulfate and extracted with five 20-ml portions of ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulfate and the solvent is removed under reduced pressure to yield 10.4 g (67.3%) of cis-(±)-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone II as a thick oil, sufficiently pure for the next step.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:6]1[CH3:31].O1CCCC1.[OH-].[Na+].Cl>CO>[C:25]1([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=2[CH3:31])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A mixture of [3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.17 g), tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was treated with 1.0 M aqueous sodium hydroxide solution (1.5 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution (1.5 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a cream solid (0.13 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([OH:24])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:32].[CH3:31][C:2]1([CH3:1])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([O:24][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-tetradecyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8](OCC)[O:9]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH:8]=[O:9]
Reactant: CCOC(C#CCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=CC#CCCCCCl
Temperature: 62.5 °C
Yield: 95 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 7-chloro-1,1-diethoxy-2-heptyne (218.7 g:1.0 mol), para-toluenesulfonic acid (8.0 g:0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 7-chloro-2-heptynal [bp: 66-72° C./0.13 KPa, 137.8 g, 0.95 mol]. [Yield: 95.3%]