Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCO
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Product: COc1ccccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydro-pyrrolo[3,2-c]quinoline(500 mg, 1.2 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 3 in the Example 38 to obtain 425 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[NH:33]([C:10]([C@@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])[NH2:34]
Reactant: O=C[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 24 h

Procedure:
18.1 g (43 mmoles) of 2,3,5-tri-O-benzyl-D-ribose are dissolved in 18 ml of absolute methanol and, while cooling and stirring 21.5 g (43.0 mmoles) of 100% hydrazine hydrate (dissolved in 20 ml of absolute methanol) are added to the solution. After a few minutes the ice bath is removed and stirring is carried out for 24 hours at room temperature. The excess hydrazine hydrate is drawn off (oil pump) together with the methanol in a rotary evaporator at room temperature. A viscous yellow oil remains which is dried further using an oil pump. Yield: 17.9 g (96%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH2:4][OH:5].[F:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[C:25]([F:28])[C:26]=1[F:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:20][C:21]1[CH:22]=[C:23]([O:5][CH2:4][C:3]2[C:2]([F:1])=[CH:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[F:19])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: CCCc1ccc(-c2cc(F)c(CO)c(F)c2)cc1
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(COc3cc(F)c(F)c(F)c3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In a nitrogen atmosphere, 10.00 g of 2,6-difluoro-4-(4-propylphenyl)benzyl alcohol, 5.65 g of 3,4,5-trifluorophenol, and 13.01 g of triphenylphosphine were dissolved in 30 mL of THF, the resultant solution was cooled to −20° C., and 8.48 g of DIAD was added dropwise at such a rate that the inside temperature did not exceed −10° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Then, the residue was suspended by adding hexane, and precipitated triphenylphosphine was filtered off. An organic layer was washed with saturated brine and dried by adding sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and then recrystallized from ethanol to yield 11.32 g of (3,4,5-trifluorophenyloxy)-[2,6-difluoro-4-(4-propylphenyl)phenyl]methane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccncc2)cc1
Yield: 77.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.051 g (77%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(OC)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid (110 g, 0.421 mol) and POCl3 (300 mL) was refluxed overnight and then was allowed to stand at room temperature for about 3 days. The reaction mixture was poured into ice-water and then was basified with NH4OH. The solid which formed was collected by filtration, washed with water and air dried to afford 100.5 g of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][F:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1.O>CN(C=O)C>[F:12][CH2:11][O:10][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1
Reactant: COC(=O)c1cnc(O)cn1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCF)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in DMF (2.0 mL). The reaction solution was stirred at 70° C. for 5 h and 30 min and then cooled to RT. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.03 (s, 3H), 6.14 (d, J=51.2 Hz, 2H), 8.42 (d, J=1.2 Hz, 1H), 8.94 (d, J=1.2 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1.[Br:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C=O>[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:18](=[O:19])[CH2:17][Br:16])=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1
Reactant: O=C(Cl)CBr
Reactant: CN1CS(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN1CS(=O)c2cc(C(=O)CBr)ccc21

Procedure:
210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm3 ground-necked flask surmounted by a condenser, and 43 cm3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 33 9 (0.20 mol) of 3-methylbenzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70° C. using an oil bath. 19.8 cm3 (0.24 mol) of bromoacetyl chloride are then added gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70° C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed with water until the filtrate is neutral and dried. The product is recrystallized in 95° strength alcohol.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][CH:8]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[NH4+].[Cl-]>C1COCC1.O>[CH2:16]([O:15][C:14](=[O:18])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:13])[N:12]=1)[CH3:17]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1cccc(Cl)n1
Reaction time: 0.75 h
Yield: 60 %

Procedure:
To a solution of n-BuLi (100 mL, 250 mmol of a 2.5 M solution in hexanes) in THF (200 mL) was added DIA (36 mL, 255 mmol) at 0° C. After stirring for 45 min, 6-methyl-2-chloropyridine (14.2 g, 111 mmol) was added slowly, maintaining the temperature <5° C. After 30 min, diethyl carbonate (30 mL, 250 mmol) was added dropwise maintaining the temperature below 10° C. The solution was stirred at 0° C. for 1 h, then water was slowly added, followed by the addition of a saturated solution of NH4Cl. The organic phase was dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified through a pad of silica gel to give the product (13.3 g, 66.6 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 2.04 (s, 2H), 4.19 (q, 2H), 7.23 (dd, 2H), 7.62 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cccc2cc[nH]c12
Product: Fc1ccccc1-c1cccc2cc[nH]c12

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-fluorophenylboronic acid: ESMS m/e: 211.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: Nc1cccnc1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Pyridinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 h. The N,N-dimethylformamide was evaporated on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 min. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification was carried out. 1.23 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](COS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (4S)-1-(tert-butyloxycarbonyl)-4-hydroxymethyl-L-proline tert-butyl ester (364 mg, 1.21 mmol) in pyridine (2 mL) cooled to 0° C. was added methanesulfonyl chloride (0.19 mL, 2.42 mmol). The reaction mixture was stirred for 2 hours at ice temperature, diluted with ethyl acetate (100 mL), washed with 1M sodium hydrogencarbonate solution, 1M citric acid, water, saturated brine solution, dried (Na2 SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 20% acetone/hexane; yield 437 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:27]3[CH2:28][CH2:29][CH:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)=[O:17])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nn(-c2ccc(Cl)c(Cl)c2)c(C)c1C(=O)O
Product: Cc1nn(-c2ccc(Cl)c(Cl)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 87 %

Procedure:
In analogy to the procedure described in Example 181, 1-(3,4-Dichloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 87% yield as white foam. MS: 421.2 (MH+, 2 Cl).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:15]([CH:19]=[O:20])=[C:14]([O:21][CH3:22])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:8])=[CH:5][N:6]=1.CN(C)C=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][O:21][C:14]1[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([C:7]([C:4]3[S:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:6][CH:5]=3)=[O:8])[CH2:18][CH2:17][C:16]=2[C:15]=1[CH:19]=[O:20]
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(Br)s1)C2
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(N3CCN(C)CC3)s1)C2
Yield: 38.3 %

Procedure:
To a solution of 2-(2-Bromo-thiazole-5-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (229 mg, 0.60 mg) in abs. N,N-dimethylformamide (4 mL), N-methyl piperazine (133 μL, 120 mg, 1.20 mmol) and dry potassium carbonate (248 mg, 1.80 mmol) was added. The resultant mixture was stirred under nitrogen at 100° C. for 2 h in a closed vial. The reaction was cooled, water (10 mL) was added, and the resultant solution was extracted with ethyl acetate (3×15 mL) The combined organic layers were dried (MgSO4) and evaporated to afford title compound (92 mg, 0.23 mmol, 38%) as a pale yellow crystalline solid.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1>>[CH:1]1([O:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(CCO)cc1
Reactant: C1=CCCCC1
Product: Cc1ccc(CCOC2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
246 grams of cyclohexene is added to a stirred slurry of p-methyl phenyl beta ethanol (408 grams) and 25 grams of Amberlyst® 15 cation exchange resin maintained at 110° C., over a 2 hour period. The reaction mass is then aged at 110° C. for an additional 3 hours whereupon it is cooled and filtered. The resulting solution is then heated at reflux with 80 grams of 30% aqueous sodium hydroxide. The reaction mass is then cooled and the resulting organic layer is washed with 1 liter of water. The organic layer is separated from the reaction mass and distilled through a 11/2"×12" Goodlow packed column to afford the following distillation fractions:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:2]=1.[CH3:16][O:17][C:18](=[O:45])[CH:19]=[CH:20][CH:21]([NH:37]C(OC(C)(C)C)=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH3:16][O:17][C:18](=[O:45])[CH2:19][CH2:20][CH:21]([NH:37][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)CCCC/C=C/c1cccnc1
Reactant: COC(=O)C=CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Product: COC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1cccnc1
Yield: 26 %

Procedure:
Isolated as a gum from (E)-7-Pyridin-3-yl-hept-6-enoic acid 76 (137 mg, 0.67 mmol) and (RS)-5-(4-Benzyloxy-phenyl)-4-tertbutoxycarbonylamino-pent-2-enoic acid methyl ester RS-40 (250 mg, 0.61 mmol) to afford the title compound (79.4 mg, 26%) as a gum: chromatographed on silica using 70:30 EtOAc:petroleum. 1H nmr (CDCl3) δ 1.30 (m, 4H), 1.49-1.82 (m, 5H), 1.82-1.95 (m, 1H), 2.08 (t, J=8 Hz, 2H), 2.34 (m, 2H), 2.59 (t, J=8 Hz), 2.69 (dd, J=7, 14 Hz, 1H), 2.77 (dd, J=7, 14 Hz, 1H), 3.65 (s, 3H), 4.15 (m, 1H), 5.03 (s, 2H), 5.36 (br d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H), 7.17-7.52 (m, 7H), 8.42 (br s, 2H). ESMS 503 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C@@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[CH3:30])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)NC(=O)[C@@H](O)CCO
Yield: 58 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 73, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 58% yield; NMR spectrum (DMSO-d6) 1.23 (d, 3H), 1.27-1.40 (m, 1H), 1.60-1.62 (m, 1H), 3.33-3.46 (m, 2H), 3.87-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-7.38 (m, 2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 543.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1)[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:7]=[C:8]([O:13][CH3:14])[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Reactant: C1COCCN1
Product: CCOC(=O)Cc1nc(OC)cc(N2CCOCC2)n1

Procedure:
1.5 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester and 20 ml of morpholine are mixed together in a microwave tube. After microwave irradiation for 1 h at 90° C., the reaction mixture is concentrated under reduced pressure and then diluted with 300 ml of ethyl acetate and 300 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. 1.9 g of (4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid ethyl ester are thus obtained in the form of a viscous oil which crystallizes and which is used as it is in the next step.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.[H-].[Na+:13].[CH2:14]1[S:19](=[O:21])(=[O:20])[O:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Na+:13].[O:1]1[CH:6]([CH2:7][O:8][CH2:17][CH2:16][CH2:15][CH2:14][S:19]([O-:21])(=[O:20])=[O:18])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: OCC1COc2cscc2O1
Reactant: O=S1(=O)CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOCC1COc2cscc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL) and blanketed by nitrogen. Sodium hydride (1.76 g) was added and stirring was continued for 30 min. Then butanesultone (6.0 g) was added dropwise after which the reaction mixture was brought to reflux for 3 h. Then it was cooled to 25° C. again, the solvent was removed, methanol was added, the mixture was stirred, filtered and the filtrate was concentrated. The remaining oil was solidified by addition of hexanes and ethanol, followed by stirring. Final filtration and drying resulted in pure 4-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-butane-1-sulfonic acid sodium salt as was demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:6]=[CH:7][CH:8]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH:11]=[CH:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: COC(OC)N(C)C
Reactant: C=CC(=O)c1cccc(OC)c1
Product: COc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A mixture of 25 g. of m-methoxyacrylophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 12 hours. Removal of any volatile material in vacuo gives a thick oil. Bulb to bulb distillation gives the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36]C(OC(C)(C)C)=O)[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(OCC)(=O)C.C(OCC)C>[ClH:44].[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH2:36])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)pentanoyl]oxyhexadecanamide (4.90 g) in 4N hydrogen chloride in ethyl acetate (10 ml) was stirred at room temperature for an hour, and then at 0° C. for an additional one hour. This solution was diluted with diethyl ether (25 ml). The resulting precipitate was collected by filtration, and washed with diethyl ether (30 ml). This crystalline solid was dried over potassium hydroxide under vacuum to yield (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl)oxyhexadecanamide hydrochloride (4.35 g).